Materiały źródłowe

• #1 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  Ankylosing spondylitis (AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain; additionally, in more advanced cases, it can cause spine fusion. […] Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen (HLA)B27 and the interleukin23/17 axis. However, the pathogenesis of AS remains unclear. […] The confusion in diagnosis and lack of disease-modifying therapeutics, including anti-TNF- and anti-IL-17 treatment of AS, are largely due to the limited knowledge of the pathogenesis, which may involve immunity, heredity and other factors. […] As an autoimmune disease, AS develops through complex interactions between genetic background and environmental factors.

• #1

  https://www.healio.com/clinical-guidance/ankylosing-spondylitis/etiology-and-pathogenesis

  The etiopathogenesis of ankylosing spondylitis (AS) is not fully understood. However, there is strong evidence indicating that genetic factors play a pivotal role in disease susceptibility, and that interaction with epigenetic and environmental factors results in immune-mediated events to release proinflammatory cytokines that lead to disease. […] Twin studies have shown that nearly 90% of the risk of developing AS is determined genetically, indicating the highly heritable nature of this disease. […] Moreover, disease activity, functional impairment, radiographic severity and age of symptom onset all show significant heritability in AS. […] The precise explanation for the association of HLA-B27 with ankylosing spondylitis/axial spondyloarthritis (AS/axSpA) has defied researchers but several hypotheses have been proposed.

• #1 Role of HLA-B27 in the pathogenesis of ankylosing spondylitis (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2017.6248

  The study of ankylosing spondylitis (AS) has made significant progress over the last decade. […] However, human leukocyte antigen (HLA)B27 has been suggested to be important in the pathogenesis of AS, contributing to ~20.1% of AS heritability. […] Genetic studies have concluded that HLA-B27 in the major histocompatibility complex (MHC) locus contributes to ~20.1% of AS heritability, with 4.3% associated with loci other than HLA-B. […] It has previously been suggested that a strong association exists between ERAP1 and AS that is restricted to HLA-B27-positive patients. […] The mechanism of antigen processing and presentation is presented in Fig. 1. […] The arthritogenic peptide hypothesis suggests that the HLA-B27-specific autoimmune response may be directly initiated for structurally unique peptide-MHC complexes, depending on the amino-acid composition of the antigen peptides.

• #1 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  The mature HLA-B27 complex is a quaternary structure with three important components. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] The binding of KIR3DL2 with HLA-B27 homodimers was revealed to stimulate the survival and differentiation of KIR3DL2+CD4+ T lymphocytes in patients with SpA. […] The IL-23/IL-17 pathway plays a crucial role in the development of the disease. […] In AS, differentiated T lymphocytes can generate IL-17 and then trigger osteoclast activation, thus suppressing bone regeneration. […] The pathogenesis of AS is very complex. Current studies suggest that it may be the result of a variety of complicated mechanisms.

• #1 A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

  https://www.mdpi.com/1422-0067/17/12/2126

  Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. […] A growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. […] The role of gut microbiome in AS pathogenesis is also suggested by many studies, and AS can be associated with IBD. […] Evidence from animal models indicates that, when raised in a germfree environment, HLA-B27 transgenic rats fail to develop inflammatory peripheral joint or intestinal disease. However, upon receiving transfer of the common gut bacteria bacteroides, the disease occurred.

• #1 Pathogenesis of Ankylosing Spondylitis and Reactive Arthritis | Musculoskeletal Key

  https://musculoskeletalkey.com/pathogenesis-of-ankylosing-spondylitis-and-reactive-arthritis/

  Genetics plays a major role in the etiology of ankylosing spondylitis. […] The gene with the greatest contribution to ankylosing spondylitis is HLA-B27. […] A major mediator of inflammation is tumor necrosis factor (TNF). […] Bone destruction occurs along with pathologic new bone formation in ankylosing spondylitis. […] The bone remodeling processes are not necessarily directly linked to the inflammatory processes in ankylosing spondylitis. […] For ankylosing spondylitis, it is commonly recognized that two major but uncoupled processes coexist inflammation and abnormal bone formation. […] The causes of ankylosing spondylitis are multifactorial and involves a number of interlinking pathways. […] The second group of critical factors contributing to ankylosing spondylitis is genetics.

• #1 An Actual Insight into the Pathogenic Pathways of Ankylosing Spondylitis

  https://www.mdpi.com/1467-3045/46/11/762

  Mechanical stress is an important factor in triggering SpA, which occurs at the entheses, the insertion points of tendons, ligaments, and the capsule into the bone. […] Under stressful conditions, such as mechanical stress, gut microbiome changes, or environmental factors, AS is linked to chronic inflammation that involves dendritic cells, macrophages, NK cells, and adaptive immune cells. […] The dysfunction of the IL-23/IL-17 pathway has been observed in various autoimmune disorders, including psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), and spondylarthritis (SpA). […] In immune-mediated rheumatic diseases, vitamin D plays a protective role, and vitamin D deficiency has been considered a risk factor associated with more severe disease. […] Knowing the pathophysiological mechanism that contributes to the onset and progression of AS is important for understanding the varied responses to therapies among individuals and is crucial in searching new solutions.

• #2 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  Ankylosing spondylitis (AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain; additionally, in more advanced cases, it can cause spine fusion. […] Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen (HLA)B27 and the interleukin23/17 axis. However, the pathogenesis of AS remains unclear. […] The confusion in diagnosis and lack of disease-modifying therapeutics, including anti-TNF- and anti-IL-17 treatment of AS, are largely due to the limited knowledge of the pathogenesis, which may involve immunity, heredity and other factors. […] As an autoimmune disease, AS develops through complex interactions between genetic background and environmental factors.

• #2 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  Genetic factors have been acknowledged as crucial in the genesis of AS. […] One of the most important genetic factors is major histocompatibility complex (MHC) class I allele HLA-B27, which was discovered in 1973. […] Despite the unclear pathomechanism, HLA-B27 has been associated with the prevalence of AS in different populations around the world. […] The familial tendency of AS was remarkable with relative risks of 94, 25, and 4 for first-, second-, and third-degree relatives, respectively. […] The human MHC, also called the HLA complex, belongs to the cell-surface proteins acting in the process of acquired immunity. […] HLA-B27, basically belonging to the MHC-I surface protein encoded by the MHC B gene on chromosome 6, is the most essential gene that predisposes an individual to AS.

• #2

  https://www.healio.com/clinical-guidance/ankylosing-spondylitis/etiology-and-pathogenesis

  A molecular mimicry hypothesis proposes that HLA-B27 itself becomes autoantigenic due to its sequence homology with certain bacterial proteins. […] As discussed later, accumulation of misfolded HLA-B27 in the endoplasmic reticulum (ER) can cause intracellular stress, unfolded protein response (UPR) and autophagy that lead to proinflammatory events. […] Moreover, modification of gut microbiome and intracellular microbial-handling of putative arthritogenic organisms by HLA-B27 that can result in an aberrant or impaired immune response in conjunction with an upregulated production of cytokines, such as IL-23, that leads to AS or related spondyloarthritis (SpA). […] The arthritogenic peptide hypothesis has been strongly revived by new data. […] The strongest evidence to date for this hypothesis has now been published by Yang and colleagues.

• #2 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  HLA-B27 heavy chains tend to form homodimers without 2m via the disulfide bonds of the cysteine at C67. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] In AS, the first indication of IL-23/IL-17 relevance came from a GWAS study in 2007 that identified an IL-23 receptor (IL-23R) SNP related to AS pathogenesis. […] Dysfunction of the IL-23/IL-17 pathway was identified in many diseases related to human immunological procedures, including psoriasis, IBD, rheumatoid arthritis and SpA; additionally, IL-17 and IL-23 act as major cytokines for axSpA and psoriatic arthritis. […] Studies have shown higher serum levels of IL-23 and IL-17 and the presence of IL-17+ cells in the facet joints in AS patients, suggesting that the innate immune system might be of greater relevance. […] The IL-23/IL-17 axis causes inflammatory molecule secretion from fibroblasts, endothelial cells, DCs or macrophages, which induce joint destruction and inflammation that are observed in both rheumatoid arthritis and AS.

• #2

  https://www.alliedacademies.org/articles/ankylosing-spondylitis-pathogenesis-and-how-to-manage-it-22375.html

  Stomach mucosal aggravation jest oceniane na 70% pacjentów z AS, advancing to clinical IBD w 5% przypadków. […] Jedna z hipotez, aby to wyjaśnić, jest to, że stały antigenic excitement może aktywować Immune system microorganisms i to może być odpowiedzialne za chronic gut inflammation. […] W ostatnich latach badacze skupili się na identyfikacji mikroorganizmów jako wyzwalaczy AS.

• #2 Pathogenesis of ankylosing spondylitis. | Sigma-Aldrich

  https://www.sigmaaldrich.com/AT/de/tech-docs/paper/e3bfa0bddb5b3cc0c44babe541e685db?srsltid=AfmBOooileDepyiVO7z8AkToJTIPSFkMcwFCq4caGNfVn2AM_CjpX3tf

  Ankylosing spondylitis (AS) is a potentially disabling form of seronegative spondyloarthritis. The pathology mainly affects the entheses, where ligaments, tendons and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion and syndesmophyte (spur) formation. Tumor necrosis factor is an important mediator of the inflammatory processes, but this proinflammatory cytokine is not closely involved in bone erosion or syndesmophyte formation. The major causative factors of AS are genetic, with the gene encoding HLA-B27 being the most important genetic factor. Several other susceptibility genes have also been identified. […] An enormous number of papers have been published and many diverse hypotheses have been generated regarding the pathogenesis of AS. This Review outlines the key areas of current research in this field, describes several hypotheses regarding the pathogenesis of AS, which are under intense investigation, and concludes with a dissection of the processes involved in bone erosion and syndesmophyte formation.

• #2 An Actual Insight into the Pathogenic Pathways of Ankylosing Spondylitis

  https://www.mdpi.com/1467-3045/46/11/762

  Mechanical stress is an important factor in triggering SpA, which occurs at the entheses, the insertion points of tendons, ligaments, and the capsule into the bone. […] Under stressful conditions, such as mechanical stress, gut microbiome changes, or environmental factors, AS is linked to chronic inflammation that involves dendritic cells, macrophages, NK cells, and adaptive immune cells. […] The dysfunction of the IL-23/IL-17 pathway has been observed in various autoimmune disorders, including psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), and spondylarthritis (SpA). […] In immune-mediated rheumatic diseases, vitamin D plays a protective role, and vitamin D deficiency has been considered a risk factor associated with more severe disease. […] Knowing the pathophysiological mechanism that contributes to the onset and progression of AS is important for understanding the varied responses to therapies among individuals and is crucial in searching new solutions.

• #2 An Actual Insight into the Pathogenic Pathways of Ankylosing Spondylitis

  https://www.mdpi.com/1467-3045/46/11/762

  Although still not fully understood, the etiopathogenesis of spondyloarthritis, and more specifically AS, has been described as involving several mechanisms of action that synergistically initiate and maintain a pro-inflammatory state, leading to disease onset. […] Genetic predisposition plays an essential role in conjunction with environmental factors, infections, and mechanical stress at the entheses, as well as the body’s immune response to triggering factors through innate and acquired immune mechanisms. […] The essential mechanisms in understanding SA pathogenesis are presented in Figure 1. […] Genetic predisposition refers to the primary role played by the HLA-B27 antigen in the onset of the disease. […] The human leukocyte antigen is a member of the class of alloantigens and is encoded by genes located in a region called the major histocompatibility complex (MHC), situated on the short arm of chromosome 6.

• #3 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  Ankylosing spondylitis (AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain; additionally, in more advanced cases, it can cause spine fusion. […] Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen (HLA)B27 and the interleukin23/17 axis. However, the pathogenesis of AS remains unclear. […] The confusion in diagnosis and lack of disease-modifying therapeutics, including anti-TNF- and anti-IL-17 treatment of AS, are largely due to the limited knowledge of the pathogenesis, which may involve immunity, heredity and other factors. […] As an autoimmune disease, AS develops through complex interactions between genetic background and environmental factors.

• #3 Pathogenesis of Ankylosing Spondylitis and Reactive Arthritis | Musculoskeletal Key

  https://musculoskeletalkey.com/pathogenesis-of-ankylosing-spondylitis-and-reactive-arthritis/

  The higher the population attributable risk, the greater the contribution to the disease. […] It is thought that the development of arthritis in these rats is related to commensal bacteria, especially in the gastrointestinal tract. […] In human ankylosing spondylitis, the only enteric bacterium that has been incriminated is Klebsiella pneumoniae. […] Over the past decade, most of the researchers studying the pathogenesis of ankylosing spondylitis have focused on identification of arthritis-causing genes. […] The most important gene, HLA-B27, was discovered in 1973. […] It contributes about 30% of the heritability of the disease. […] The population attributable risks for the first three are 90%, 26%, and 9%, respectively. […] Hence, HLA-B27 is the largest contributor. […] The arthritogenic peptide hypothesis postulates that in the case of ankylosing spondylitis, there is a breakdown of tolerance to certain self-peptides, and this breakdown is a consequence of mimicry between the self-peptides and certain pathogen-derived and arthritis-causing peptides.

• #3 Role of HLA-B27 in the pathogenesis of ankylosing spondylitis (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2017.6248

  The study of ankylosing spondylitis (AS) has made significant progress over the last decade. […] However, human leukocyte antigen (HLA)B27 has been suggested to be important in the pathogenesis of AS, contributing to ~20.1% of AS heritability. […] Genetic studies have concluded that HLA-B27 in the major histocompatibility complex (MHC) locus contributes to ~20.1% of AS heritability, with 4.3% associated with loci other than HLA-B. […] It has previously been suggested that a strong association exists between ERAP1 and AS that is restricted to HLA-B27-positive patients. […] The mechanism of antigen processing and presentation is presented in Fig. 1. […] The arthritogenic peptide hypothesis suggests that the HLA-B27-specific autoimmune response may be directly initiated for structurally unique peptide-MHC complexes, depending on the amino-acid composition of the antigen peptides.

• #3 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  HLA-B27 heavy chains tend to form homodimers without 2m via the disulfide bonds of the cysteine at C67. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] In AS, the first indication of IL-23/IL-17 relevance came from a GWAS study in 2007 that identified an IL-23 receptor (IL-23R) SNP related to AS pathogenesis. […] Dysfunction of the IL-23/IL-17 pathway was identified in many diseases related to human immunological procedures, including psoriasis, IBD, rheumatoid arthritis and SpA; additionally, IL-17 and IL-23 act as major cytokines for axSpA and psoriatic arthritis. […] Studies have shown higher serum levels of IL-23 and IL-17 and the presence of IL-17+ cells in the facet joints in AS patients, suggesting that the innate immune system might be of greater relevance. […] The IL-23/IL-17 axis causes inflammatory molecule secretion from fibroblasts, endothelial cells, DCs or macrophages, which induce joint destruction and inflammation that are observed in both rheumatoid arthritis and AS.

• #3 Updates on ankylosing spondylitis: pathogenesis and therapeutic agents

  https://www.jrd.or.kr/journal/view.html?uid=1553&vmd=Full

  Pathogenesis of ankylosing spondylitis. Gut microbiome produces short-chain fatty acids, tryptophan metabolites, and amino acids. Also, Paneth cells are source of IL-23 in the terminal ileum. HLA-B*27 provides arthritogenic peptide to TCR, and misfolded HLA-B*27 and accumulated protein induce UPR resulting in production of IL-23. Mechanical stress in enthesis induce DAMPs and IL-1. As a result, produced IL-23 plays a pivotal role in initiating ankylosing spondylitis. Immune cells are involved to progress the disease by inducing IL-17, IL-22, and TNF-. Bone remodeling is activated, as a result, new bone formation and bone resorption are promoted through cytokines. […] TCR: T-cell receptor, UPR: unfolded protein response, DAMPs: danger-associated molecular pattern, IL: interleukin, TNF: tumor necrosis factor, NK: natural killer, ERAP: endoplasmic reticulum aminopeptidases.

• #3 Pathogenesis of ankylosing spondylitis. | Sigma-Aldrich

  https://www.sigmaaldrich.com/AT/de/tech-docs/paper/e3bfa0bddb5b3cc0c44babe541e685db?srsltid=AfmBOooileDepyiVO7z8AkToJTIPSFkMcwFCq4caGNfVn2AM_CjpX3tf

  Ankylosing spondylitis (AS) is a potentially disabling form of seronegative spondyloarthritis. The pathology mainly affects the entheses, where ligaments, tendons and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion and syndesmophyte (spur) formation. Tumor necrosis factor is an important mediator of the inflammatory processes, but this proinflammatory cytokine is not closely involved in bone erosion or syndesmophyte formation. The major causative factors of AS are genetic, with the gene encoding HLA-B27 being the most important genetic factor. Several other susceptibility genes have also been identified. […] An enormous number of papers have been published and many diverse hypotheses have been generated regarding the pathogenesis of AS. This Review outlines the key areas of current research in this field, describes several hypotheses regarding the pathogenesis of AS, which are under intense investigation, and concludes with a dissection of the processes involved in bone erosion and syndesmophyte formation.

• #3 Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/332945-overview

  Another possible mechanism in the induction of AS is presentation of an arthritogenic peptide from enteric bacteria by specific HLA molecules. Many patients with AS have subclinical GI tract inflammation and elevated IgA antibodies directed against Klebsiella. The bacteria may invade the GI tract of a genetically susceptible host, leading to chronic inflammation and increased permeability. Over time, bacterial antigens containing arthritogenic peptides enter the organism via the bloodstream. […] Localization of pathology to certain types of connective tissues (eg, entheses) may be explained by affinity of bacterial antigens to these specific sites. Biomechanical stress, such as that which occurs at entheses in the spine and feet, may predispose to clinical enthesitis at these sites. […] The spondyloarthropathies are the only known autoimmune diseases linked to an HLA class-I rather than HLA class-II genes. The cytotoxic CD8+ T-cell response appears to be important; it would respond to antigen presented by HLA class-I molecules on the surface of cells. The association of spondyloarthropathies (eg, ReA) with HIV infection in certain areas of the world supports the relative importance of the CD8+ cytotoxic T-cell responses compared with the CD4+ helper cells in these conditions.

• #3 Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis | RMD Open

  https://rmdopen.bmj.com/content/9/3/e003102

  Key pathways identified include aminopeptidases (ERAP) and interleukin (IL)-23 but multiple other pathways have been reported. […] The chances of an HLA B27+ individual to develop AS in a lifetime are only 1%2%. […] The combination of HLA B60 with HLA B27 increases chances of developing AS by 36 times. […] The relationship between various ethnicities and the prevalence of HLA B27 is well known, and the prevalence of AS is closely related. […] The introduction of HLA B27 and human 2-microglobulin genes into a species of rats known to be quite susceptible to experimentally induced inflammatory disease has drawn a lot of intention more than 30 years ago because the pattern of organ system involvement with the gastrointestinal tract, peripheral and vertebral joints, the male genital tract, skin, nails and the heart showed a striking resemblance to HLA B27-associated human diseases. […] In conclusion of this part, the pathogenetic background of the strong HLA association of AS has not been fully elucidated to date. Recent findings have rather supported the arthritogenic peptide hypothesis.

• #4 Ankylosing Spondylitis – Musculoskeletal and Connective Tissue Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/ankylosing-spondylitis

  Ankylosing spondylitis is the prototypical spondyloarthropathy and a systemic disorder characterized by inflammation of the axial skeleton, large peripheral joints, and digits; nocturnal back pain; morning back stiffness; accentuated kyphosis; constitutional symptoms; aortitis; cardiac conduction abnormalities; and anterior uveitis. […] The human leukocyte antigen B27 (HLA-B27) allele is present in 90% of White patients with ankylosing spondylitis, but it is also present in up to 10% of the general population depending on ethnicity. […] Increased prevalence of HLA-B27 in White people or HLA-B7 in Black people supports a genetic predisposition. However, the concordance rate in identical twins is only approximately 50%, suggesting that environmental factors contribute. […] The HLA-B27 allele is present in 90% of White patients with ankylosing spondylitis, but it is also present in up to 10% of the general population depending on ethnicity.

• #4 Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/332945-overview

  The etiology of AS is not understood completely; however, a strong genetic predisposition exists. A direct relationship between AS and the HLA-B27 gene has been determined. The precise role of HLA-B27 in precipitating AS remains unknown; however, one hypothesis is molecular mimicry in which HLA-B27 preferentially presents a bacterial (arthritogenic) antigen that induces an immune response to a self-antigen and autoimmunity. […] The primary pathology of the spondyloarthropathies is enthesitis with chronic inflammation, including CD4+ and CD8+ T lymphocytes and macrophages. Cytokines, particularly tumor necrosis factor- (TNF-) and transforming growth factor- (TGF-), are also important in the inflammatory process by leading to inflammation, fibrosis, and ossification at sites of enthesitis. The IL-23/IL-17 axis is also important in the spondyloarthropathies including the induction of Th17 cells and the production of the proinflammatory cytokine IL-17.

• #4 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  HLA-B27 heavy chains tend to form homodimers without 2m via the disulfide bonds of the cysteine at C67. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] In AS, the first indication of IL-23/IL-17 relevance came from a GWAS study in 2007 that identified an IL-23 receptor (IL-23R) SNP related to AS pathogenesis. […] Dysfunction of the IL-23/IL-17 pathway was identified in many diseases related to human immunological procedures, including psoriasis, IBD, rheumatoid arthritis and SpA; additionally, IL-17 and IL-23 act as major cytokines for axSpA and psoriatic arthritis. […] Studies have shown higher serum levels of IL-23 and IL-17 and the presence of IL-17+ cells in the facet joints in AS patients, suggesting that the innate immune system might be of greater relevance. […] The IL-23/IL-17 axis causes inflammatory molecule secretion from fibroblasts, endothelial cells, DCs or macrophages, which induce joint destruction and inflammation that are observed in both rheumatoid arthritis and AS.

• #4 A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

  https://www.mdpi.com/1422-0067/17/12/2126

  Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. […] A growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. […] The role of gut microbiome in AS pathogenesis is also suggested by many studies, and AS can be associated with IBD. […] Evidence from animal models indicates that, when raised in a germfree environment, HLA-B27 transgenic rats fail to develop inflammatory peripheral joint or intestinal disease. However, upon receiving transfer of the common gut bacteria bacteroides, the disease occurred.

• #4 Pathogenesis of ankylosing spondylitis. | Sigma-Aldrich

  https://www.sigmaaldrich.com/AT/de/tech-docs/paper/e3bfa0bddb5b3cc0c44babe541e685db?srsltid=AfmBOooileDepyiVO7z8AkToJTIPSFkMcwFCq4caGNfVn2AM_CjpX3tf

  Ankylosing spondylitis (AS) is a potentially disabling form of seronegative spondyloarthritis. The pathology mainly affects the entheses, where ligaments, tendons and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion and syndesmophyte (spur) formation. Tumor necrosis factor is an important mediator of the inflammatory processes, but this proinflammatory cytokine is not closely involved in bone erosion or syndesmophyte formation. The major causative factors of AS are genetic, with the gene encoding HLA-B27 being the most important genetic factor. Several other susceptibility genes have also been identified. […] An enormous number of papers have been published and many diverse hypotheses have been generated regarding the pathogenesis of AS. This Review outlines the key areas of current research in this field, describes several hypotheses regarding the pathogenesis of AS, which are under intense investigation, and concludes with a dissection of the processes involved in bone erosion and syndesmophyte formation.

• #4 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1064241

  Besides the genetic background, environmental triggers such as microorganisms and mechanical stress are emerging as initiating and perpetuating factors for AS. […] Current concepts regard new bone formation at the enthesis as a pathological response to biomechanical stress and microbial consequences such as dysbiosis in gut inflammation.

• #4 Pathogenesis of ankylosing spondylitis — recent advances and future directions | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2017.56

  More than 100 genetic loci have been associated with ankylosing spondylitis (AS), but together they explain less than 30% of AS heritability. […] Multiple genes involved in antigen processing and presentation are associated with AS. […] Investigation into the cellular sources and regulation of IL-17 production is crucial to understanding the pathogenesis of AS. […] Cells involved in type 3 immunity produce IL-17 and include innate lymphoid cells and T cells. […] Given the efficacy of the anti-IL-17 monoclonal antibody secukinumab in the treatment of AS, other therapies targeting type 3 immunity could also be effective. […] In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

• #5 Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis | RMD Open

  https://rmdopen.bmj.com/content/9/3/e003102

  Key pathways identified include aminopeptidases (ERAP) and interleukin (IL)-23 but multiple other pathways have been reported. […] The chances of an HLA B27+ individual to develop AS in a lifetime are only 1%2%. […] The combination of HLA B60 with HLA B27 increases chances of developing AS by 36 times. […] The relationship between various ethnicities and the prevalence of HLA B27 is well known, and the prevalence of AS is closely related. […] The introduction of HLA B27 and human 2-microglobulin genes into a species of rats known to be quite susceptible to experimentally induced inflammatory disease has drawn a lot of intention more than 30 years ago because the pattern of organ system involvement with the gastrointestinal tract, peripheral and vertebral joints, the male genital tract, skin, nails and the heart showed a striking resemblance to HLA B27-associated human diseases. […] In conclusion of this part, the pathogenetic background of the strong HLA association of AS has not been fully elucidated to date. Recent findings have rather supported the arthritogenic peptide hypothesis.

• #5

  https://www.healio.com/clinical-guidance/ankylosing-spondylitis/etiology-and-pathogenesis

  This suggests that T cells expressing the disease associated TCRs have undergone clonal expansion in the inflamed tissues. […] Studies beginning as far back as 45 years ago have indicated genotypic influence of HLA-B27 on clinical phenotype of AS, exemplified by the difference between HLA-B27(+) and HLA-B27(-) patients. […] The above-mentioned 35-year follow-up study of axSpA patients and their first-degree relative (FDR) also observed an increased prevalence of discomfort of possibly inflammatory origin among healthy (never diagnosed) HLA-B27(+) relatives, with up to 25% experiencing at least one symptom, compared to 9% among healthy HLA-B27(-) relatives. […] Other genes, including, HLA-B40, HLA-B47, HLA-B51, HLA-A2 and DRB1*0103 also show some increased risk for AS, whereas HLA-B7 and HLA-B57 may have some protective effect.

• #5 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  HLA-B27 heavy chains tend to form homodimers without 2m via the disulfide bonds of the cysteine at C67. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] In AS, the first indication of IL-23/IL-17 relevance came from a GWAS study in 2007 that identified an IL-23 receptor (IL-23R) SNP related to AS pathogenesis. […] Dysfunction of the IL-23/IL-17 pathway was identified in many diseases related to human immunological procedures, including psoriasis, IBD, rheumatoid arthritis and SpA; additionally, IL-17 and IL-23 act as major cytokines for axSpA and psoriatic arthritis. […] Studies have shown higher serum levels of IL-23 and IL-17 and the presence of IL-17+ cells in the facet joints in AS patients, suggesting that the innate immune system might be of greater relevance. […] The IL-23/IL-17 axis causes inflammatory molecule secretion from fibroblasts, endothelial cells, DCs or macrophages, which induce joint destruction and inflammation that are observed in both rheumatoid arthritis and AS.

• #5 A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

  https://www.mdpi.com/1422-0067/17/12/2126

  Taken together, multiple lines of evidence firmly implicate intestinal microbiome as a possible contributor to the pathogenesis of AS. […] While evidence for the role of the gut microbiota in the AS progression is mounting, several mechanisms have been suggested to explain the role of microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. […] The major challenges now remain to confirm the role of microbiota in AS, and to investigate how the microbiome shapes the immune response and influences both local and systemic inflammation.

• #5 Ankylosing spondylitis pathogenesis | PPT

  https://www.slideshare.net/slideshow/ankylosing-spondylitis-pathogenesis/32264058

  21) Patients usually present with low back pain and stiffness, which improves with activity Decreased range of motion in lumbar spine Thoraco-cervical kyphosis (late) One-third of patients will have acute, unilateral uveitis […] 22) Pseudoarthrosis (Anderson lesion), cervical spine fracture, C1-C2 subluxation, cauda equina syndrome Peripheral joint ankylosis Restrictive lung disease, upper lobe fibrosis Aortic root dilation (20%) murmur (2%) […] #12: Tumor Necrosis Factor: Functions of the Proinflammatory Cytokine TNF is a proinflammatory cytokine. Its functions include: Stimulation of endothelial cells to express adhesion molecules Recruitment of white blood cells in inflamed synovium and skin Induction of inflammatory cytokine production (eg, IL-1, IL-6) Stimulation of synovial cells to release collagenases Induction of bone and cartilage resorption Stimulation of fibroblast proliferation […] #13: Pathogenesis of Joint Destruction TNF has been identified as a key role player in the pathogenesis of chronic inflammatory diseases, including AS, and appears to have a central role in the pathogenesis of joint destruction as illustrated.

• #5 Ankylosing Spondylitis Pathogenesis and Pathophysiology | IntechOpen

  https://www.intechopen.com/chapters/85619

  Theories and emerging evidence in the literature are reviewed. […] Autoimmune vs. autoinflammatory immunological features involved in AS pathogenesis and the interplay between disturbances of the gut microbiome, including by infection and diet leading to altered immune response. The IL-17-23 and IL-12 pathways are discussed in some details. […] The complex dynamic relationship involved with inflammatory cytokines in the development of AS includes the IL17/23 axis, which is the most well studied of these pathways, but IL6, IL10, IL22 and tumour necrosis factor are also recognised as contributing to chronic inflammation. Other inflammatory cytokines have been postulated as playing a role including IL37, but the facts remain that the detailed mechanisms are unknown. […] Strong evidence suggests a central role of IL-17 secreting T cells in the pathogenesis of AS.

• #6 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  Genetic factors have been acknowledged as crucial in the genesis of AS. […] One of the most important genetic factors is major histocompatibility complex (MHC) class I allele HLA-B27, which was discovered in 1973. […] Despite the unclear pathomechanism, HLA-B27 has been associated with the prevalence of AS in different populations around the world. […] The familial tendency of AS was remarkable with relative risks of 94, 25, and 4 for first-, second-, and third-degree relatives, respectively. […] The human MHC, also called the HLA complex, belongs to the cell-surface proteins acting in the process of acquired immunity. […] HLA-B27, basically belonging to the MHC-I surface protein encoded by the MHC B gene on chromosome 6, is the most essential gene that predisposes an individual to AS.

• #6 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  The connection between HLA-B27 and AS has not yet been fully elucidated, although it is widely accepted that the entire intracellular process of HLA-B27 formation needs to be considered. […] The molecular mimicry hypothesis posits that the antigenic components of infectious bacterial pathogens partially resembling or cross-reacting with HLA molecules can stimulate CD8+ T lymphocytes, followed by responding to one HLAB27 relevant selfpeptide or the peptides directly produced by HLAB27. […] These cross-reactions give rise to an amount of antibacterial antibodies that link to HLA molecules on immunocytes, chondrocytes and fibroblasts, further triggering a cascade of inflammatory reactions with the amount of cytokines, complement proteins, proteinases and the like produced. […] The mature HLA-B27 complex is a quaternary structure with three important components.

• #6 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  The mature HLA-B27 complex is a quaternary structure with three important components. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] The binding of KIR3DL2 with HLA-B27 homodimers was revealed to stimulate the survival and differentiation of KIR3DL2+CD4+ T lymphocytes in patients with SpA. […] The IL-23/IL-17 pathway plays a crucial role in the development of the disease. […] In AS, differentiated T lymphocytes can generate IL-17 and then trigger osteoclast activation, thus suppressing bone regeneration. […] The pathogenesis of AS is very complex. Current studies suggest that it may be the result of a variety of complicated mechanisms.

• #6

  https://www.healio.com/clinical-guidance/ankylosing-spondylitis/etiology-and-pathogenesis

  A molecular mimicry hypothesis proposes that HLA-B27 itself becomes autoantigenic due to its sequence homology with certain bacterial proteins. […] As discussed later, accumulation of misfolded HLA-B27 in the endoplasmic reticulum (ER) can cause intracellular stress, unfolded protein response (UPR) and autophagy that lead to proinflammatory events. […] Moreover, modification of gut microbiome and intracellular microbial-handling of putative arthritogenic organisms by HLA-B27 that can result in an aberrant or impaired immune response in conjunction with an upregulated production of cytokines, such as IL-23, that leads to AS or related spondyloarthritis (SpA). […] The arthritogenic peptide hypothesis has been strongly revived by new data. […] The strongest evidence to date for this hypothesis has now been published by Yang and colleagues.

• #6 Insights into the pathogenesis of ankylosing spondylitis | JIR

  https://www.dovepress.com/fibroblast-insights-into-the-pathogenesis-of-ankylosing-spondylitis-peer-reviewed-fulltext-article-JIR

  Emerging evidence has shown that ankylosing spondylitis fibroblasts (ASFs) act as crucial participants in inflammation and abnormal ossification in ankylosing spondylitis (AS). […] ASFs organize immune functions by recruiting immune cells and influencing their differentiation and activation, thus mediate the inflammatory response in the early phase of disease. […] ASFs promote joint destruction at sites of cartilage and actively promote abnormal ossification by recruiting osteoblasts, differentiation into myofibroblasts or ossification directly. […] Many signaling pathways and cytokines such as Wnt signaling and BMP/TGF- signaling are involved in ASF ossification. […] ASFs play a key role in AS inflammation and osteogenesis. […] This suggests that ankylosing spondylitis fibroblasts (ASFs) may play a crucial role in the etiology of AS.

• #6 A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis

  https://www.mdpi.com/1422-0067/17/12/2126

  Taken together, multiple lines of evidence firmly implicate intestinal microbiome as a possible contributor to the pathogenesis of AS. […] While evidence for the role of the gut microbiota in the AS progression is mounting, several mechanisms have been suggested to explain the role of microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. […] The major challenges now remain to confirm the role of microbiota in AS, and to investigate how the microbiome shapes the immune response and influences both local and systemic inflammation.

• #7 Ankylosing spondylitis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/ankylosing-spondylitis/

  Ankylosing spondylitis is likely caused by a combination of genetic and environmental factors, most of which have not been identified. […] The HLA-B gene provides instructions for making a protein that plays an important role in the immune system. […] A normal variant of the HLA-B gene called HLA-B27 significantly increases the risk of developing ankylosing spondylitis. […] Variations in several additional genes, including ERAP1, IL1A, and IL23R, have also been associated with ankylosing spondylitis. […] Changes in genes that have not yet been identified also likely affect the chances of developing ankylosing spondylitis and influence the progression of the disorder. […] It is not fully known how HLA-B27 increases the risk of developing ankylosing spondylitis.

• #7 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  The connection between HLA-B27 and AS has not yet been fully elucidated, although it is widely accepted that the entire intracellular process of HLA-B27 formation needs to be considered. […] The molecular mimicry hypothesis posits that the antigenic components of infectious bacterial pathogens partially resembling or cross-reacting with HLA molecules can stimulate CD8+ T lymphocytes, followed by responding to one HLAB27 relevant selfpeptide or the peptides directly produced by HLAB27. […] These cross-reactions give rise to an amount of antibacterial antibodies that link to HLA molecules on immunocytes, chondrocytes and fibroblasts, further triggering a cascade of inflammatory reactions with the amount of cytokines, complement proteins, proteinases and the like produced. […] The mature HLA-B27 complex is a quaternary structure with three important components.

• #7 Pathogenesis of ankylosing spondylitis — recent advances and future directions | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2017.56

  More than 100 genetic loci have been associated with ankylosing spondylitis (AS), but together they explain less than 30% of AS heritability. […] Multiple genes involved in antigen processing and presentation are associated with AS. […] Investigation into the cellular sources and regulation of IL-17 production is crucial to understanding the pathogenesis of AS. […] Cells involved in type 3 immunity produce IL-17 and include innate lymphoid cells and T cells. […] Given the efficacy of the anti-IL-17 monoclonal antibody secukinumab in the treatment of AS, other therapies targeting type 3 immunity could also be effective. […] In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

• #7 Insights into the pathogenesis of ankylosing spondylitis | JIR

  https://www.dovepress.com/fibroblast-insights-into-the-pathogenesis-of-ankylosing-spondylitis-peer-reviewed-fulltext-article-JIR

  Fibroblasts are now thought to organize immune functions by recruiting immune cells and influencing their differentiation and activation. […] The mediation of bone erosion is illustrated by ASFs secretion of RANKL as mesenchymal cells, which directly induces osteoclast development and bone resorption when binding to RANK. […] In vitro ASF ossification research, Wnt signaling and BMP/TGF- signaling are proved to be the major factors. […] ASFs may also play a key role in the abnormal bone proliferation of AS. […] The study of Yeremenko et al suggested that ASFs participation in bone remodeling is mostly independent from the inflammatory environment and instead seems to be caused by an intrinsic transcriptional signature. […] Recent studies have shown that ASFs have the potential for osteogenic differentiation themselves, either by observation at the tissue level or by isolated cultures of fibroblasts from patients.

• #7 An Actual Insight into the Pathogenic Pathways of Ankylosing Spondylitis

  https://www.mdpi.com/1467-3045/46/11/762

  Mechanical stress is an important factor in triggering SpA, which occurs at the entheses, the insertion points of tendons, ligaments, and the capsule into the bone. […] Under stressful conditions, such as mechanical stress, gut microbiome changes, or environmental factors, AS is linked to chronic inflammation that involves dendritic cells, macrophages, NK cells, and adaptive immune cells. […] The dysfunction of the IL-23/IL-17 pathway has been observed in various autoimmune disorders, including psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), and spondylarthritis (SpA). […] In immune-mediated rheumatic diseases, vitamin D plays a protective role, and vitamin D deficiency has been considered a risk factor associated with more severe disease. […] Knowing the pathophysiological mechanism that contributes to the onset and progression of AS is important for understanding the varied responses to therapies among individuals and is crucial in searching new solutions.

• #8 Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis | RMD Open

  https://rmdopen.bmj.com/content/9/3/e003102

  Key pathways identified include aminopeptidases (ERAP) and interleukin (IL)-23 but multiple other pathways have been reported. […] The chances of an HLA B27+ individual to develop AS in a lifetime are only 1%2%. […] The combination of HLA B60 with HLA B27 increases chances of developing AS by 36 times. […] The relationship between various ethnicities and the prevalence of HLA B27 is well known, and the prevalence of AS is closely related. […] The introduction of HLA B27 and human 2-microglobulin genes into a species of rats known to be quite susceptible to experimentally induced inflammatory disease has drawn a lot of intention more than 30 years ago because the pattern of organ system involvement with the gastrointestinal tract, peripheral and vertebral joints, the male genital tract, skin, nails and the heart showed a striking resemblance to HLA B27-associated human diseases. […] In conclusion of this part, the pathogenetic background of the strong HLA association of AS has not been fully elucidated to date. Recent findings have rather supported the arthritogenic peptide hypothesis.

• #8 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  Genetic factors have been acknowledged as crucial in the genesis of AS. […] One of the most important genetic factors is major histocompatibility complex (MHC) class I allele HLA-B27, which was discovered in 1973. […] Despite the unclear pathomechanism, HLA-B27 has been associated with the prevalence of AS in different populations around the world. […] The familial tendency of AS was remarkable with relative risks of 94, 25, and 4 for first-, second-, and third-degree relatives, respectively. […] HLA-B27 has a high degree of polymorphism. […] HLA-B27 tends to fold slower than other HLA alleles, and without proper folding, these defective HLA-B27 proteins continually gather in the ER. […] Improperly folded HLA-B27 proteins accumulate in the ER and activate autophagy and the interleukin (IL)-23/IL-17 pathway.

• #8 Insights into the pathogenesis of ankylosing spondylitis | JIR

  https://www.dovepress.com/fibroblast-insights-into-the-pathogenesis-of-ankylosing-spondylitis-peer-reviewed-fulltext-article-JIR

  Emerging evidence has shown that ankylosing spondylitis fibroblasts (ASFs) act as crucial participants in inflammation and abnormal ossification in ankylosing spondylitis (AS). […] ASFs organize immune functions by recruiting immune cells and influencing their differentiation and activation, thus mediate the inflammatory response in the early phase of disease. […] ASFs promote joint destruction at sites of cartilage and actively promote abnormal ossification by recruiting osteoblasts, differentiation into myofibroblasts or ossification directly. […] Many signaling pathways and cytokines such as Wnt signaling and BMP/TGF- signaling are involved in ASF ossification. […] ASFs play a key role in AS inflammation and osteogenesis. […] This suggests that ankylosing spondylitis fibroblasts (ASFs) may play a crucial role in the etiology of AS.

• #8 Cited

  https://koreamed.org/SearchBasic.php?RID=2222907

  Besides the genetic background, environmental triggers such as microorganisms and mechanical stress are emerging as initiating and perpetuating factors for AS. […] Current concepts regard new bone formation at the enthesis as a pathological response to biomechanical stress and microbial consequences such as dysbiosis in gut inflammation. […] The recent key role of interleukin (IL)-23 mediated cascade leads to an inflammation driven concept to the disease with new bone formation. […] Cells of both innate and adaptive immune cells are implicated in the pathogenesis of AS.

• #9 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  Genetic factors have been acknowledged as crucial in the genesis of AS. […] One of the most important genetic factors is major histocompatibility complex (MHC) class I allele HLA-B27, which was discovered in 1973. […] Despite the unclear pathomechanism, HLA-B27 has been associated with the prevalence of AS in different populations around the world. […] The familial tendency of AS was remarkable with relative risks of 94, 25, and 4 for first-, second-, and third-degree relatives, respectively. […] HLA-B27 has a high degree of polymorphism. […] HLA-B27 tends to fold slower than other HLA alleles, and without proper folding, these defective HLA-B27 proteins continually gather in the ER. […] Improperly folded HLA-B27 proteins accumulate in the ER and activate autophagy and the interleukin (IL)-23/IL-17 pathway.

• #9 Preosteoclast plays a pathogenic role in syndesmophyte formation of ankylosing spondylitis through the secreted PDGFB — GRB2/ERK/RUNX2 pathway | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-023-03142-3

  Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the sacroiliac joint and spine. However, the real mechanisms of immune cells acting on syndesmophyte formation in AS are not well identified. We aimed to find the key AS-associated cytokine and assess its pathogenic role in AS. […] The PDGF pathway was observed to have abnormal expression in the protein array, and PDGFB expression was further found to be up-regulated in 140 Chinese AS patients. Importantly, PDGFB expression was significantly correlated with BASFI (Pearson coefficient/p value=0.62/6.70E8) and with the variance of the mSASSS score (mSASSS 2 years baseline, Pearson coefficient/p value=0.76/8.75E10). In AS patients, preosteoclasts secreted more PDGFB than the healthy controls (p value=1.16E2), which could promote ADSCs osteogenesis and enhance collagen synthesis (COLI and COLIII) of osteoblasts (hFOB 1.19).

• #9 Ankylosing Spondylitis Pathogenesis and Pathophysiology | IntechOpen

  https://www.intechopen.com/chapters/85619

  The pathogenesis and pathophysiology of Ankylosing Spondylitis (AS) is complex and remains only partially understood. Contributory genes including a variety of HLA-B27 subset genes and many other non-HLA genes are implicated in the literature. Dysregulation of the enteric microbiome with a corresponding aberrant immunological response is recognised in research. Certain infectious agents are thought to play a role. A variety of other influences including environmental exposures, dietary and lifestyle factors and sex hormones appear to play a role in AS pathogenesis. There is emerging evidence that that pathophysiological response in AS is an elaborate combination of both autoinflammatory and autoimmune components, however the IL-17/IL-23 pathway remains the major pathway in AS according to studies to date. The specific mechanisms that lead to characteristic clinical features of AS including sacroiliitis, spondylitis, ankylosis, uveitis and other extra articular manifestations remain occult. Further research to establish these is ongoing.

• #10

  https://www.healio.com/clinical-guidance/ankylosing-spondylitis/etiology-and-pathogenesis

  A molecular mimicry hypothesis proposes that HLA-B27 itself becomes autoantigenic due to its sequence homology with certain bacterial proteins. […] As discussed later, accumulation of misfolded HLA-B27 in the endoplasmic reticulum (ER) can cause intracellular stress, unfolded protein response (UPR) and autophagy that lead to proinflammatory events. […] Moreover, modification of gut microbiome and intracellular microbial-handling of putative arthritogenic organisms by HLA-B27 that can result in an aberrant or impaired immune response in conjunction with an upregulated production of cytokines, such as IL-23, that leads to AS or related spondyloarthritis (SpA). […] The arthritogenic peptide hypothesis has been strongly revived by new data. […] The strongest evidence to date for this hypothesis has now been published by Yang and colleagues.

• #10 Preosteoclast plays a pathogenic role in syndesmophyte formation of ankylosing spondylitis through the secreted PDGFB — GRB2/ERK/RUNX2 pathway | Arthritis Research & Therapy | Full Text

  https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-023-03142-3

  PDGFB stimulates the GRB2/ERK/RUNX2 pathway in ADSCs, promotes osteoblastogenesis of ADSCs, and enhances the extracellular matrix of osteoblasts, which may contribute to pathological bone formation in AS. […] PDGFB was elevated in plasma in AS patients than in healthy controls. Excessive PDGFB was secreted from preosteoclast and could promote osteogenesis of ADSCs by activating the GRB2/p-ERK/RUNX2 pathways. PDGFB enhanced the extracellular matrix of osteoblasts and may contribute to syndesmophyte formation. […] PDGFB promotes the osteoblastogenesis of ADSCs, activates the GRB2/ERK/RUNX2 pathway in ADSCs, and enhances the extracellular matrix of preosteoblasts, which may contribute to pathological bone formation. This previously unrecognized pathogenic mechanism of PDGFB provides the potential for a novel therapeutic target to treat inflammatory spinal damage in AS.

• #10 Ankylosing Spondylitis – Musculoskeletal and Connective Tissue Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/ankylosing-spondylitis

  The earliest abnormalities on radiographs are pseudo-widening caused by subchondral erosions, followed by sclerosis or later narrowing and eventually fusion in the sacroiliac joints. […] Changes typical of ankylosing spondylitis may not become visible on radiographs for years. MRI shows changes earlier, but there is no consensus regarding its role in routine diagnosis given the lack of prospective, validated data in regard to its diagnostic utility. […] The goals of treatment are relieving pain, maintaining joint range of motion, and preventing end-organ damage. […] TNF inhibitors (eg, etanercept, infliximab, adalimumab, certolizumab, golimumab) are often strikingly effective for inflammatory back pain. […] Secukinumab, an IL-17 inhibitor, is effective in reducing inflammation and joint symptoms.

• #11 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  The connection between HLA-B27 and AS has not yet been fully elucidated, although it is widely accepted that the entire intracellular process of HLA-B27 formation needs to be considered. […] The molecular mimicry hypothesis posits that the antigenic components of infectious bacterial pathogens partially resembling or cross-reacting with HLA molecules can stimulate CD8+ T lymphocytes, followed by responding to one HLAB27 relevant selfpeptide or the peptides directly produced by HLAB27. […] These cross-reactions give rise to an amount of antibacterial antibodies that link to HLA molecules on immunocytes, chondrocytes and fibroblasts, further triggering a cascade of inflammatory reactions with the amount of cytokines, complement proteins, proteinases and the like produced. […] The mature HLA-B27 complex is a quaternary structure with three important components.

• #11 Ankylosing Spondylitis – Musculoskeletal and Connective Tissue Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/ankylosing-spondylitis

  JAK inhibitors (eg, upadacitinib, tofacitinib) are targeted synthetic disease-modifying antirheumatic drugs (DMARDs) that may be used after patients have demonstrated an inadequate response to NSAIDs. […] Ankylosing spondylitis is characterized by mild or moderate flares of active inflammation alternating with periods of little or no inflammation. Proper treatment in most patients results in minimal or no disability and in a full, productive life despite back stiffness.

• #12 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  HLA-B27 heavy chains tend to form homodimers without 2m via the disulfide bonds of the cysteine at C67. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] In AS, the first indication of IL-23/IL-17 relevance came from a GWAS study in 2007 that identified an IL-23 receptor (IL-23R) SNP related to AS pathogenesis. […] Dysfunction of the IL-23/IL-17 pathway was identified in many diseases related to human immunological procedures, including psoriasis, IBD, rheumatoid arthritis and SpA; additionally, IL-17 and IL-23 act as major cytokines for axSpA and psoriatic arthritis. […] Studies have shown higher serum levels of IL-23 and IL-17 and the presence of IL-17+ cells in the facet joints in AS patients, suggesting that the innate immune system might be of greater relevance. […] The IL-23/IL-17 axis causes inflammatory molecule secretion from fibroblasts, endothelial cells, DCs or macrophages, which induce joint destruction and inflammation that are observed in both rheumatoid arthritis and AS.

• #12 A review of the pathogenesis of ankylosing spondylitis in: Neurosurgical Focus Volume 24 Issue 1 (2008) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/24/1/article-pE2.xml

  Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease involving primarily the sacroiliac joints and the axial skeleton. The current understanding of the pathogenesis of this disorder is limited. Despite the strong association between human leukocyte antigen B27 (HLA-B27) and susceptibility to AS reported over the past 30 years, the exact pathogenic role of HLA-B27 in AS and other spondyloarthropathies has yet to be determined. […] Ankylosing spondylitis is a polygenic disorder, with HLA-B27 playing a critical causative role in its pathogenesis. […] Over the past decade there has been increasing interest in the critical role of the misfolding and unfolded protein response of the heavy chain HLA-B27 in the modulation of the inflammatory response. […] Although there have been significant new findings in the understanding of the pathogenesis of AS, the exact mechanisms have yet to be identified.

• #13 Ankylosing spondylitis: etiology, pathogenesis, and treatments | Bone Research

  https://www.nature.com/articles/s41413-019-0057-8

  HLA-B27 heavy chains tend to form homodimers without 2m via the disulfide bonds of the cysteine at C67. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] In AS, the first indication of IL-23/IL-17 relevance came from a GWAS study in 2007 that identified an IL-23 receptor (IL-23R) SNP related to AS pathogenesis. […] Dysfunction of the IL-23/IL-17 pathway was identified in many diseases related to human immunological procedures, including psoriasis, IBD, rheumatoid arthritis and SpA; additionally, IL-17 and IL-23 act as major cytokines for axSpA and psoriatic arthritis. […] Studies have shown higher serum levels of IL-23 and IL-17 and the presence of IL-17+ cells in the facet joints in AS patients, suggesting that the innate immune system might be of greater relevance. […] The IL-23/IL-17 axis causes inflammatory molecule secretion from fibroblasts, endothelial cells, DCs or macrophages, which induce joint destruction and inflammation that are observed in both rheumatoid arthritis and AS.

• #14 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  The mature HLA-B27 complex is a quaternary structure with three important components. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] The binding of KIR3DL2 with HLA-B27 homodimers was revealed to stimulate the survival and differentiation of KIR3DL2+CD4+ T lymphocytes in patients with SpA. […] The IL-23/IL-17 pathway plays a crucial role in the development of the disease. […] In AS, differentiated T lymphocytes can generate IL-17 and then trigger osteoclast activation, thus suppressing bone regeneration. […] The pathogenesis of AS is very complex. Current studies suggest that it may be the result of a variety of complicated mechanisms.

• #15 Ankylosing spondylitis: etiology, pathogenesis, and treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6804882/

  The mature HLA-B27 complex is a quaternary structure with three important components. […] The hypothesis of cell-surface HLAB27 homodimer formation suggests that HLA-B27 dimers might contribute to the development of AS. […] The binding of KIR3DL2 with HLA-B27 homodimers was revealed to stimulate the survival and differentiation of KIR3DL2+CD4+ T lymphocytes in patients with SpA. […] The IL-23/IL-17 pathway plays a crucial role in the development of the disease. […] In AS, differentiated T lymphocytes can generate IL-17 and then trigger osteoclast activation, thus suppressing bone regeneration. […] The pathogenesis of AS is very complex. Current studies suggest that it may be the result of a variety of complicated mechanisms.

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