Materiały źródłowe

• #1 Celiac disease: From pathophysiology to treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/

  Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. […] The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. […] Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.

• #2 Celiac Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441900/

  Celiac disease, also known as gluten-sensitive enteropathy, is an autoimmune inflammatory condition triggered by an immune-mediated response to dietary gluten, which is a protein found in wheat, barley, and rye. This response causes damage to the small intestinal mucosa, leading to villous atrophy, gastrointestinal symptoms, malabsorption, and systemic extraintestinal manifestations. […] Celiac disease is an autoimmune disorder triggered by an immune-mediated response of the small intestine to dietary gluten, which is a protein found in wheat, barley, and rye. Although traditionally viewed as a gastrointestinal condition primarily associated with malabsorption, it is now more accurately classified as an autoimmune disorder with systemic manifestations. Celiac disease occurs in genetically predisposed individuals and results in a lifelong condition characterized by immune-mediated damage to the lining of the small intestine due to the immune response to gluten. This damage is evidenced by villous atrophy, crypt hyperplasia, and infiltration of the lamina propria by immune cells, which in turn leads to malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate.

• #3 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  Celiac disease (CD) is an autoimmune condition characterized by a specific serological and histological profile triggered by gluten ingestion in genetically predisposed individuals. Gluten is the general term for alcohol-soluble proteins present in various cereals, including wheat, rye, barley, spelt, and kamut. In recent years, there have been significant changes in the diagnosis, pathogenesis, and natural history of this condition, with CD undergoing a true metamorphosis due to the steady increase in the number of diagnoses identified, even in geriatric patients. This has been mainly attributed to the greater availability of sensitive and specific screening tests, which allow identification of the risk groups for CD and led to a significant raise in diagnoses worldwide. Several theories have suggested that the globalization and ubiquitous spread of false or extreme versions of the Mediterranean diet including the consumption of very high quantities of gluten (up to 20g/day), has led to an increased prevalence and incidence of CD. In addition, the quality of gluten itself might also play a contributory role. Indeed, the production of new grain variants due to technological rather than nutritional reasons may have influenced the observed increase in the number of CD diagnoses in recent years. However, these hypotheses have not been confirmed and the real cause of the risk in CD diagnoses remains unknown. Furthermore, the epidemiological observation that similar epidemics are reported for other autoimmune diseases in the Western hemisphere suggests that environmental factors other than gluten can be at play.

• #4

  https://www.jci.org/articles/view/30253

  Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] Acquired T cell-mediated immune mechanisms and innate immune mechanisms have an important role in the pathogenesis of CD. […] The pathogenesis of CD is firmly rooted in host genetic factors. […] The role of dietary proteins in disease pathogenesis. CD is activated by proteins in the dietary cereal grains wheat, rye, and barley. […] Gliadins, glutenins, hordeins, and secalins have a high proline and glutamine content. […] The production of IFN- is a signature of gluten peptide-specific HLA-DQ2 and HLA-DQ8-restricted T cells that are isolated from the mucosa of the small intestine of CD patients, and it is considered to have a key role in the downstream initiation of mucosal damage.

• #5 Celiac Disease (Sprue): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/171805-overview

  Celiac disease has a strong hereditary component. The prevalence of the condition in first-degree relatives is approximately 10%. […] A strong association exists between celiac disease and two human leukocyte antigen (HLA) haplotypes (DQ2 and DQ8). Damage to the small intestinal mucosa occurs with the presentation of gluten-derived peptide gliadin, consisting of 33 amino acids, by the HLA molecules to helper T cells. Helper T cells mediate the inflammatory response. Endogenous tissue transglutaminase deamidates gliadin into a negatively charged protein, increasing its immunogenicity. Autoantibodies to type 2 transglutaminase (TG2) is a hallmark of celiac disease. […] Celiac disease results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors.

• #6 Pathogenesis of celiac disease – Dr. Schär Institute

  https://www.drschaer.com/us/institute/a/pathogenesis-celiac-disease

  Celiac disease has a complex pathology resulting from interaction between a number of genetic and exogenous factors. […] A high incidence of celiac disease within affected families (approximately 10% among first-degree relatives and 80% among twins) suggests a genetic involvement in the pathogenesis of celiac disease. […] An important genetic factor is the human leukocyte antigen (HLA) system, a gene complex whose task is to recognize foreign molecules. […] 90% of celiac patients carry genes encoding HLA DQ2, while most of the remainder carry the HLA DQ8 haplotype. […] Although these are necessary for the disease to develop, they are not solely responsible for it. […] It is known that these genes are also present in up to 40% of individuals in Western populations, however, the frequency is population dependent. […] The presence of gluten in the diet is clearly a pre-requisite for the development of celiac disease.

• #7 Coeliac disease – Wikipedia

  https://en.wikipedia.org/wiki/Coeliac_disease

  Coeliac disease is caused by a reaction to gluten, a group of various proteins found in wheat and in other grains such as barley and rye. […] Upon exposure to gluten, an abnormal immune response may lead to the production of several different autoantibodies that can affect a number of different organs. […] In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy). […] Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person. […] Almost all people (95%) with coeliac disease have either the variant HLA-DQ2 allele or (less commonly) the HLA-DQ8 allele. […] The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of chromosome 6.

• #8 Celiac Disease (Sprue): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/171805-overview

  The interaction of alcohol-soluble gliadin in wheat, barley, and rye with the mucosa of the small intestine is crucial to the pathogenesis of celiac disease. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in the enteric epithelial cells, stimulating the proliferation of the natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes. […] Cell-mediated immune responses are also important for the pathogenesis of celiac disease, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium. […] Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to the expression of the proinflammatory cytokine interferon gamma and the activation of CD4+ T lymphocytes.

• #9 Development of Celiac Disease; Pathogenesis and Strategies to Con

  https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html

  Celiac disease (CD) is an intestinal chronic disorder with multifactorial etiology resulting in small intestinal mucosal injuries and malabsorption. Trigger from gluten and related cereal proteins, HLA-DQ2/DQ8 molecules and autoantibodies to tissue transglutaminase, are essential to precipitate the disease. […] Specific anchoring sites in DQ2/DQ8 peptide binding motifs show affinity to tTG deamidated peptides of gluten and present to gluten restricted T cells to form celiac lesions. […] Presence of Human Leukocytic Antigens mainly HLA-DQ2 or HLA DQ-8 molecules, trigger from gluten protein of wheat and related cereal, and the generation of circulating autoantibodies to tissue transglutaminase (tTG) are essential to precipitate the disease. […] CD is one of the HLA-linked disorders. Two gluten/gliadin peptide presenting HLA-DQ molecules namely DQ (1*0501, 1*02)/ DQ2 or to a lesser extent DQ (1*03, 1*0302)/DQ8 which are present on antigen presenting cells are considered as principal genetic factors responsible for CD. HLA DQ2 heterodimer is prevalent and present in 90% of patients with CD.

• #10 Coeliac disease – Wikipedia

  https://en.wikipedia.org/wiki/Coeliac_disease

  Coeliac disease is caused by a reaction to gluten, a group of various proteins found in wheat and in other grains such as barley and rye. […] Upon exposure to gluten, an abnormal immune response may lead to the production of several different autoantibodies that can affect a number of different organs. […] In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy). […] Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person. […] Almost all people (95%) with coeliac disease have either the variant HLA-DQ2 allele or (less commonly) the HLA-DQ8 allele. […] The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of chromosome 6.

• #11 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults – UpToDate

  https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-adults

  Celiac disease, also known as gluten-sensitive enteropathy, is a common immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals. […] Celiac disease is an immune disorder triggered by an environmental agent (the gluten component of wheat and related cereals) in genetically predisposed individuals. The genetic basis of celiac disease is supported by the frequent intrafamilial occurrence and the remarkably close association with the human leukocyte antigen (HLA) DR3-DQ2 and/or DR4-DQ8 gene locus. More than 99 percent of individuals with celiac disease have HLA DR3-DQ2 and/or DR4-DQ8, compared with 30 to 40 percent of the general population of most countries. […] In patients with celiac disease, immune responses to gliadin fractions promote an inflammatory reaction, characterized by infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy. This response is mediated by both the innate and adaptive immune systems.

• #12

  https://haematologica.org/article/view/5094

  The role of the human leukocyte antigen region (HLA) in celiac disease has been suggested by the observation that nearly all patients with celiac disease possess either the HLA-DQ2 (90%) or HLA-DQ8 heterodimer. However, HLA-DQ2 is also found in 30% of the healthy Caucasian population indicating that it is a necessary but not sufficient component for the development of celiac disease. […] The participation of HLA-DQ2 in the pathogenesis of celiac disease is described schematically. In addition to the role of A-gliadin p3143 described above, a second gluten peptide p5773 is presented to mesenteric lymph node T cells by HLA-DQ2 on antigen presenting dendritic cells (DC). HLA-DQ2 preferentially binds peptides with negatively charged amino acids. Tissue transglutaminase (TTG), the target of antiendomysial antibodies in celiac disease, has an important role in converting glutamine to glutamate residues generating negatively charged amino acids that are better bound by HLA-DQ2. Although anti-TTG antibodies are highly specific and sensitive indicators of celiac disease, the primary role of such antibodies in the pathogenesis of this disease is unclear. Antigen specific mesenteric T cells subsequently migrate to the peripheral blood and home back to the intestine employing specific cell adhesion molecules, inducing cell death by cytokine release, mainly interferon-.

• #13 IJMS | Special Issue : Celiac Disease: Genetics, Pathogenesis and Therapy: 2nd Edition

  https://www.mdpi.com/journal/ijms/special_issues/48HZPGQ595

  Celiac disease is regarded as an autoimmune disorder triggered, in genetically predisposed individuals, by exposure to gluten. […] Throughout the years, our understanding of celiac disease has changed quite dramatically, and data obtained by several research groups have allowed us to better define the pathogenesis of this multifactorial disorder. […] Although it is known that a specific HLA is necessary for the development of the disease, the presence of the DQ2.5 or DQ8 heterodimer is not sufficient; several loci, harboring genes involved in the immune response, have been identified using GWAS, but still about 50% of genetic predisposition is unknown. […] Thus, further clarification of the genetic as well as pathogenetic mechanisms is still needed. This could include the evaluation of epigenetic mechanisms, such as DNA methylation, but also of the role of miRNAs and other non-coding RNAs. Further, the interactions between the various gliadin peptides and specific cellular pathways can still provide additional data that could help to further elucidate the mechanisms involved in the generation of intestinal damage.

• #14 RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215132

  Our findings that patients with active CD had an upregulation in cytokine-cytokine receptor interaction and the chemokine signaling pathway is expected given our understanding of CD pathogenesis and the inflammation associated with active CD. […] Our analysis identified the upregulation of cell adhesion molecules such as IGSF4 and others involved in leukocyte transendothelial migration such as ITAGAM in active CD. […] Our analysis shows upregulation of CDX genes related to the MAPK signaling pathway in active CD compared to CD in remission. […] Our findings support a possible link between the microbiome, innate immune response, and the development of CD and highlight possible associations that with future validation may lead to crucial knowledge of the steps leading to loss of tolerance to gluten. […] Our data serve to act as a launching point to suggest areas of further investigation and validation for CD pathogenesis, treatment, and associations with other autoimmune disease.

• #15

  https://www.jci.org/articles/view/30253

  Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] Acquired T cell-mediated immune mechanisms and innate immune mechanisms have an important role in the pathogenesis of CD. […] The pathogenesis of CD is firmly rooted in host genetic factors. […] The role of dietary proteins in disease pathogenesis. CD is activated by proteins in the dietary cereal grains wheat, rye, and barley. […] Gliadins, glutenins, hordeins, and secalins have a high proline and glutamine content. […] The production of IFN- is a signature of gluten peptide-specific HLA-DQ2 and HLA-DQ8-restricted T cells that are isolated from the mucosa of the small intestine of CD patients, and it is considered to have a key role in the downstream initiation of mucosal damage.

• #16 Coeliac disease – Wikipedia

  https://en.wikipedia.org/wiki/Coeliac_disease

  The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. […] The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. […] One protease-resistant peptide from -gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. […] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. […] The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel’s mucosal lining and causes malabsorption as it impairs the body’s ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food.

• #17 Celiac Disease

  http://courses.washington.edu/pbio376/celiac/celiacdisease-376.html

  Celiac disease is a type of autoimmune disease. The immune response is a delayed response (on the course of hours to days) and involves helper T cells, which coordinate an immune response leading to tissue damage in the small intestine. […] The figure shows a simplified illustration of our understanding of the pathogenesis of celiac disease. Peptides derived from gluten contain many proline and glutamine residues, making them resistant to digestion by pancreatic and small intestine enzymes. […] Once in the lamina propria, an enzyme modifies these peptides, making them even more antigenic. They are engulfed by antigen presenting cells (APC’s) which display them on their surface bound to MHC II molecules. They stimulate helper T cells, which secrete cytokines that orchestrate the inflammatory response that leads to tissue damage.

• #18 Development of Celiac Disease; Pathogenesis and Strategies to Con

  https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html

  High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity. […] tTG deamidated gluten residues presented by HLA-DQ2 and DQ8 molecules turn on the gliadin reactive CD4 TH cells which is crucial for CD pathogenesis. […] Understanding pathogenesis at molecular level allows various strategies to treat CD at different levels more effectively.

• #19 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism

  https://journals.eco-vector.com/2658-4433/article/view/90770

  Furthermore, the consumption of gluten and gluten-like proteins is the main environmental factor influencing the development of celiac disease. Gluten is partially hydrolyzed in the digestive system after consumption, forming native peptides, which do not undergo further proteolysis, consequently penetrating the small intestine submucosa. These peptides include α-, ω-, γ-gliadins, gluten derivatives from various wheat cultivars, and gluteins from other cereals, such as hordein found in barley and secaline from rye that both undergo deamination by transglutaminase 2 (also called tissue transglutaminase, TG2). Notably, deaminated peptides have a high affinity for the DQ2 and DQ8 molecules of the antigen-presenting cells. According to research results, the severity of this process is higher for modern wheat varieties than for those previously used.

• #20 Celiac disease: From pathophysiology to treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/

  Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. […] The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. […] Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.

• #21 Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review

  https://www.mdpi.com/1422-0067/24/20/15482

  Despite considerable advances in understanding celiac disease, numerous questions regarding its exact mechanisms and immune-pathophysiology remain unanswered. […] The activation of GALT by these gluten-derived peptides precipitates an inflammatory response, which is the crux of the pathogenesis in celiac disease. […] Following the ingestion of gluten, gliadin binds to the chemokine receptor CXCR3 on the luminal aspect of the intestinal epithelium. This binding prompts enterocytes to release the protein Zonulin. […] Type I IFN potentially provokes the release of IFN-γ and interleukin-15 (IL-15) by dendritic cells (DCs). The role of IL-15 within this pathogenic framework is multifaceted and instrumental. […] IL-15 production is notably upregulated in untreated celiac disease and plays a crucial role in the activation and expansion of CD8+ T intraepithelial lymphocytes (IELs), the key players in epithelial damage.

• #22 Diagnosis and treatment of celiac disease | Mucosal Immunology

  https://www.nature.com/articles/mi200874

  The understanding of the pathogenesis of celiac disease has made huge advances in recent years. The disease is caused by an inappropriate immune response to dietary gluten proteins. This immune response is controlled by CD4+ T cells in the lamina propria that recognize gluten peptides in the context of disease predisposing HLA-DQ2 and HLA-DQ8 molecules. These T cells are specific for proline- and glutamine-rich gluten peptides that are resistant to proteolysis and that have been become deamidated by the enzyme transglutaminase 2 (TG2). […] TG2 is an enzyme with many functions, and it is directly involved in celiac disease pathogenesis by modifying gluten peptides in a process where glutamine residues are deamidated to glutamic acid. The deamidated peptides bind better to the HLA-DQ2 and HLA-DQ8 molecules, and the intestinal T cells of celiac disease patients preferentially recognize such deamidated gluten peptides. […] One can also envision treating celiac disease by hindering the activation of gluten reactive CD4+ T cells. This can be achieved by preventing the formation of deamidated peptides, or by blocking the peptide-binding site of the gluten presenting HLA molecules DQ2 and DQ8.

• #23 Celiac Disease – Intestinal Diseases – Gastrointestinal Diseases – Gastroenterology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.4.10.

  Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by gluten in genetically predisposed individuals who carry the HLA-DQ2 or HLA-DQ8 haplotype. […] Gluten proteins have a high concentration of the amino acids proline and glutamine, rendering them resistant to enzymatic degradation by digestive enzymes. As a result, large and potentially immunogenic peptides may reach the mucosa of the small intestine and initiate an immune response. The high proline and glutamine content in gluten peptides also renders them excellent substrates for tissue transglutaminase type 2 (tTG2). tTG2 is a ubiquitous intracellular enzyme that is released extracellularly and activated during inflammation. tTG2 deamidates gluten peptides, which converts glutamine to negatively charged glutamic acid residues, increasing their binding affinity to HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells. Gluten-specific T cells from patients with CD preferentially recognize deamidated gluten peptides and produce the type 1 helper T cell (Th1) cytokines interferon gamma and interleukin 21 (IL-21). Gluten-specific Th1 cells also provide help for the activation of B cells to form antigluten and anti-tTG2 producing plasma cells. […] This together with the rising prevalence of CD in the past 40 years suggests that unknown environmental factors may also play a role in disease pathogenesis.

• #24 Celiac Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441900/

  Celiac disease results from a combination of genetic, environmental, and immune factors that trigger an inappropriate immune response to dietary gluten found in wheat, barley, and rye. A key trigger is gliadin, a protein component of gluten, which has a central role in initiating the pathological process. During digestion, gluten is broken down into smaller peptides, including gliadin. In individuals with celiac disease, these peptides resist complete digestion and exhibit strong immunogenicity. They cross the intestinal epithelial barrier and enter the lamina propria, where tTG modifies them through deamidation. This modification enhances their ability to bind to HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells (APCs). […] The peptide-HLA complexes formed on APCs are then presented to circulating CD4+ T cells, which recognize them as harmful. This recognition triggers 3 key immune responses: CD4+ T cells release pro-inflammatory cytokines, driving inflammation, crypt hyperplasia, and the destruction of intestinal villi, collectively resulting in enteropathy.

• #25 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism

  https://journals.eco-vector.com/2658-4433/article/view/90770

  Furthermore, the consumption of gluten and gluten-like proteins is the main environmental factor influencing the development of celiac disease. Gluten is partially hydrolyzed in the digestive system after consumption, forming native peptides, which do not undergo further proteolysis, consequently penetrating the small intestine submucosa. These peptides include α-, ω-, γ-gliadins, gluten derivatives from various wheat cultivars, and gluteins from other cereals, such as hordein found in barley and secaline from rye that both undergo deamination by transglutaminase 2 (also called tissue transglutaminase, TG2). Notably, deaminated peptides have a high affinity for the DQ2 and DQ8 molecules of the antigen-presenting cells. According to research results, the severity of this process is higher for modern wheat varieties than for those previously used.

• #26 Development of Celiac Disease; Pathogenesis and Strategies to Con

  https://www.longdom.org/open-access/development-of-celiac-disease-pathogenesis-and-strategies-to-control-amolecular-approach-34058.html

  High proline content enables gluten peptides resistant to gastric, pancreatic and intestinal protease activity and enhances their survivability in the small intestine. Either by epithelial transcytosis or by increasing the epithelial tight junction permeability, gluten peptides reach lamina propia and undergo tissue transglutaminase (tTG) mediated deamidation. […] The conversion of glutamine to glutamic acid residues by deamidation would result in relatively large numbers of negatively charged residues in gliadin peptides that bind to HLA-DQ2 or HLA-DQ8 molecules with great affinity. […] tTG deamidated gluten residues presented by HLA-DQ2 and DQ8 molecules turn on the gliadin reactive CD4 TH cells which is crucial for CD pathogenesis. […] Understanding pathogenesis at molecular level allows various strategies to treat CD at different levels more effectively.

• #27

  https://haematologica.org/article/view/5094

  The role of the human leukocyte antigen region (HLA) in celiac disease has been suggested by the observation that nearly all patients with celiac disease possess either the HLA-DQ2 (90%) or HLA-DQ8 heterodimer. However, HLA-DQ2 is also found in 30% of the healthy Caucasian population indicating that it is a necessary but not sufficient component for the development of celiac disease. […] The participation of HLA-DQ2 in the pathogenesis of celiac disease is described schematically. In addition to the role of A-gliadin p3143 described above, a second gluten peptide p5773 is presented to mesenteric lymph node T cells by HLA-DQ2 on antigen presenting dendritic cells (DC). HLA-DQ2 preferentially binds peptides with negatively charged amino acids. Tissue transglutaminase (TTG), the target of antiendomysial antibodies in celiac disease, has an important role in converting glutamine to glutamate residues generating negatively charged amino acids that are better bound by HLA-DQ2. Although anti-TTG antibodies are highly specific and sensitive indicators of celiac disease, the primary role of such antibodies in the pathogenesis of this disease is unclear. Antigen specific mesenteric T cells subsequently migrate to the peripheral blood and home back to the intestine employing specific cell adhesion molecules, inducing cell death by cytokine release, mainly interferon-.

• #28 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism

  https://journals.eco-vector.com/2658-4433/article/view/90770

  The contribution of TG2 (transglutaminase-2) in celiac disease development is not limited to the deamination of gluten-like peptides but to the role of the enzyme as a target for antibody production. Typically, antibodies against TG2 are not produced; however, there are specific B-lymphocytes against TG2. The production of antibodies is encouraged by the gliadin-specific CD4+ T-lymphocytes, especially when the gliadin and TG2 are bound to the small intestinal mucosa. IgA and, to a lesser extent, IgM and IgG mainly represent antibodies against TG2. The level of antibodies does not reduce the enzyme activity despite their high affinity to TG2. Additionally, there is evidence that antibodies encourage the mobilization of Ca2+, which induces intracellular activation of TG2. Although the final role of antibodies to TG2 in celiac disease development is unclear, a direct relationship has been established between the level of autoantibodies and the severity of the inflammatory process in the intestine. Moreover, anti-TG2 IgA represents a specific and sensitive marker of celiac disease usually detected in almost all patients.

• #29 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  CD is a unique autoimmune disease in that its key genetic elements (human leukocyte antigen (HLA)-DQ2 and HLA-DQ8), the auto-antigen involved (tissue transglutaminase (tTG)), and the environmental trigger (gluten) are all well defined. A major drawback in CD research has been the lack of a reliable and reproducible animal model, with the possible exception of the Irish setter dog, which may develop a gluten-related disease. Nevertheless, new technologies pertinent to human gut biology and immunology are opening unprecedented opportunities for major research breakthroughs. […] As with many other autoimmune diseases, we have witnessed an epidemic of CD, questioning the previous paradigm that gluten is the only key element dictating the onset of the disease in genetically at-risk subjects. Improved hygiene and lack of exposure to various microorganisms also have been linked with a steep increase in autoimmune disorders in industrialized countries during the past 40 years. The hygiene hypothesis argues that the rising incidence of many autoimmune diseases may partially be the result of lifestyle and environmental changes that have reduced our exposure to pathogens. With breakthroughs in the role of the gut microbiological ecosystem in dictating the balance between tolerance and immune response leading to autoimmunity, this hypothesis is under scrutiny. Regardless of whether autoimmune diseases are due to too much or too little exposure to microorganisms, it is generally accepted that adaptive immunity and imbalance between T helper 1 and 2 cell responses are key elements of the pathogenesis of the autoimmune process. Besides genetic predisposition and exposure to gluten, loss of intestinal barrier function, a pro-inflammatory innate immune response triggered by gluten, inappropriate adaptive immune response, and an imbalanced gut microbiome all seem to be key ingredients of the CD autoimmunity recipe.

• #30 Immunopathogenesis of Celiac Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-030-82401-3_4

  Celiac disease (CD) is a systemic disorder with an immunological basis caused by an abnormal immune response to cereal gluten proteins, affecting to genetically susceptible individuals. The interaction of genetic and environmental factors leads to the loss of tolerance to these proteins and the development of an intestinal lesion characterized by lymphocyte infiltration, mucosal remodelling and epithelial destruction. […] Gluten proteins are partially hydrolysed in the intestine forming large peptides which cross the epithelium and are translocated to the lamina propria, where an adaptive immune response is activated following the recognition by gluten-reactive CD4 + T cells of deamidated gluten T-cell epitopes bound to HLA-DQ molecules in the membrane of antigen presenting cells. […] Upon activation, these cells release a cytokine profile characterized by interferon (IFN)- and interleukin- (IL)-21 and provide help to B cells to produce antibodies to gluten and tissue transglutaminase (TG2). […] Moreover, they also control another hallmark of the disease, the infiltration of cytotoxic intraepithelial T CD8 + lymphocytes with activating NK receptors, which recognize stress-induced ligands expressed on epithelial cells and are involved in HLA-DQ2 independent tissue destruction.

• #31 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  The erroneous adaptive immune response consequence of a highly specific interplay between selected gluten peptides and major histocompatibility complex class II HLA-DQ2/8-antigen restricted T cells plays a paramount role in CD pathogenesis. Dependent on the post-translational deamidation of gluten peptides by transglutaminase 2 (TG2), this interplay is influenced by the initial imprinting of the innate immune system through IL-15 upregulation that promotes the CD4+ T cell adaptive immune response. Presentation of gluten to CD4+ T cells carried out by dendritic cells as well as macrophages, B cells, and even enterocytes expressing HLA class II, can cause their recirculation in the lamina propria. The contact of CD4+ T cells in the lamina propria with gluten induces their activation and proliferation, with production of proinflammatory cytokines, metalloproteases, and keratinocyte growth factor by stromal cells, which induces cryptal hyperplasia and villous blunting secondary to intestinal epithelial cell death induced by intraepithelial lymphocytes (IELs).

• #32 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. […] The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL.

• #33 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism

  https://journals.eco-vector.com/2658-4433/article/view/90770

  The interaction of deaminated peptides with HLA DQ2 and DQ8 receptors of antigen-presenting cells activates the T-lymphocytes. The process releases pro-inflammatory factors such as interferon-gamma, tumor necrosis factor (TNF-α), and interleukin-2 (IL-2). Also, this inflammatory process occurs in the intestine, causing atrophy of the small intestine villi and deep tissue damage. The intestinal intraepithelial lymphocytes also contribute to the development of this condition. The emergence of the gluten-specific generation of CD4+ T-lymphocytes forms a stable local immune response. The CD4+ T-lymphocytes produce a large amount of TNF-γ, IL-2, and IL-21 upon contact with gluten, contributing to the inflammatory process. Furthermore, a critical link in the celiac disease pathogenesis is also an impairment of the limitation of inflammation. Although the count of regulatory T cells does not change in celiac disease, in vitro studies showed reduced functional activity.

• #34 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  A strict GFD remains the only treatment in uncomplicated CD but is difficult to maintain. […] Several novel therapeutic approaches are under development to replace or, at least, alleviate diet. […] Overall, these data explain why anti-TG2 antibodies are exclusively present in patients exposed to gluten and why these antibodies represent a highly reliable biomarker to monitor the antigluten response. […] In conclusion, the adaptive immune response against gluten is now well characterised and drives disease pathogenesis. Yet, gluten-specific CD4+ T cells do not mediate directly tissue damage. Rather, they act by promoting expansion and activation of cytotoxic CD8+ T IEL that execute the autoimmune-like destruction of epithelial cells. […] Current data converge to indicate that, in untreated CD, the autoimmune-like attack of the gut epithelium by CD8+ T IEL is orchestrated by the three cytokines (IFN, IL-21 and IL-2) produced by gluten-specific CD4+ T cells and by IL-15. […] In keeping with a key role of this pathway, CD8+ T IEL activated in CD share many overlapping features with the CD8+ T cells driving autoimmunity in patients and mice carrying constitutive STAT3 gain-of-function (GOF) mutations.

• #35 Celiac disease: From pathophysiology to treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/

  Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. […] The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. […] Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.

• #36 Immunopathogenesis of Celiac Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-030-82401-3_4

  Celiac disease (CD) is a systemic disorder with an immunological basis caused by an abnormal immune response to cereal gluten proteins, affecting to genetically susceptible individuals. The interaction of genetic and environmental factors leads to the loss of tolerance to these proteins and the development of an intestinal lesion characterized by lymphocyte infiltration, mucosal remodelling and epithelial destruction. […] Gluten proteins are partially hydrolysed in the intestine forming large peptides which cross the epithelium and are translocated to the lamina propria, where an adaptive immune response is activated following the recognition by gluten-reactive CD4 + T cells of deamidated gluten T-cell epitopes bound to HLA-DQ molecules in the membrane of antigen presenting cells. […] Upon activation, these cells release a cytokine profile characterized by interferon (IFN)- and interleukin- (IL)-21 and provide help to B cells to produce antibodies to gluten and tissue transglutaminase (TG2). […] Moreover, they also control another hallmark of the disease, the infiltration of cytotoxic intraepithelial T CD8 + lymphocytes with activating NK receptors, which recognize stress-induced ligands expressed on epithelial cells and are involved in HLA-DQ2 independent tissue destruction.

• #37 Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review

  https://www.mdpi.com/1422-0067/24/20/15482

  Despite considerable advances in understanding celiac disease, numerous questions regarding its exact mechanisms and immune-pathophysiology remain unanswered. […] The activation of GALT by these gluten-derived peptides precipitates an inflammatory response, which is the crux of the pathogenesis in celiac disease. […] Following the ingestion of gluten, gliadin binds to the chemokine receptor CXCR3 on the luminal aspect of the intestinal epithelium. This binding prompts enterocytes to release the protein Zonulin. […] Type I IFN potentially provokes the release of IFN-γ and interleukin-15 (IL-15) by dendritic cells (DCs). The role of IL-15 within this pathogenic framework is multifaceted and instrumental. […] IL-15 production is notably upregulated in untreated celiac disease and plays a crucial role in the activation and expansion of CD8+ T intraepithelial lymphocytes (IELs), the key players in epithelial damage.

• #38

  https://haematologica.org/article/view/5094

  The key steps underlying the intestinal inflammatory response in celiac disease have been reviewed recently by van Heel and West. The toxic fractions of wheat proteins relevant to celiac disease have now been well characterized. Because of their high proline and glutamine content, gluten peptides are hydrophobic and resistant to degradation by gastric, pancreatic and intestinal brush border membrane proteases. Several peptides of key importance have been identified. A-gliadin p3143 induces interleukin 15, a key cytokine involved in T-cell activation. Interleukin 15 induces the expression of a stress molecule, MICA (major histocompatibility complex class I-related chain A) on enterocytes and upregulates NKG2D (activating natural killer cell receptors) on intraepithelial lymphocytes (IEL). This interaction results in direct enterocyte killing and is a likely cause of villous atrophy.

• #39

  https://www.jci.org/articles/view/30253

  HLA-DQ2 and HLA-DQ8 heterodimers on APCs can bind and subsequently present gluten peptides to populations of CD4+ T cells in the lamina propria of the small intestine. […] Activation of CD4+ T cells specific for gluten peptides in the lamina propria clearly requires that those peptides be presented by APCs (probably DCs) that express HLA-DQ2 or HLA-DQ8. […] Recent studies suggest that activation of the innate immune system is important in the pathogenesis of CD and in some of the complications of this disease, namely in refractory CD and in the development of EATLs. […] A model that I have proposed to conceptualize the role of the adaptive T cell response in CD pathogenesis divides pathogenesis into 3 phases: luminal and early mucosal events; activation of pathogenic CD4+ T cells; and events leading to tissue damage. […] The cytokine IL-15 takes center stage in this process. […] Does knowledge of the immunopathogenesis of CD suggest alternative or adjunctive therapeutic approaches? A GFD currently is the only accepted therapy for CD.

• #40 Pediatric Celiac Disease (Sprue): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/932104-overview

  Celiac disease is an autoimmune disease, and the enzyme tissue transglutaminase (tTG) has been identified as the autoantigen against which the abnormal immune response is directed. Gluten is the single major environmental factor that triggers celiac disease, which has a narrow and highly specific association with class II haplotypes of HLA DQ2 (haplotypes DR-17 or DR5/7) and, to a lesser extent, DQ8 (haplotype DR-4). […] Scientific knowledge on the pathogenesis of celiac disease has markedly increased in the past few years; the combined roles of innate and adaptive immunity are now better understood. […] Intraepithelial lymphocytes (IELs) play an important role in the destruction of epithelial cells. Through specific natural killer receptors (NKR) expressed on their surface, IELs recognize nonclassical major histocompatibility complex (MHC)-I molecules induced on the surface of enterocytes by stress and inflammation. This interaction leads to activation of these armed effector IELs to become lymphokine-activated killing cells; they cause epithelial cell death in a T-cell receptor (TCR)independent manner. This killing is particularly enhanced through the cytokine interleukin (IL)-15, which is highly expressed in celiac mucosa. NKG2D has been found to play a crucial role in intestinal inflammation in celiac disease.

• #41 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. […] If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. […] Gluten-specific CD4+ T cells play a driver role in coeliac disease (CD) pathogenesis and can persist for decades under gluten-free diet (GFD). […] Gluten-specific CD4+ T cells cooperate with IL-15 produced by intestinal epithelial and myeloid cells to promote the activation of cytotoxic CD8+ T intraepithelial lymphocytes and license the autoimmune-like destruction of epithelial cells.

• #42 Celiac disease: From pathophysiology to treatment

  https://www.wjgnet.com/2150-5330/full/v8/i2/27.htm

  Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. Celiac disease was first described in 1888 by Samuel Gee, but only in 1953 it became clear the importance of the gluten in the origin of this pathology. In celiac subjects the ingestion of gluten leads to an enteropathy with an impairment of the mucosal surface and, consequently, abnormal absorption of nutrients. Celiac disease might be considered a syndrome, because of the wide spectrum of clinical manifestations and the involvement of various human systems. Celiac disease shows peculiar features in comparison to others autoimmune disorders, including the complete recovery of the mucosal damage as well as the reversibility of its progression and chronic dynamics, with a total avoidance of gluten. Conversely, it is now ascertained that undiagnosed celiac disease, might have severe consequences in children as well as in adult subjects. The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. Some gliadin peptides that are not recognized by T-lymphocytes activate both APCs and intestinal epithelial cells; in particular, CD8+ T-lymphocytes may be stimulated by interleukin (IL)-15. An increased density of CD8+ intraepithelial cells is considered as a hallmark of celiac disease.

• #43 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. […] The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL.

• #44 Immunopathogenesis of Celiac Disease | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-030-82401-3_4

  Celiac disease (CD) is a systemic disorder with an immunological basis caused by an abnormal immune response to cereal gluten proteins, affecting to genetically susceptible individuals. The interaction of genetic and environmental factors leads to the loss of tolerance to these proteins and the development of an intestinal lesion characterized by lymphocyte infiltration, mucosal remodelling and epithelial destruction. […] Gluten proteins are partially hydrolysed in the intestine forming large peptides which cross the epithelium and are translocated to the lamina propria, where an adaptive immune response is activated following the recognition by gluten-reactive CD4 + T cells of deamidated gluten T-cell epitopes bound to HLA-DQ molecules in the membrane of antigen presenting cells. […] Upon activation, these cells release a cytokine profile characterized by interferon (IFN)- and interleukin- (IL)-21 and provide help to B cells to produce antibodies to gluten and tissue transglutaminase (TG2). […] Moreover, they also control another hallmark of the disease, the infiltration of cytotoxic intraepithelial T CD8 + lymphocytes with activating NK receptors, which recognize stress-induced ligands expressed on epithelial cells and are involved in HLA-DQ2 independent tissue destruction.

• #45 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  A strict GFD remains the only treatment in uncomplicated CD but is difficult to maintain. […] Several novel therapeutic approaches are under development to replace or, at least, alleviate diet. […] Overall, these data explain why anti-TG2 antibodies are exclusively present in patients exposed to gluten and why these antibodies represent a highly reliable biomarker to monitor the antigluten response. […] In conclusion, the adaptive immune response against gluten is now well characterised and drives disease pathogenesis. Yet, gluten-specific CD4+ T cells do not mediate directly tissue damage. Rather, they act by promoting expansion and activation of cytotoxic CD8+ T IEL that execute the autoimmune-like destruction of epithelial cells. […] Current data converge to indicate that, in untreated CD, the autoimmune-like attack of the gut epithelium by CD8+ T IEL is orchestrated by the three cytokines (IFN, IL-21 and IL-2) produced by gluten-specific CD4+ T cells and by IL-15. […] In keeping with a key role of this pathway, CD8+ T IEL activated in CD share many overlapping features with the CD8+ T cells driving autoimmunity in patients and mice carrying constitutive STAT3 gain-of-function (GOF) mutations.

• #46 Mechanisms of Disease: immunopathogenesis of celiac disease | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/ncpgasthep0582

  Celiac disease is a genetic inflammatory disorder with autoimmune components that is induced by the ingestion of dietary gluten. […] Although the importance of the adaptive immune response to gluten has been well established, observations now also point towards a central role for the gluten-induced innate stress response in the pathogenesis of celiac disease and its malignant complications. […] There is emerging evidence that the adaptive and innate immune responses to gluten might exist independently and are both required to induce epithelial cell destruction, which results in villous atrophy and clinical symptoms related to malabsorption.

• #47 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  A strict GFD remains the only treatment in uncomplicated CD but is difficult to maintain. […] Several novel therapeutic approaches are under development to replace or, at least, alleviate diet. […] Overall, these data explain why anti-TG2 antibodies are exclusively present in patients exposed to gluten and why these antibodies represent a highly reliable biomarker to monitor the antigluten response. […] In conclusion, the adaptive immune response against gluten is now well characterised and drives disease pathogenesis. Yet, gluten-specific CD4+ T cells do not mediate directly tissue damage. Rather, they act by promoting expansion and activation of cytotoxic CD8+ T IEL that execute the autoimmune-like destruction of epithelial cells. […] Current data converge to indicate that, in untreated CD, the autoimmune-like attack of the gut epithelium by CD8+ T IEL is orchestrated by the three cytokines (IFN, IL-21 and IL-2) produced by gluten-specific CD4+ T cells and by IL-15. […] In keeping with a key role of this pathway, CD8+ T IEL activated in CD share many overlapping features with the CD8+ T cells driving autoimmunity in patients and mice carrying constitutive STAT3 gain-of-function (GOF) mutations.

• #48 MedlinePlus: Gluten and Celiac DiseaseLock

  https://medlineplus.gov/medlineplus-videos/gluten-and-celiac-disease/

  Celiac disease sometimes is hereditary, meaning it runs in families. […] In celiac disease, gluten can trigger the immune system to attack the small intestine. […] Immune cells damage small, fingerlike growths in the small intestine called villi, and the brushy intestinal lining becomes flattened. […] When the villi are damaged, the body cannot get the nutrients it needs. […] The immune system’s reaction can lead to other health problems as well. […] If untreated, celiac disease can lead to serious complications like anemia, infertility, and weak and brittle bones.

• #49 Celiac Disease

  http://courses.washington.edu/pbio376/celiac/celiacdisease-376.html

  The consequence of the tissue damage is a change in the mucosa in the small intestine. This can be observed in a duodenal biopsy, which is a key test in the diagnosis of celiac disease. Instead of the normal architecture of tall villi and deep crypts, what is observed in celiac disease is a flattened mucosa lacking villi. This can greatly decrease the surface area of the small intestine, causing malabsorption of nutrients, which can cause diarrhea and malnutrition. […] Duodenal tissue also shows increased numbers of intraepithelial lymphocytes.

• #50 Celiac Disease – Intestinal Diseases – Gastrointestinal Diseases – Gastroenterology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.4.10.

  Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by gluten in genetically predisposed individuals who carry the HLA-DQ2 or HLA-DQ8 haplotype. […] Gluten proteins have a high concentration of the amino acids proline and glutamine, rendering them resistant to enzymatic degradation by digestive enzymes. As a result, large and potentially immunogenic peptides may reach the mucosa of the small intestine and initiate an immune response. The high proline and glutamine content in gluten peptides also renders them excellent substrates for tissue transglutaminase type 2 (tTG2). tTG2 is a ubiquitous intracellular enzyme that is released extracellularly and activated during inflammation. tTG2 deamidates gluten peptides, which converts glutamine to negatively charged glutamic acid residues, increasing their binding affinity to HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells. Gluten-specific T cells from patients with CD preferentially recognize deamidated gluten peptides and produce the type 1 helper T cell (Th1) cytokines interferon gamma and interleukin 21 (IL-21). Gluten-specific Th1 cells also provide help for the activation of B cells to form antigluten and anti-tTG2 producing plasma cells. […] This together with the rising prevalence of CD in the past 40 years suggests that unknown environmental factors may also play a role in disease pathogenesis.

• #51 The role of epithelial cells differentiation in the pathogenesis of celiac disease – Gastroscience Michael Scharl

  https://www.gastroscience.ch/research/inflammation/the-role-of-epithelial-cells-differentatiation-in-the-pathogenesis-of-celiac-disease/

  Celiac disease (CeD) is an autoimmune disorder that occurs in genetically predisposed individuals. […] Its onset is triggered by the ingestion of gluten or related proteins found in wheat, barley and rye. […] The disease primarily affects the small intestine and is characterized by villous atrophy, destruction of enterocytes, crypts hyperplasia, complex remodeling of tissue, and increased numbers of intraepithelial lymphocytes in lamina propria. […] Typical diagnostic findings during histologic investigation, include small intestine crypt hyperplasia and villi atrophy due to intraepithelial T cells killing enterocytes. […] Taking into account the highly regenerative potential of the small intestine witch enterocytes shed and replaced after 3-5 days and that CeD pathogenesis cannot be fully explained only by genetic background and presence of gluten, we hypothesize, that regulation of crypt stem cells differentiation into villi enterocytes might play a role.

• #52 Celiac Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441900/

  Celiac disease, also known as gluten-sensitive enteropathy, is an autoimmune inflammatory condition triggered by an immune-mediated response to dietary gluten, which is a protein found in wheat, barley, and rye. This response causes damage to the small intestinal mucosa, leading to villous atrophy, gastrointestinal symptoms, malabsorption, and systemic extraintestinal manifestations. […] Celiac disease is an autoimmune disorder triggered by an immune-mediated response of the small intestine to dietary gluten, which is a protein found in wheat, barley, and rye. Although traditionally viewed as a gastrointestinal condition primarily associated with malabsorption, it is now more accurately classified as an autoimmune disorder with systemic manifestations. Celiac disease occurs in genetically predisposed individuals and results in a lifelong condition characterized by immune-mediated damage to the lining of the small intestine due to the immune response to gluten. This damage is evidenced by villous atrophy, crypt hyperplasia, and infiltration of the lamina propria by immune cells, which in turn leads to malabsorption of essential nutrients, including micronutrients, fat-soluble vitamins, iron, vitamin B12, and folate.

• #53

  https://haematologica.org/article/view/5094

  A number of causative factors deserve consideration for explaining the mechanism of anemia in celiac disease. The most obvious cause of anemia in celiac disease is impaired absorption of iron and other nutrients including folate and cobalamin. Villous atrophy of the intestinal mucosa is an important cause of abnormal iron absorption and this is reflected in the clearcut laboratory evidence of iron deficiency anemia in most anemic patients with celiac disease. Abnormal iron absorption is also supported by the failure to increase serum iron following oral iron loading, and refractoriness to oral iron treatment. […] As discussed above, pro-inflammatory cytokines play an essential role in the inflammatory and cytotoxic mechanisms involved in the pathogenesis of celiac disease. Such cytokines, in particular interferon- (IFN-), and IL6, are powerful mediators of hypoferremia in inflammation inducing the synthesis of the iron regulatory hormone hepcidin. Increased hepcidin synthesis in turn is responsible for increased ferroportin degradation and the inhibition of iron release from macrophages and enterocytes leading to the well known abnormalities in iron homeostasis associated with the anemia of chronic disease.

• #54 Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis | Gut

  https://gut.bmj.com/content/61/9/1355

  Coeliac disease is a gut disease driven by an abnormal immune response towards dietary gluten in genetically susceptible individuals. […] This paper summarises the interactions of gluten-derived peptides with the intestinal epithelium and discusses the mechanisms that control their transport across the epithelium. […] It shows how recent data point to a key role for the transcellular pathway and highlights the Trojan horse role of secretory IgA which can hijack the transferrin receptor and allow the rapid translocation of intact gluten peptides into the mucosa. […] These recent findings might be useful for the design of new treatments.

• #55 Celiac disease: From pathophysiology to treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5437500/

  Celiac disease defined an autoimmune disorder originating by an aberrant adaptive immune response against gluten-containing grains in susceptible individuals. […] The primary mechanism involved in celiac disease is related to an inappropriate adaptive immune response to gluten-derived peptides. It has been ascertained that prolamines contain critical epitopes presented by either HLA-DQ2 or HLA-DQ8 induce a CD4+ T-lymphocytes response. In celiac disease pathogenesis the role exerted by the intestinal epithelia barrier, physiologically impermeable to macromolecules such as gliadin is actually recognized. In people with a genetic susceptibility to develop celiac disease, gliadin interacts with the intestinal cells to trigger the disassembling of the inter-enterocyte tight junctions (TJs). The impairment of the TJs determines the up-regulation of zonulin, a peptide involved in TJ regulation and responsible for the increased gut permeability. Gliadin peptides pass through the epithelial barrier and activate T-lymphocytes located in the lamina propria. Activated CD4+ T-lymphocytes produce high levels of pro-inflammatory cytokines, inducing either a T-helper 1 pattern dominated by IFN-, and a T-helper 2 pattern, which causes a clonal expansion of B-lymphocytes that subsequently differentiate in plasma-cells secreting anti-gliadin and anti-tissue-transglutaminase antibodies. […] Gliadin-specific T-cell responses have been found to be enhanced by the action of tissue transglutaminase, an enzyme located in the extracellular space of the sub-epithelial region or at the epithelial brush border.

• #56 Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review

  https://www.mdpi.com/1422-0067/24/20/15482

  Despite considerable advances in understanding celiac disease, numerous questions regarding its exact mechanisms and immune-pathophysiology remain unanswered. […] The activation of GALT by these gluten-derived peptides precipitates an inflammatory response, which is the crux of the pathogenesis in celiac disease. […] Following the ingestion of gluten, gliadin binds to the chemokine receptor CXCR3 on the luminal aspect of the intestinal epithelium. This binding prompts enterocytes to release the protein Zonulin. […] Type I IFN potentially provokes the release of IFN-γ and interleukin-15 (IL-15) by dendritic cells (DCs). The role of IL-15 within this pathogenic framework is multifaceted and instrumental. […] IL-15 production is notably upregulated in untreated celiac disease and plays a crucial role in the activation and expansion of CD8+ T intraepithelial lymphocytes (IELs), the key players in epithelial damage.

• #57 What is Celiac Disease? | Celiac Disease FoundationBack to HomeBack to HomeAbout the DiseaseGluten-Free ResourcesResearch ResourcesAdvocacy and Public PolicyJoin the EffortSupport the FoundationShare on FacebookShare on TwitterEmail this pageprinter-miniR

  https://celiac.org/about-celiac-disease/what-is-celiac-disease/

  Celiac disease is a serious autoimmune disease that occurs in genetically predisposed people where the ingestion of gluten leads to damage in the small intestine. […] When people with celiac disease eat gluten (a protein found in wheat, rye, and barley), their body mounts an immune response that attacks the small intestine. These attacks lead to damage on the villi, small fingerlike projections that line the small intestine, that promote nutrient absorption. When the villi get damaged, nutrients cannot be absorbed properly into the body. […] Celiac disease can develop at any age after people start consuming gluten. Left untreated, celiac disease can lead to additional serious health problems. […] Untreated celiac disease can lead to the development of other autoimmune disorders like type 1 diabetes and multiple sclerosis (MS), and many other conditions, including dermatitis herpetiformis (an itchy skin rash), anemia, osteoporosis, infertility and miscarriage, neurological conditions like epilepsy and migraines, short stature, heart disease, and intestinal cancers.

• #58 Pathogenesis | Celiac Disease Center at Columbia University Medical Center

  https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/

  Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.

• #59 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  The combination of epidemiological, clinical, and animal studies suggests that broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life are associated with protection against CD and that pre-, peri-, and post-natal environmental factors may strongly influence the gut ecosystem. Therefore, the hygiene hypothesis concept can be misleading, while an environment-dependent dysbiosis hypothesis would more closely reflect the interplay between host and environmental pressure dictating the balance between health and disease. Several studies have shown an association between CD and a change in the microbiome composition. However, these associative studies do not necessarily imply causation between microbiota composition and CD pathogenesis. Many environmental factors known to influence the composition of the intestinal microbiota are also thought to play a role in the development of CD.

• #60 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism

  https://journals.eco-vector.com/2658-4433/article/view/90770

  Celiac disease is an autoimmune disease characterized by the development of atrophy of the small intestinal mucosa when patients with a genetic predisposition consume gluten. The disease prevalence is approximately 0.5%–1% in the general population. […] The disease’s most studied genetic risk factor is the expression of major histocompatibility complex (MHC) class II proteins, HLA-DQ2 and HLA-DQ8. The HLA-DQ2 haplotype is detected in most patients with celiac disease, whereas DR-4-DQ8 is detected in other cases. These specific changes in MHC proteins are the most critical risk factors and are significant in developing the autoimmune process in celiac disease. Additionally, polymorphisms of the IL-2 and IL-21 genes, namely, cytokines, have been identified to contribute to the inflammatory process in celiac disease, including the disease predisposition. Additional risk factors are low microbiota diversity and viral infections. Research suggests that viruses that cause intestinal infections, such as reoviruses and other species, disrupt the intestine’s immune homeostasis and provoke autoimmune reactions.

• #61 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Celiac disease pathophysiology. […] Celiac disease: From pathogenesis to novel therapies. […] Mechanisms by which gut microorganisms influence food sensitivities. […] Novel players in coeliac disease pathogenesis: Role of the gut microbiota. […] Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease. […] Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. […] The potential utility of tight junction regulation in celiac disease: Focus on larazotide acetate. […] A randomized trial of a transglutaminase 2 inhibitor for celiac disease. […] The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues.

• #62 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  The combination of epidemiological, clinical, and animal studies suggests that broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life are associated with protection against CD and that pre-, peri-, and post-natal environmental factors may strongly influence the gut ecosystem. Therefore, the hygiene hypothesis concept can be misleading, while an environment-dependent dysbiosis hypothesis would more closely reflect the interplay between host and environmental pressure dictating the balance between health and disease. Several studies have shown an association between CD and a change in the microbiome composition. However, these associative studies do not necessarily imply causation between microbiota composition and CD pathogenesis. Many environmental factors known to influence the composition of the intestinal microbiota are also thought to play a role in the development of CD.

• #63

  https://grantome.com/grant/NIH/R01-DK098435-06

  The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of tolerance (LOT) to oral antigen and induce celiac disease (CD) and to design strategies to prevent virus-induced LOT and CD onset. […] CD is a T cell-mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. […] Reoviruses are human dsRNA viruses recently linked to CD. […] We discovered that reovirus strain T1L abrogates tolerance to dietary antigens including gluten using a pathway dependent on IRF1, whereas strain T3D-RV does not. […] We propose to enhance an understanding of how viruses influence the development of autoimmune inflammatory disorders and prevent CD by identifying virus and host factors that influence LOT to dietary antigen and defining strategies to block virus-induced LOT and CD development.

• #64 Pathogenesis | Celiac Disease Center at Columbia University Medical Center

  https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/

  Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.

• #65 Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases – Kaminarskaya – Clinical nutrition and metabolism

  https://journals.eco-vector.com/2658-4433/article/view/90770

  Celiac disease is an autoimmune disease characterized by the development of atrophy of the small intestinal mucosa when patients with a genetic predisposition consume gluten. The disease prevalence is approximately 0.5%–1% in the general population. […] The disease’s most studied genetic risk factor is the expression of major histocompatibility complex (MHC) class II proteins, HLA-DQ2 and HLA-DQ8. The HLA-DQ2 haplotype is detected in most patients with celiac disease, whereas DR-4-DQ8 is detected in other cases. These specific changes in MHC proteins are the most critical risk factors and are significant in developing the autoimmune process in celiac disease. Additionally, polymorphisms of the IL-2 and IL-21 genes, namely, cytokines, have been identified to contribute to the inflammatory process in celiac disease, including the disease predisposition. Additional risk factors are low microbiota diversity and viral infections. Research suggests that viruses that cause intestinal infections, such as reoviruses and other species, disrupt the intestine’s immune homeostasis and provoke autoimmune reactions.

• #66

  https://grantome.com/grant/NIH/R01-DK098435-06

  The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of tolerance (LOT) to oral antigen and induce celiac disease (CD) and to design strategies to prevent virus-induced LOT and CD onset. […] CD is a T cell-mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. […] Reoviruses are human dsRNA viruses recently linked to CD. […] We discovered that reovirus strain T1L abrogates tolerance to dietary antigens including gluten using a pathway dependent on IRF1, whereas strain T3D-RV does not. […] We propose to enhance an understanding of how viruses influence the development of autoimmune inflammatory disorders and prevent CD by identifying virus and host factors that influence LOT to dietary antigen and defining strategies to block virus-induced LOT and CD development.

• #67 Pathogenesis | Celiac Disease Center at Columbia University Medical Center

  https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/

  Celiac disease occurs in any individual due to an interaction of genetic factors, environmental factors and gluten. […] The genetic factors are HLA DQ2 or DQ8 as well as non HLA genes. […] The environmental factors include gastrointestinal infections in childhood, timing and amount gluten ingestion around the time of weaning, and the presence or absence of breastfeeding. […] Gluten is known to be poorly digested in the upper gastrointestinal tract of man. As a result, large molecules of gliadin are present within the intestine. […] These molecules are acted on by tTg that makes them more toxic to susceptible individuals (HLA DQ2 or DQ8 positive). […] The immune response to the presence of these toxic fragments of gliadin results in cytokine liberation and tissue damage. […] The tissue damage results in the characteristic pathological finding of villous atrophy and inflammation.

• #68 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  Celiac disease (CD) is an autoimmune condition characterized by a specific serological and histological profile triggered by gluten ingestion in genetically predisposed individuals. Gluten is the general term for alcohol-soluble proteins present in various cereals, including wheat, rye, barley, spelt, and kamut. In recent years, there have been significant changes in the diagnosis, pathogenesis, and natural history of this condition, with CD undergoing a true metamorphosis due to the steady increase in the number of diagnoses identified, even in geriatric patients. This has been mainly attributed to the greater availability of sensitive and specific screening tests, which allow identification of the risk groups for CD and led to a significant raise in diagnoses worldwide. Several theories have suggested that the globalization and ubiquitous spread of false or extreme versions of the Mediterranean diet including the consumption of very high quantities of gluten (up to 20g/day), has led to an increased prevalence and incidence of CD. In addition, the quality of gluten itself might also play a contributory role. Indeed, the production of new grain variants due to technological rather than nutritional reasons may have influenced the observed increase in the number of CD diagnoses in recent years. However, these hypotheses have not been confirmed and the real cause of the risk in CD diagnoses remains unknown. Furthermore, the epidemiological observation that similar epidemics are reported for other autoimmune diseases in the Western hemisphere suggests that environmental factors other than gluten can be at play.

• #69 Celiac Disease: Pathogenesis and Novel Therapeutic Strategies

  https://eurekaselect.com/public/article/28091

  Celiac disease is a digestive disease, considered as an autoimmune disorder, that damages the small intestine and interferes with absorption of nutrients. […] Celiac disease is a genetic condition that is triggered or becomes active for the first time after surgery, pregnancy, childbirth, viral infection, or severe emotional stress. […] The only treatment for celiac disease is to follow a gluten-free diet. […] Various other approaches are being studied that would reduce the need of dieting. One of those promising new approaches involves treating celiac patients with AT-1001, a paracellular permeability inhibitor, and with R-spondin1, a recombinant, secreted protein that early animal studies have shown to act as a highly specific stimulator of the gastrointestinal (GI) epithelial cells.

• #70 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults – UpToDate

  https://www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults

  Thus, another gene or genes at an HLA-unlinked locus must also participate. […] Moreover, novel genetic and especially epigenetic factors that increase the risk or severity of celiac disease have been identified. […] Celiac disease is associated with a number of autoimmune disorders, including type 1 diabetes mellitus and autoimmune thyroid disease. […] In patients with celiac disease, immune responses to gliadin fractions promote an inflammatory reaction, characterized by infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy. This response is mediated by both the innate and adaptive immune systems.

• #71 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults – UpToDate

  https://www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults

  Thus, another gene or genes at an HLA-unlinked locus must also participate. […] Moreover, novel genetic and especially epigenetic factors that increase the risk or severity of celiac disease have been identified. […] Celiac disease is associated with a number of autoimmune disorders, including type 1 diabetes mellitus and autoimmune thyroid disease. […] In patients with celiac disease, immune responses to gliadin fractions promote an inflammatory reaction, characterized by infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy. This response is mediated by both the innate and adaptive immune systems.

• #72 What is Celiac Disease? | Celiac Disease FoundationBack to HomeBack to HomeAbout the DiseaseGluten-Free ResourcesResearch ResourcesAdvocacy and Public PolicyJoin the EffortSupport the FoundationShare on FacebookShare on TwitterEmail this pageprinter-miniR

  https://celiac.org/about-celiac-disease/what-is-celiac-disease/

  Celiac disease is a serious autoimmune disease that occurs in genetically predisposed people where the ingestion of gluten leads to damage in the small intestine. […] When people with celiac disease eat gluten (a protein found in wheat, rye, and barley), their body mounts an immune response that attacks the small intestine. These attacks lead to damage on the villi, small fingerlike projections that line the small intestine, that promote nutrient absorption. When the villi get damaged, nutrients cannot be absorbed properly into the body. […] Celiac disease can develop at any age after people start consuming gluten. Left untreated, celiac disease can lead to additional serious health problems. […] Untreated celiac disease can lead to the development of other autoimmune disorders like type 1 diabetes and multiple sclerosis (MS), and many other conditions, including dermatitis herpetiformis (an itchy skin rash), anemia, osteoporosis, infertility and miscarriage, neurological conditions like epilepsy and migraines, short stature, heart disease, and intestinal cancers.

• #73 A Possible Mechanism behind Autoimmune Disorders Discovered By Genome-Wide Linkage and Association Analysis in Celiac Disease | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070174

  Whether this up-regulation of TGM2 is of importance for the immune response leading to formation of IgA-tTG and IgG-tTG autoantibodies, the serological markers for CD is still unresolved. […] In order to discover possible functional connections between DUSP10 and other genes, we analyzed genes surrounding the top 603 markers. […] The most significant finding from our non-stratified linkage GWAS analysis was the association with the PPP1R12B gene region. […] The second most significant region in the HLA-stratified analysis after DUSP10 contains the SVIL gene. […] If the expression or presence of an autoantigen, like TGM2, was stimulated by the disturbed proline/glutamine homeostasis, it can explain why symptoms in CD also disappear by withdrawal of gluten. […] Our data points towards genes that are involved in cancer as well as metabolic and cardiovascular diseases.

• #74 Celiac disease: a comprehensive current review | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1380-z

  Celiac disease (CD) is an autoimmune condition characterized by a specific serological and histological profile triggered by gluten ingestion in genetically predisposed individuals. Gluten is the general term for alcohol-soluble proteins present in various cereals, including wheat, rye, barley, spelt, and kamut. In recent years, there have been significant changes in the diagnosis, pathogenesis, and natural history of this condition, with CD undergoing a true metamorphosis due to the steady increase in the number of diagnoses identified, even in geriatric patients. This has been mainly attributed to the greater availability of sensitive and specific screening tests, which allow identification of the risk groups for CD and led to a significant raise in diagnoses worldwide. Several theories have suggested that the globalization and ubiquitous spread of false or extreme versions of the Mediterranean diet including the consumption of very high quantities of gluten (up to 20g/day), has led to an increased prevalence and incidence of CD. In addition, the quality of gluten itself might also play a contributory role. Indeed, the production of new grain variants due to technological rather than nutritional reasons may have influenced the observed increase in the number of CD diagnoses in recent years. However, these hypotheses have not been confirmed and the real cause of the risk in CD diagnoses remains unknown. Furthermore, the epidemiological observation that similar epidemics are reported for other autoimmune diseases in the Western hemisphere suggests that environmental factors other than gluten can be at play.

• #75 MedlinePlus: Gluten and Celiac DiseaseLock

  https://medlineplus.gov/medlineplus-videos/gluten-and-celiac-disease/

  Celiac disease sometimes is hereditary, meaning it runs in families. […] In celiac disease, gluten can trigger the immune system to attack the small intestine. […] Immune cells damage small, fingerlike growths in the small intestine called villi, and the brushy intestinal lining becomes flattened. […] When the villi are damaged, the body cannot get the nutrients it needs. […] The immune system’s reaction can lead to other health problems as well. […] If untreated, celiac disease can lead to serious complications like anemia, infertility, and weak and brittle bones.

• #76 What is Celiac Disease? | Celiac Disease FoundationBack to HomeBack to HomeAbout the DiseaseGluten-Free ResourcesResearch ResourcesAdvocacy and Public PolicyJoin the EffortSupport the FoundationShare on FacebookShare on TwitterEmail this pageprinter-miniR

  https://celiac.org/about-celiac-disease/what-is-celiac-disease/

  Celiac disease is a serious autoimmune disease that occurs in genetically predisposed people where the ingestion of gluten leads to damage in the small intestine. […] When people with celiac disease eat gluten (a protein found in wheat, rye, and barley), their body mounts an immune response that attacks the small intestine. These attacks lead to damage on the villi, small fingerlike projections that line the small intestine, that promote nutrient absorption. When the villi get damaged, nutrients cannot be absorbed properly into the body. […] Celiac disease can develop at any age after people start consuming gluten. Left untreated, celiac disease can lead to additional serious health problems. […] Untreated celiac disease can lead to the development of other autoimmune disorders like type 1 diabetes and multiple sclerosis (MS), and many other conditions, including dermatitis herpetiformis (an itchy skin rash), anemia, osteoporosis, infertility and miscarriage, neurological conditions like epilepsy and migraines, short stature, heart disease, and intestinal cancers.

• #77 Celiac disease: Managing a multisystem disorder | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/3/217

  Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia. […] Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process. […] The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. […] In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase.

• #78 Celiac Disease: Symptoms & How It’s Treated

  https://my.clevelandclinic.org/health/diseases/14240-celiac-disease

  Complications of chronic inflammation can include: Compromised immunity. When your immune system is chronically overactive, it’s left with fewer resources to address an acute attack, such as an infection. […] Chronic inflammation leads to an increased risk of cancer in your small intestine. Studies show about 7% of people with celiac disease develop intestinal lymphomas, usually after several decades.

• #79 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. […] If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. […] Gluten-specific CD4+ T cells play a driver role in coeliac disease (CD) pathogenesis and can persist for decades under gluten-free diet (GFD). […] Gluten-specific CD4+ T cells cooperate with IL-15 produced by intestinal epithelial and myeloid cells to promote the activation of cytotoxic CD8+ T intraepithelial lymphocytes and license the autoimmune-like destruction of epithelial cells.

• #80 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults – UpToDate

  https://www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-celiac-disease-in-adults

  Celiac disease, also known as gluten-sensitive enteropathy, is a common immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals. […] Celiac disease is an immune disorder triggered by an environmental agent (the gluten component of wheat and related cereals) in genetically predisposed individuals. […] The genetic basis of celiac disease is supported by the frequent intrafamilial occurrence and the remarkably close association with the human leukocyte antigen (HLA) DR3-DQ2 and/or DR4-DQ8 gene locus. […] Homozygosity for HLA DQ2 has been associated with an increased risk for celiac disease and enteropathy-associated T-cell lymphoma. […] It has been estimated that the HLA contribution to the development of celiac disease among siblings is 36 percent.

• #81 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. […] If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. […] Gluten-specific CD4+ T cells play a driver role in coeliac disease (CD) pathogenesis and can persist for decades under gluten-free diet (GFD). […] Gluten-specific CD4+ T cells cooperate with IL-15 produced by intestinal epithelial and myeloid cells to promote the activation of cytotoxic CD8+ T intraepithelial lymphocytes and license the autoimmune-like destruction of epithelial cells.

• #82 Celiac Disease: Pathogenesis and Novel Therapeutic Strategies

  https://eurekaselect.com/public/article/28091

  Celiac disease is a digestive disease, considered as an autoimmune disorder, that damages the small intestine and interferes with absorption of nutrients. […] Celiac disease is a genetic condition that is triggered or becomes active for the first time after surgery, pregnancy, childbirth, viral infection, or severe emotional stress. […] The only treatment for celiac disease is to follow a gluten-free diet. […] Various other approaches are being studied that would reduce the need of dieting. One of those promising new approaches involves treating celiac patients with AT-1001, a paracellular permeability inhibitor, and with R-spondin1, a recombinant, secreted protein that early animal studies have shown to act as a highly specific stimulator of the gastrointestinal (GI) epithelial cells.

• #83 Celiac disease: pathogenesis of a model immunogenetic disease. – Document – Gale Academic OneFile

  https://go.gale.com/ps/i.do?id=GALE%7CA157592730&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=00219738&p=AONE&sw=w

  Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. […] Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. […] As is discussed in this article, acquired T cell-mediated immune mechanisms and innate immune mechanisms have an important role in the pathogenesis of CD. […] recent advances in our understanding of the immunopathogenesis of CD might lead to alternative treatments for this disease.

• #84 IJMS | Special Issue : Celiac Disease: Genetics, Pathogenesis and Therapy: 2nd Edition

  https://www.mdpi.com/journal/ijms/special_issues/48HZPGQ595

  The understanding of pathogenetic pathways allows us to identify possible targets for new therapies, among which there could be molecules that are able to prevent gliadin peptide intestinal passage and their interaction with transglutaminase and/or the immune system. A deeper understanding of the microbiota could also provide different therapeutic strategies, aiming to degrade gliadin or to reduce the inflammatory milieu.

• #85 Targeting gluten: Researchers delete proteins in wheat harmful to people with celiac disease

  https://phys.org/news/2025-05-gluten-delete-proteins-wheat-people.html

  Wheat is a major source of calories, carbohydrates and protein worldwide, and its distinctive gluten proteins are what gives bread and pasta dough texture and elasticity. But it also can cause autoimmune reactions such as celiac disease, which is growing in prevalence worldwide. […] Researchers at the University of California, Davis, have deleted a cluster of genes in wheat that generates gluten proteins that can trigger immune reactions without harming the breadmaking quality of this globally nutritious crop. […] „The gluten proteins we eliminated are the ones that trigger the strongest response in people with celiac disease, and their elimination can reduce the risk of triggering the disease in people without celiac disease,” Dubcovsky said. […] The research team used gamma radiation to target and delete alpha-gliadins, which can cause severe reactions in people with celiac disease. […] „Alpha-gliadins are definitely candidates for removal in terms of trying to create a less allergenic wheat.” […] „Our study shows that this is not always the case and that we can reduce wheat allergenicity and improve quality at the same time.”

• #86 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Highly efficient gluten degradation with a newly identified prolyl endoprotease: Implications for celiac disease. […] The toxic alpha-gliadin peptide 31-43 enters cells without a surface membrane receptor. […] Antigen-specific gut inflammation and systemic immune responses induced by pro-longing wheat gluten sensitization in BALB/c murine model. […] The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. […] The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study. […] Vaccine immunotherapy for celiac disease. […] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. […] IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. […] Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease.

• #87 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Celiac disease pathophysiology. […] Celiac disease: From pathogenesis to novel therapies. […] Mechanisms by which gut microorganisms influence food sensitivities. […] Novel players in coeliac disease pathogenesis: Role of the gut microbiota. […] Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease. […] Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. […] The potential utility of tight junction regulation in celiac disease: Focus on larazotide acetate. […] A randomized trial of a transglutaminase 2 inhibitor for celiac disease. […] The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues.

• #88 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Celiac disease pathophysiology. […] Celiac disease: From pathogenesis to novel therapies. […] Mechanisms by which gut microorganisms influence food sensitivities. […] Novel players in coeliac disease pathogenesis: Role of the gut microbiota. […] Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease. […] Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. […] The potential utility of tight junction regulation in celiac disease: Focus on larazotide acetate. […] A randomized trial of a transglutaminase 2 inhibitor for celiac disease. […] The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues.

• #89 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Celiac disease pathophysiology. […] Celiac disease: From pathogenesis to novel therapies. […] Mechanisms by which gut microorganisms influence food sensitivities. […] Novel players in coeliac disease pathogenesis: Role of the gut microbiota. […] Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease. […] Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: Role of the innate immune response in Celiac disease. […] The potential utility of tight junction regulation in celiac disease: Focus on larazotide acetate. […] A randomized trial of a transglutaminase 2 inhibitor for celiac disease. […] The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues.

• #90 Diagnosis and treatment of celiac disease | Mucosal Immunology

  https://www.nature.com/articles/mi200874

  The understanding of the pathogenesis of celiac disease has made huge advances in recent years. The disease is caused by an inappropriate immune response to dietary gluten proteins. This immune response is controlled by CD4+ T cells in the lamina propria that recognize gluten peptides in the context of disease predisposing HLA-DQ2 and HLA-DQ8 molecules. These T cells are specific for proline- and glutamine-rich gluten peptides that are resistant to proteolysis and that have been become deamidated by the enzyme transglutaminase 2 (TG2). […] TG2 is an enzyme with many functions, and it is directly involved in celiac disease pathogenesis by modifying gluten peptides in a process where glutamine residues are deamidated to glutamic acid. The deamidated peptides bind better to the HLA-DQ2 and HLA-DQ8 molecules, and the intestinal T cells of celiac disease patients preferentially recognize such deamidated gluten peptides. […] One can also envision treating celiac disease by hindering the activation of gluten reactive CD4+ T cells. This can be achieved by preventing the formation of deamidated peptides, or by blocking the peptide-binding site of the gluten presenting HLA molecules DQ2 and DQ8.

• #91 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Highly efficient gluten degradation with a newly identified prolyl endoprotease: Implications for celiac disease. […] The toxic alpha-gliadin peptide 31-43 enters cells without a surface membrane receptor. […] Antigen-specific gut inflammation and systemic immune responses induced by pro-longing wheat gluten sensitization in BALB/c murine model. […] The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. […] The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study. […] Vaccine immunotherapy for celiac disease. […] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. […] IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. […] Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease.

• #92 Open Access Macedonian Journal of Medical Sciences (OAMJMS).

  https://oamjms.eu/index.php/mjms/article/view/11024

  Highly efficient gluten degradation with a newly identified prolyl endoprotease: Implications for celiac disease. […] The toxic alpha-gliadin peptide 31-43 enters cells without a surface membrane receptor. […] Antigen-specific gut inflammation and systemic immune responses induced by pro-longing wheat gluten sensitization in BALB/c murine model. […] The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. […] The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study. […] Vaccine immunotherapy for celiac disease. […] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. […] IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. […] Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease.

• #93 IJMS | Special Issue : Celiac Disease: Genetics, Pathogenesis and Therapy: 2nd Edition

  https://www.mdpi.com/journal/ijms/special_issues/48HZPGQ595

  The understanding of pathogenetic pathways allows us to identify possible targets for new therapies, among which there could be molecules that are able to prevent gliadin peptide intestinal passage and their interaction with transglutaminase and/or the immune system. A deeper understanding of the microbiota could also provide different therapeutic strategies, aiming to degrade gliadin or to reduce the inflammatory milieu.

• #94 Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review

  https://www.mdpi.com/1422-0067/24/20/15482

  Despite considerable advances in understanding celiac disease, numerous questions regarding its exact mechanisms and immune-pathophysiology remain unanswered. […] The activation of GALT by these gluten-derived peptides precipitates an inflammatory response, which is the crux of the pathogenesis in celiac disease. […] Following the ingestion of gluten, gliadin binds to the chemokine receptor CXCR3 on the luminal aspect of the intestinal epithelium. This binding prompts enterocytes to release the protein Zonulin. […] Type I IFN potentially provokes the release of IFN-γ and interleukin-15 (IL-15) by dendritic cells (DCs). The role of IL-15 within this pathogenic framework is multifaceted and instrumental. […] IL-15 production is notably upregulated in untreated celiac disease and plays a crucial role in the activation and expansion of CD8+ T intraepithelial lymphocytes (IELs), the key players in epithelial damage.

• #95 Pathogenesis | Celiac Disease Center at Columbia University Medical Center

  https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/

  In celiac disease, the epithelium is infiltrated with lymphocytes and the epithelial cells are damaged. […] The arm of the immune system responsible for this damage is the innate immune system. […] This process occurring in the lamina propria is the site of the interaction of gliadin with tissue transglutaminase and the DQ2/DQ8 molecules and the generation of the cytokines that result in tissue damage and villous atrophy. […] It is also very important to identify all the other genes (apart from HLA DQ2 and DQ8) that may be interacting in any given individual to result in celiac disease. […] It is through research in these areas that the mechanism of the development of celiac disease will be fully defined. […] Not until all the mechanisms of the development of celiac disease are fully understood can adequate therapies be developed.

• #96 Pathogenesis and environmental factors contributing to celiac disease and opportunities for non-dietary therapies

  https://open.bu.edu/items/9054b77e-c665-4509-ac1f-5e164aafe2a5

  Celiac Disease (CD) is a common autoimmune disease with a worldwide prevalence of 1%, and the incidence and prevalence rates appear to be trending upward. […] The genes encoding for Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 are highly associated with CD and the gluten protein gliadin triggers the inflammatory immune response, causing mucosal damage and villi atrophy. […] While these studies have helped bridge the gaps in our understanding of the specific mechanisms involved in the pathogenies of CD, there is still a lack of knowledge of the exact role of environmental factors and associated diseases in the progression of CD. Further exploration of the environmental triggers of CD is warranted not only to find other treatments but to also be able to prevent the development of CD.

• #97

  https://grantome.com/grant/NIH/R01-DK098435-06

  Knowledge gained through these efforts will enhance an understanding of how viral infections lead to the development of gastrointestinal inflammatory disorders and foster new strategies to prevent CD in genetically vulnerable individuals. […] Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease.

• #98 Immunopathogenesis and environmental triggers in coeliac disease | Gut

  https://gut.bmj.com/content/71/11/2337

  Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. […] If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. […] Gluten-specific CD4+ T cells play a driver role in coeliac disease (CD) pathogenesis and can persist for decades under gluten-free diet (GFD). […] Gluten-specific CD4+ T cells cooperate with IL-15 produced by intestinal epithelial and myeloid cells to promote the activation of cytotoxic CD8+ T intraepithelial lymphocytes and license the autoimmune-like destruction of epithelial cells.

• #99 Organoid models elucidate Celiac disease pathogenesis | Immunopaedia

  https://www.immunopaedia.org.za/breaking-news/organoid-models-elucidate-celiac-disease-pathogenesis/

  Recent advancements in tissue engineering have yielded a powerful tool for investigating complex diseases: organoids. […] In the context of celiac disease, intestinal organoids have emerged as a valuable model system to elucidate disease mechanisms. […] The data suggest a pivotal role for IL-7 in orchestrating the inflammatory cascade that underlies celiac disease pathogenesis. […] The development of organoid technology represents a significant leap forward in celiac disease research. By providing a more physiologically relevant model compared to traditional cell culture or animal studies, organoids enable precise dissection of disease mechanisms and facilitate the evaluation of novel therapeutic strategies.

• #100 Biological consequences of transglutaminase 2 activity : insights into pathogenesis of celiac disease | Stanford Digital Repository

  https://purl.stanford.edu/gj991md8222

  A deeper understanding of these TG2-related events will not only enable definitive verification that transglutaminase activity is necessary for gluten induced pathogenesis in CD, but could also cast fundamentally new light on the biological function(s) of TG2. […] These and other investigations also suggest that the reaction catalyzed by TG2 on dietary gluten peptides is essential for the pathogenesis of CD. […] The main goal of this project and the subject of this dissertation were the design, development, and application of disease relevant models and biochemical tools for the study of TG2 activity and its potential physiological roles in CD pathogenesis.

• #101 Pathogenesis | Celiac Disease Center at Columbia University Medical Center

  https://celiacdiseasecenter.columbia.edu/celiac-disease/pathogenesis/

  In celiac disease, the epithelium is infiltrated with lymphocytes and the epithelial cells are damaged. […] The arm of the immune system responsible for this damage is the innate immune system. […] This process occurring in the lamina propria is the site of the interaction of gliadin with tissue transglutaminase and the DQ2/DQ8 molecules and the generation of the cytokines that result in tissue damage and villous atrophy. […] It is also very important to identify all the other genes (apart from HLA DQ2 and DQ8) that may be interacting in any given individual to result in celiac disease. […] It is through research in these areas that the mechanism of the development of celiac disease will be fully defined. […] Not until all the mechanisms of the development of celiac disease are fully understood can adequate therapies be developed.

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