Materiały źródłowe

• #1 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. […] This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. […] The heterogeneity of JIA disease subtypes adds complexity to the investigation of cause and mechanism of pathogenesis, and the initiating factors of JIA remain unresolved. […] Environmental factors, including infectious agents, vaccinations, antibiotics, vitamin D deficiency, stress and trauma have been proposed as risk factors. […] The pathogenesis of ERA is driven by HLA-B27-mediated presentation of arthritogenic peptide following T-cell activation and IL23 and IL17 secretion.

• #2 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16 and lasting 6 weeks or longer. […] The cause and trigger of chronic arthritis in JIA remain unclear. Abnormal immune responses triggered by the interactions between environmental factors in a genetically susceptible individual are speculative. […] Based on familial aggregation studies and the concordance rate of 25% to 40% in monozygotic twins, genetic factors play a significant role. […] The imbalance of regulatory T cells, Th1 (interferon-gamma secreting T cells), and Th17 (interleukin -17 secreting T cells) of adaptive immunity is the feature of most subtypes of JIA. IL-17 induces proinflammatory cytokines and matrix metalloproteinases, leading to joint damage in oligoarthritis, polyarthritis, and psoriatic arthritis.

• #3 Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis

  https://www.mdpi.com/1422-0067/24/3/1846

  Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in the paediatric population. […] Despite significant improvements over the past decade, the aetiology and molecular mechanisms of JIA remain unclear. It has been suggested that the immunopathogenesis is characterised by complex interactions between genetic background and environmental factors that may differ between JIA subtypes. Human leukocyte antigen (HLA) haplotypes and non-HLA genes play a crucial role in the abnormal activation of both innate and adaptive immune cells that cooperate in causing the inflammatory process. […] The pathogenesis of JIA is characterised by a disrupted balance between regulatory cells, mostly represented by T regulatory (T reg) cells, and effector cells, that include CD4+ T helper (Th) cells, such as Th1 and Th17. This disequilibrium is caused by complex interactions between genetic and environmental factors, and nowadays the literature is showing a growing interest in this field.

• #4

  https://journals.lww.com/md-journal/fulltext/2024/03290/advancements_and_progress_in_juvenile_idiopathic.70.aspx

  Juvenile idiopathic arthritis (JIA) is a chronic clinical condition characterized by arthritic features in children under the age of 16, with at least 6 weeks of active symptoms. The etiology of JIA remains unknown, and it is associated with prolonged synovial inflammation and structural joint damage influenced by environmental and genetic factors. […] The pathophysiology of JIA remains idiopathic, impeding the development of a definitive diagnostic algorithm and the identification of molecular biomarkers that could aid in early diagnosis. […] The pathophysiology of JIA involves an autoimmune response where the body’s immune system attacks its own cells. This process is driven by interactions among immune cells, such as lymphocytes, monocytes, macrophages, and neutrophils, along with pro-inflammatory cytokines like interleukins (IL) as shown in Figure 2. These interactions lead to an inflammatory response characteristic of JIA.

• #5 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  JIA subtypes represent a heterogeneous group of diseases with multifactorial and different pathogenesis. […] It is not completely understood how the combination of the environmental triggers and genetic susceptibility disrupt the balance between regulatory and effector cells in the pathogenesis of JIA. […] Initiation of the JIA pathophysiological cascade includes abnormal activation of T-cells, B-cells, natural killer (NK) cells, dendritic cells (DC), macrophages and neutrophils and the production of pro-inflammatory mediators that cause joint destruction and systemic complications. […] Inflammation is considered to be a consequence of disrupted balance between pro-inflammatory Th1/Th17 and anti-inflammatory regulatory T-cells (Treg). […] The collective data available to date, suggests that cytokine patterns may be appropriate for accurate disease classification in early JIA with the potential as targets for improving diagnosis and treatment strategies for patients with paediatric autoimmune disease.

• #6 Overview of Juvenile Idiopathic Arthritis

  https://openorthopaedicsjournal.com/VOLUME/14/PAGE/101/FULLTEXT/

  There is likely a complex interplay of genetic susceptibility, environmental triggers, and a disordered immune response that leads to the development of JIA. However, the exact pathogenesis is unknown, and it is likely that the pathogenesis of each subtype differs. […] Most obviously different is the pathophysiology of systemic JIA. It has distinct clinical manifestations and an inflammatory immune response with elevations of cytokines, such as IL-1 and IL-18. Systemic JIA more closely resembles an autoinflammatory disease. […] It is hypothesized that an environmental exposure in a genetically susceptible child leads to an altered immune response. The genetics of JIA have been extensively studied, and it is likely a polygenic disease. […] Furthermore, multiple studies have described an association between HLA alleles and both oligoarticular and polyarticular JIA.

• #7 Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis

  https://www.mdpi.com/1422-0067/24/3/1846

  This disrupted immune balance results in an increased production of proinflammatory cytokines, such as IL-17, and the subsequent joint damage due to expression of MMPs and IL-6 by synoviocytes. […] The pathophysiology of JIA is characterised by a strong genetic background. […] The development of innovative approaches for the analysis of conventional HLA alleles from genotyping array data is providing more detailed knowledge of the JIA molecular background. […] The important HLA contribution to JIA development is estimated at a rate of around 20%. […] The largest study evaluating the connection between HLA haplotypes and JIA subtypes evidenced both differences and similarities across the various forms of the disease. […] These findings help to better understand the pathogenesis of JIA and suggest that the current ILAR classification is not accurate enough and new classification criteria, giving more relevance to pathophysiological mechanisms and evidence-based improvements, are needed.

• #8 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16 and lasting 6 weeks or longer. […] The cause and trigger of chronic arthritis in JIA remain unclear. Abnormal immune responses triggered by the interactions between environmental factors in a genetically susceptible individual are speculative. […] Based on familial aggregation studies and the concordance rate of 25% to 40% in monozygotic twins, genetic factors play a significant role. […] The imbalance of regulatory T cells, Th1 (interferon-gamma secreting T cells), and Th17 (interleukin -17 secreting T cells) of adaptive immunity is the feature of most subtypes of JIA. IL-17 induces proinflammatory cytokines and matrix metalloproteinases, leading to joint damage in oligoarthritis, polyarthritis, and psoriatic arthritis.

• #9 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. […] The most well-established genetic factors for JRA are the HLA genes. […] Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. […] TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. […] The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type and the absence of autoantibodies and autoreactive T cells. […] Recent data indicate that IL-1 has a prominent role in systemic onset disease. […] The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement. […] The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4.

• #10 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. […] The most well-established genetic factors for JRA are the HLA genes. […] Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. […] TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. […] The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type and the absence of autoantibodies and autoreactive T cells. […] Recent data indicate that IL-1 has a prominent role in systemic onset disease. […] The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement. […] The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4.

• #11 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases. […] JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. […] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort). […] A study by Ombrello examined the MHC locus in a large collection of systemic juvenile idiopathic arthritis patients and verified the relationship between the class II HLA region and systemic juvenile idiopathic arthritis, implicating adaptive immune molecules in the pathogenesis of the disease.

• #12 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases. […] JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. […] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort). […] A study by Ombrello examined the MHC locus in a large collection of systemic juvenile idiopathic arthritis patients and verified the relationship between the class II HLA region and systemic juvenile idiopathic arthritis, implicating adaptive immune molecules in the pathogenesis of the disease.

• #13 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases. […] JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. […] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort). […] A study by Ombrello examined the MHC locus in a large collection of systemic juvenile idiopathic arthritis patients and verified the relationship between the class II HLA region and systemic juvenile idiopathic arthritis, implicating adaptive immune molecules in the pathogenesis of the disease.

• #14 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. […] This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. […] The heterogeneity of JIA disease subtypes adds complexity to the investigation of cause and mechanism of pathogenesis, and the initiating factors of JIA remain unresolved. […] Environmental factors, including infectious agents, vaccinations, antibiotics, vitamin D deficiency, stress and trauma have been proposed as risk factors. […] The pathogenesis of ERA is driven by HLA-B27-mediated presentation of arthritogenic peptide following T-cell activation and IL23 and IL17 secretion.

• #15 Early Identification of Juvenile Idiopathic Arthritis

  https://www.hcplive.com/view/early-identification-juvenile-idiopathic-arthritis

  The cause of JIA remains unknown, but it seems to result from a complex genetic trait with an immunoinflammatory pathogenesis, possibly influenced by external antigens. Abnormalities both cell-mediated (via inflammatory cells, cytokines, and activated T cells) and humoral (via autoantibodies) are implicated. The various phenotypes of the disease point toward interactions of multiple genes affecting immunity and inflammation. […] There are HLA associations for each JIA subtype, the strongest in children with oligoarticular disease. HLA-B27 may contribute to the disease pathogenesis via molecular mimicry among patients with enthesitis-related arthritis (ERA). […] Immune dysfunction in JIA is evident with the presence of autoantibodies, such as antinuclear antibodies (ANAs)-present in 40% of patients-and rheumatoid factor (RF)-present in 5% to 10% of patients. Although undoubtedly there are genetic predispositions to JIA, other contributing factors have been suggested, such as environmental agents, infectious vectors, trauma, psychological stress, and hormonal abnormalities.

• #16 Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis

  https://www.mdpi.com/1422-0067/24/3/1846

  This disrupted immune balance results in an increased production of proinflammatory cytokines, such as IL-17, and the subsequent joint damage due to expression of MMPs and IL-6 by synoviocytes. […] The pathophysiology of JIA is characterised by a strong genetic background. […] The development of innovative approaches for the analysis of conventional HLA alleles from genotyping array data is providing more detailed knowledge of the JIA molecular background. […] The important HLA contribution to JIA development is estimated at a rate of around 20%. […] The largest study evaluating the connection between HLA haplotypes and JIA subtypes evidenced both differences and similarities across the various forms of the disease. […] These findings help to better understand the pathogenesis of JIA and suggest that the current ILAR classification is not accurate enough and new classification criteria, giving more relevance to pathophysiological mechanisms and evidence-based improvements, are needed.

• #17 Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis

  https://www.mdpi.com/1422-0067/24/3/1846

  This disrupted immune balance results in an increased production of proinflammatory cytokines, such as IL-17, and the subsequent joint damage due to expression of MMPs and IL-6 by synoviocytes. […] The pathophysiology of JIA is characterised by a strong genetic background. […] The development of innovative approaches for the analysis of conventional HLA alleles from genotyping array data is providing more detailed knowledge of the JIA molecular background. […] The important HLA contribution to JIA development is estimated at a rate of around 20%. […] The largest study evaluating the connection between HLA haplotypes and JIA subtypes evidenced both differences and similarities across the various forms of the disease. […] These findings help to better understand the pathogenesis of JIA and suggest that the current ILAR classification is not accurate enough and new classification criteria, giving more relevance to pathophysiological mechanisms and evidence-based improvements, are needed.

• #18 Overview of Juvenile Idiopathic Arthritis

  https://openorthopaedicsjournal.com/VOLUME/14/PAGE/101/FULLTEXT/

  Genome-wide association studies have identified multiple single nucleotide polymorphisms that are associated with oligoarticular and RF negative polyarticular JIA, likely uniquely contributing to their pathogenesis. […] A possible theory for an environmental trigger is an infection as heat shock proteins are found to be elevated in JIA patients. However, no specific infection has yet been confirmed. Further studies are needed to describe the role of genetics and the environment in the pathogenesis of JIA.

• #19 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases. […] JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. […] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort). […] A study by Ombrello examined the MHC locus in a large collection of systemic juvenile idiopathic arthritis patients and verified the relationship between the class II HLA region and systemic juvenile idiopathic arthritis, implicating adaptive immune molecules in the pathogenesis of the disease.

• #20 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases. […] JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene. […] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort). […] A study by Ombrello examined the MHC locus in a large collection of systemic juvenile idiopathic arthritis patients and verified the relationship between the class II HLA region and systemic juvenile idiopathic arthritis, implicating adaptive immune molecules in the pathogenesis of the disease.

• #21

  https://journals.lww.com/md-journal/fulltext/2024/03290/advancements_and_progress_in_juvenile_idiopathic.70.aspx

  Multi-omics investigations have significantly contributed to the study of genetic and molecular mechanisms involved in the pathogenesis of JIA. […] The identification of monogenic variants of JIA has significantly improved our understanding of key molecular pathways, which is particularly important given the poorly understood causes of JIA and the ambiguities in its classification. […] Large-scale genotype-phenotype association studies have played a vital role in identifying genetic variants associated with JIA, enabling a deeper understanding of its etiology and pathogenesis. […] GWAS studies have identified multiple genetic loci that have been implicated in the pathogenesis of JIA. Genes such as protein tyrosine phosphatase non-receptor type 2 (PTPN2), protein tyrosine phosphatase non-receptor type 22 (PTPN22), TNF alpha induced protein 3 (TNFAIP3), and interleukin 2 receptor subunit alpha (IL2RA), involved in immune responses, have been reported to cause JIA. […] The interdisciplinary use of genetic association studies has provided a comprehensive overview of the pathogenesis and potential treatments for different JIA subtypes by comparing the genotypes of affected patients to healthy groups.

• #22

  https://journals.lww.com/md-journal/fulltext/2024/03290/advancements_and_progress_in_juvenile_idiopathic.70.aspx

  Multi-omics investigations have significantly contributed to the study of genetic and molecular mechanisms involved in the pathogenesis of JIA. […] The identification of monogenic variants of JIA has significantly improved our understanding of key molecular pathways, which is particularly important given the poorly understood causes of JIA and the ambiguities in its classification. […] Large-scale genotype-phenotype association studies have played a vital role in identifying genetic variants associated with JIA, enabling a deeper understanding of its etiology and pathogenesis. […] GWAS studies have identified multiple genetic loci that have been implicated in the pathogenesis of JIA. Genes such as protein tyrosine phosphatase non-receptor type 2 (PTPN2), protein tyrosine phosphatase non-receptor type 22 (PTPN22), TNF alpha induced protein 3 (TNFAIP3), and interleukin 2 receptor subunit alpha (IL2RA), involved in immune responses, have been reported to cause JIA. […] The interdisciplinary use of genetic association studies has provided a comprehensive overview of the pathogenesis and potential treatments for different JIA subtypes by comparing the genotypes of affected patients to healthy groups.

• #23

  https://link.springer.com/article/10.1007/s10067-021-05756-x

  Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. […] We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. […] The strongest associations in the All-JIA analysis were identified at PRKG1 (P=2,54106), LTBP1 (P=9,45106), and ELMO1 (P=1,05105). […] This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. […] The majority of reported associations appeared in genes encoding proteins that have roles in immune system regulation and/or MHC antigen processing and presentation.

• #24

  https://link.springer.com/article/10.1007/s10067-021-05756-x

  We identified 12 novel loci not previously implicated in genetics of JIA and/or JIA subtypes. […] The above-mentioned genes have roles in immune system regulation and/or major histocompatibility complex (MHC) antigen processing and presentation, apoptosis, and T cell receptor repertoire. […] The involvement of TGF-1/Smad signaling pathway in epithelial-mesenchymal transition and contribution to migration and invasion in RA FLSs were shown, warranting further studies of JIA FLSs. […] The results of this study further emphasize the role of common genetic variation and add to the understanding of the genomic architecture influencing the risk of oligoarticular and RF-negative polyarticular JIA in Estonian patients.

• #25 Review of environmental factors and juvenile idiopathic arthritis | OARRR

  https://www.dovepress.com/review-of-environmental-factors-and-juvenile-idiopathic-arthritis-peer-reviewed-fulltext-article-OARRR

  Juvenile idiopathic arthritis is a common rheumatic disease that presents as chronic childhood arthritis. JIA is considered a multifactorial disease that may result from diverse genetic and environmental risk factors. A minority of the population-attributable risk of JIA is estimated to be due to familial factors. Thus, non-genetic or environmental factors likely account for a majority of the risk of developing JIA. […] JIA is thought to originate from a complex interplay of non-Mendelian genetics and environmental influences leading to chronic inflammation of joints and other tissues. Familial epidemiologic studies and genome-wide association studies have produced estimates of the contribution of genetic factors to JIA ranging from 13% to 25%. […] Mechanistically, environmental influences may trigger JIA via several different mechanisms, including epigenetic changes, imbalance of microbiota, and direct modulation of the immune system.

• #26 Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthritis. | The Journal of Rheumatology

  https://www.jrheum.org/content/34/6/1336

  Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthritis. […] Our study confirms recent observations regarding a high prevalence of viral DNA in JIA patients and a possible role of this viral infection in JIA pathogenesis.

• #27 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  Some pediatric rheumatologists view systemic-onset JIA as an autoinflammatory disorder, such as familial Mediterranean fever (FMF) or cryopyrin-associated periodic fever syndromes, rather than a subtype of JIA. This theory is supported by work demonstrating similar expression patterns of a phagocytic protein (S100A12) in systemic-onset JIA and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists. […] FMF is associated with mutations in the MEFV gene; these mutations are associated with activation of the IL-1b pathway, resulting in inflammation. A study by Ayaz et al found an increased frequency of MEFV mutations in Turkish children who were diagnosed with systemic JIA; this study has not been replicated in other populations. […] In a nested casecontrol study of 153 children with juvenile arthritis and 1,530 matched controls, researchers found that exposure to antibiotics during childhood significantly increased the risk for developing JIA (adjusted odds ratio = 2.6) in a dose-dependent manner. Compared with those with no exposure, the odds ratio for developing JIA was 3.1 for children exposed to one or two courses of antibiotics, and for those exposed to three to five courses the odds ratio was 3.8.

• #28 Review of environmental factors and juvenile idiopathic arthritis | OARRR

  https://www.dovepress.com/review-of-environmental-factors-and-juvenile-idiopathic-arthritis-peer-reviewed-fulltext-article-OARRR

  In this narrative review, we discuss recent advances in our understanding of environmental factors that might relate to JIA pathogenesis and highlight some limitations of research on environmental influences on disease. […] Evidence on the role of environmental factors in the development of JIA is slowly expanding, including potential protective influences from breast feeding and household siblings and potential risks from antibiotic exposure and C-section deliveries. Nonetheless, many uncertainties remain about the role of these and other factors in JIA pathogenesis.

• #29 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. […] This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. […] The heterogeneity of JIA disease subtypes adds complexity to the investigation of cause and mechanism of pathogenesis, and the initiating factors of JIA remain unresolved. […] Environmental factors, including infectious agents, vaccinations, antibiotics, vitamin D deficiency, stress and trauma have been proposed as risk factors. […] The pathogenesis of ERA is driven by HLA-B27-mediated presentation of arthritogenic peptide following T-cell activation and IL23 and IL17 secretion.

• #30 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. […] This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. […] The heterogeneity of JIA disease subtypes adds complexity to the investigation of cause and mechanism of pathogenesis, and the initiating factors of JIA remain unresolved. […] Environmental factors, including infectious agents, vaccinations, antibiotics, vitamin D deficiency, stress and trauma have been proposed as risk factors. […] The pathogenesis of ERA is driven by HLA-B27-mediated presentation of arthritogenic peptide following T-cell activation and IL23 and IL17 secretion.

• #31 Early Identification of Juvenile Idiopathic Arthritis

  https://www.hcplive.com/view/early-identification-juvenile-idiopathic-arthritis

  The cause of JIA remains unknown, but it seems to result from a complex genetic trait with an immunoinflammatory pathogenesis, possibly influenced by external antigens. Abnormalities both cell-mediated (via inflammatory cells, cytokines, and activated T cells) and humoral (via autoantibodies) are implicated. The various phenotypes of the disease point toward interactions of multiple genes affecting immunity and inflammation. […] There are HLA associations for each JIA subtype, the strongest in children with oligoarticular disease. HLA-B27 may contribute to the disease pathogenesis via molecular mimicry among patients with enthesitis-related arthritis (ERA). […] Immune dysfunction in JIA is evident with the presence of autoantibodies, such as antinuclear antibodies (ANAs)-present in 40% of patients-and rheumatoid factor (RF)-present in 5% to 10% of patients. Although undoubtedly there are genetic predispositions to JIA, other contributing factors have been suggested, such as environmental agents, infectious vectors, trauma, psychological stress, and hormonal abnormalities.

• #32 Review of environmental factors and juvenile idiopathic arthritis | OARRR

  https://www.dovepress.com/review-of-environmental-factors-and-juvenile-idiopathic-arthritis-peer-reviewed-fulltext-article-OARRR

  Juvenile idiopathic arthritis is a common rheumatic disease that presents as chronic childhood arthritis. JIA is considered a multifactorial disease that may result from diverse genetic and environmental risk factors. A minority of the population-attributable risk of JIA is estimated to be due to familial factors. Thus, non-genetic or environmental factors likely account for a majority of the risk of developing JIA. […] JIA is thought to originate from a complex interplay of non-Mendelian genetics and environmental influences leading to chronic inflammation of joints and other tissues. Familial epidemiologic studies and genome-wide association studies have produced estimates of the contribution of genetic factors to JIA ranging from 13% to 25%. […] Mechanistically, environmental influences may trigger JIA via several different mechanisms, including epigenetic changes, imbalance of microbiota, and direct modulation of the immune system.

• #33 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  JIA subtypes represent a heterogeneous group of diseases with multifactorial and different pathogenesis. […] It is not completely understood how the combination of the environmental triggers and genetic susceptibility disrupt the balance between regulatory and effector cells in the pathogenesis of JIA. […] Initiation of the JIA pathophysiological cascade includes abnormal activation of T-cells, B-cells, natural killer (NK) cells, dendritic cells (DC), macrophages and neutrophils and the production of pro-inflammatory mediators that cause joint destruction and systemic complications. […] Inflammation is considered to be a consequence of disrupted balance between pro-inflammatory Th1/Th17 and anti-inflammatory regulatory T-cells (Treg). […] The collective data available to date, suggests that cytokine patterns may be appropriate for accurate disease classification in early JIA with the potential as targets for improving diagnosis and treatment strategies for patients with paediatric autoimmune disease.

• #34 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  The triggers that initiate and progress the pathology of JIA have not been identified. […] As with other autoimmune conditions, both genetic susceptibility and environmental factors are implicated in producing disease. […] The overarching mechanism in all JIA subsets is aberrant activation of the immune system. […] Different components of the immune system are involved in each subtype, and additional variation may exist within subtypes. […] One major distinction lies in whether the aberrancy involves the innate or adaptive immune system, described as autoinflammatory and autoimmune processes, respectively. […] Cytokine dysregulation is common to the pathogenesis of both autoinflammatory and autoimmune diseases. […] For example, IL-1 is the proinflammatory cytokine most involved in autoinflammatory diseases.

• #35 Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis | Pediatric Research

  https://www.nature.com/articles/pr2013187

  Systemic juvenile idiopathic arthritis (s-JIA) is clinically distinct from other types of JIA. […] Recent investigations have highlighted dysregulation of the innate immune system as the critical pathogenic driver of s-JIA. Key innate immune mediators of s-JIA are the macrophage-derived cytokines interleukin-1 (IL-1) and IL-6. […] Recent evidence supports the idea that s-JIA arises due to dysregulation of the innate immune system. This is in contrast with other forms of JIA, which are driven primarily by the adaptive immune system. Dysregulation of the innate immune system in s-JIA results in increased production of inflammatory cytokines, leading to the distinctive clinical features of the disease. […] The macrophage-derived cytokines IL-6, IL-1, and IL-18 predominate the inflammatory milieu in s-JIA.

• #36 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  IL-1 binds to its receptor (IL-1R type I) and thus induces the transcription of proinflammatory genes leading to inflammation and tissue damage. […] Disorders of innate and adaptive immunity most likely represent a spectrum of immune dysfunction, with many rheumatologic conditions being polygenic in nature. […] Autoinflammatory disease involving a predominant abnormality of the innate immune system. […] The multi-system inflammation seen in this subtype is due to complex underlying interactions of immune cells, and the host of cytokines they produce. […] Early in the disease process, cells of the innate immune system (monocytes, macrophages and neutrophils) are activated, and secrete pro-inflammatory cytokines and proteins (such as IL-1 , IL-6, IL-8, IL-18, TNF-a, and macrophage colony-stimulating factor).

• #37 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  These cytokines amplify the inflammatory process and generate clinical signs and symptoms. […] Oligo-/polyarticular JIA are understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells, but with emerging evidence for a component of innate immune system dysfunction. […] It is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance. […] Auto-antigen(s) (which are not known) in joint tissue activate autoreactive T cells (T helper cells, Th1 and Th17), which produce pro-inflammatory cytokines, namely IFN- and IL-17. […] Large numbers of autoreactive T cells can be found in the arthritic joint, clustered around antigen-presenting cells.

• #38 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  At the same time, regulatory T cells (CD4+ and CD25+) seem to be inhibited by the milieu of inflammatory factors; TNF and 1L-6, for example, inhibit their activity. […] Treg cells normally function to maintain immunologic self-tolerance and negative control in both physiological and pathological immune responses. […] In JIA their function appears to be inhibited, and the inflammatory balance is disrupted in favour of inflammation. […] The complex balance between pro- and anti-inflammatory mediators in the arthritic joint determines progression and outcome of disease. […] ERA encompasses Ankylosing Spondylitis, Reactive Arthritis, and Arthritis associated with IBD (though the term spondyloarthropathies also includes psoriatic arthritis when sacroiliitis or spondylitis is present). […] Traditionally considered to be an autoimmune disease triggered by GI or GU infections in HLA-B27 positive individuals (i.e. infection induces CD8T-cell clones that react against bacterial antigens and auto-antigens in joint tissue).

• #39 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. […] Specifically, the HLA-B27 molecule may be prone to misfolding within the cells endoplasmic reticulum, activating the innate immune system. […] Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. […] A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohns disease. […] Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. […] Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

• #40 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  JIA subtypes represent a heterogeneous group of diseases with multifactorial and different pathogenesis. […] It is not completely understood how the combination of the environmental triggers and genetic susceptibility disrupt the balance between regulatory and effector cells in the pathogenesis of JIA. […] Initiation of the JIA pathophysiological cascade includes abnormal activation of T-cells, B-cells, natural killer (NK) cells, dendritic cells (DC), macrophages and neutrophils and the production of pro-inflammatory mediators that cause joint destruction and systemic complications. […] Inflammation is considered to be a consequence of disrupted balance between pro-inflammatory Th1/Th17 and anti-inflammatory regulatory T-cells (Treg). […] The collective data available to date, suggests that cytokine patterns may be appropriate for accurate disease classification in early JIA with the potential as targets for improving diagnosis and treatment strategies for patients with paediatric autoimmune disease.

• #41 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16 and lasting 6 weeks or longer. […] The cause and trigger of chronic arthritis in JIA remain unclear. Abnormal immune responses triggered by the interactions between environmental factors in a genetically susceptible individual are speculative. […] Based on familial aggregation studies and the concordance rate of 25% to 40% in monozygotic twins, genetic factors play a significant role. […] The imbalance of regulatory T cells, Th1 (interferon-gamma secreting T cells), and Th17 (interleukin -17 secreting T cells) of adaptive immunity is the feature of most subtypes of JIA. IL-17 induces proinflammatory cytokines and matrix metalloproteinases, leading to joint damage in oligoarthritis, polyarthritis, and psoriatic arthritis.

• #42 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  These cytokines amplify the inflammatory process and generate clinical signs and symptoms. […] Oligo-/polyarticular JIA are understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells, but with emerging evidence for a component of innate immune system dysfunction. […] It is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance. […] Auto-antigen(s) (which are not known) in joint tissue activate autoreactive T cells (T helper cells, Th1 and Th17), which produce pro-inflammatory cytokines, namely IFN- and IL-17. […] Large numbers of autoreactive T cells can be found in the arthritic joint, clustered around antigen-presenting cells.

• #43 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  At the same time, regulatory T cells (CD4+ and CD25+) seem to be inhibited by the milieu of inflammatory factors; TNF and 1L-6, for example, inhibit their activity. […] Treg cells normally function to maintain immunologic self-tolerance and negative control in both physiological and pathological immune responses. […] In JIA their function appears to be inhibited, and the inflammatory balance is disrupted in favour of inflammation. […] The complex balance between pro- and anti-inflammatory mediators in the arthritic joint determines progression and outcome of disease. […] ERA encompasses Ankylosing Spondylitis, Reactive Arthritis, and Arthritis associated with IBD (though the term spondyloarthropathies also includes psoriatic arthritis when sacroiliitis or spondylitis is present). […] Traditionally considered to be an autoimmune disease triggered by GI or GU infections in HLA-B27 positive individuals (i.e. infection induces CD8T-cell clones that react against bacterial antigens and auto-antigens in joint tissue).

• #44 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. T lymphocytes have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factoralpha [TNF-], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A disordered interaction between type 1 and type 2 T-helper cells has been postulated. […] Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for synovial nonself antigens. Evidence for abnormalities in the humoral immune system include the increased presence of autoantibodies (especially antinuclear antibodies), increased serum immunoglobulins, the presence of circulating immune complexes, and complement activation. […] Chronic inflammation of synovium is characterized by B-lymphocyte infiltration and expansion. Macrophages and T-cell invasion are associated with the release of cytokines, which evoke synoviocyte proliferation. A study by Scola et al found synovium to contain messenger ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin 1, as well as for their receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease.

• #45 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. T lymphocytes have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factoralpha [TNF-], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A disordered interaction between type 1 and type 2 T-helper cells has been postulated. […] Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for synovial nonself antigens. Evidence for abnormalities in the humoral immune system include the increased presence of autoantibodies (especially antinuclear antibodies), increased serum immunoglobulins, the presence of circulating immune complexes, and complement activation. […] Chronic inflammation of synovium is characterized by B-lymphocyte infiltration and expansion. Macrophages and T-cell invasion are associated with the release of cytokines, which evoke synoviocyte proliferation. A study by Scola et al found synovium to contain messenger ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin 1, as well as for their receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease.

• #46 Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation | RMD Open

  https://rmdopen.bmj.com/content/9/3/e002901

  Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation. […] Our results suggest a potential role and/or activation profile of B and Th17-like Tfh cells in the pathogenesis of extended oligo JIA and poly JIA, but not persistent oligo JIA. […] Evidence from the literature suggests that B cells might have a relevant role in the pathogenesis of JIA. […] Our study suggests that alterations in circulating B cells and follicular T cell subsets, particularly Th17-like T follicular helper cells, might be associated to the pathogenesis of extended oligoarticular JIA and polyarticular JIA. […] These results suggest a potential role of these cytokines in JIA pathogenesis, considering their relevance in B cell activation, differentiation and function and, therefore, reinforce B cell contribution in JIA pathophysiology. […] Overall, this study suggests that B cells, Tregs and follicular T cell subsets, particularly Th17-like Tfh cells, might be associated to the pathogenesis of extended oligo JIA and poly JIA.

• #47 Neutrophils: the forgotten cell in JIA disease pathogenesis | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/1546-0096-5-13

  Juvenile idiopathic arthritis (JIA) has long been assumed to be an autoimmune disease, triggered by aberrant recognition of „self” antigens by T-cells. […] In particular, new data suggest an important role for neutrophils in JIA pathogenesis. […] In this review, we will discuss emerging evidence that demonstrates the importance of neutrophils in regulating and informing the adaptive immune response, suggesting, therefore, that innate immunity may play a larger role in JIA pathogenesis than has been previously thought. […] Thus, rather than being „downstream” of the putative pathological events in JIA, neutrophils are arguably at the very center. […] New data from multiple laboratories, using techniques as diverse as genomics, in silico modeling, and single-cell microscopy, all suggest that we have overlooked the critical role neutrophils may play in JIA pathogenesis.

• #48

  https://journals.lww.com/co-rheumatology/fulltext/9900/pathogenesis_of_juvenile_idiopathic_arthritis.174.aspx

  To provide an overview of the most recent updates in the pathogenesis of juvenile idiopathic arthritis (JIA). […] Recent genetic studies on the pathogenesis of JIA have revolved around using in silico multiomic analyses to identify genetic variants that may play a role in the pathogenesis of JIA. […] Immune dysregulation is a major driver of JIA pathogenesis and neutrophil extracellular traps (NETs) are emerging as contributors to disease progression. […] The contribution of immune cells to the microenvironment in the inflamed joints of patients with JIA may hold the key to how inflammation is regulated and how the immune response from these cells contributes to disease progression. […] This review will focus on emerging insights from large scale multiomic studies, which reveal pathways involved in JIA pathogenesis. […] In addition, recent studies have identified immune dysregulation, especially in the microenvironment of the inflamed joint.

• #49 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  JIA subtypes represent a heterogeneous group of diseases with multifactorial and different pathogenesis. […] It is not completely understood how the combination of the environmental triggers and genetic susceptibility disrupt the balance between regulatory and effector cells in the pathogenesis of JIA. […] Initiation of the JIA pathophysiological cascade includes abnormal activation of T-cells, B-cells, natural killer (NK) cells, dendritic cells (DC), macrophages and neutrophils and the production of pro-inflammatory mediators that cause joint destruction and systemic complications. […] Inflammation is considered to be a consequence of disrupted balance between pro-inflammatory Th1/Th17 and anti-inflammatory regulatory T-cells (Treg). […] The collective data available to date, suggests that cytokine patterns may be appropriate for accurate disease classification in early JIA with the potential as targets for improving diagnosis and treatment strategies for patients with paediatric autoimmune disease.

• #50 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. […] The most well-established genetic factors for JRA are the HLA genes. […] Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. […] TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. […] The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type and the absence of autoantibodies and autoreactive T cells. […] Recent data indicate that IL-1 has a prominent role in systemic onset disease. […] The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement. […] The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4.

• #51 Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade.

  https://vivo.weill.cornell.edu/display/pubid15851489

  Systemic onset juvenile idiopathic arthritis (SoJIA) encompasses approximately 10% of cases of arthritis that begin in childhood. […] Here, we show that serum from SoJIA patients induces the transcription of innate immunity genes, including interleukin (IL)-1 in healthy peripheral blood mononuclear cells (PBMCs). […] We conclude that IL-1 is a major mediator of the inflammatory cascade that underlies SoJIA and that this cytokine represents a target for therapy in this disease.

• #52 Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis | Pediatric Research

  https://www.nature.com/articles/pr2013187

  IL-1 is a key contributor to the pathogenesis of s-JIA. […] Thus, macrophage-derived cytokines are more than simply markers of disease activity and appear to be key players in the pathogenesis of s-JIA. […] In conclusion, recent studies have demonstrated that s-JIA is a disease stemming from dysregulation of the innate immune system characterized by production of macrophage-derived proinflammatory cytokines, namely IL-1, IL-6, and IL-18.

• #53 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. […] The most well-established genetic factors for JRA are the HLA genes. […] Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. […] TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. […] The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type and the absence of autoantibodies and autoreactive T cells. […] Recent data indicate that IL-1 has a prominent role in systemic onset disease. […] The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement. […] The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4.

• #54 Systemic Juvenile Idiopathic Arthritis – The Rheumatologist

  https://www.the-rheumatologist.org/article/systemic-juvenile-idiopathic-arthritis/?singlepage=1

  SJIA is also characterized by markedly elevated levels of IL-6 in serum and synovial fluid. […] Moreover, elevated IL-6 serum levels have been shown to correlate with the fever spikes and are associated with the development of arthritis, hypochromic microcytic anemia, high inflammatory markers, growth failure, and osteoporosis seen in this disease.

• #55 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16 and lasting 6 weeks or longer. […] The cause and trigger of chronic arthritis in JIA remain unclear. Abnormal immune responses triggered by the interactions between environmental factors in a genetically susceptible individual are speculative. […] Based on familial aggregation studies and the concordance rate of 25% to 40% in monozygotic twins, genetic factors play a significant role. […] The imbalance of regulatory T cells, Th1 (interferon-gamma secreting T cells), and Th17 (interleukin -17 secreting T cells) of adaptive immunity is the feature of most subtypes of JIA. IL-17 induces proinflammatory cytokines and matrix metalloproteinases, leading to joint damage in oligoarthritis, polyarthritis, and psoriatic arthritis.

• #56 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  IL-1 binds to its receptor (IL-1R type I) and thus induces the transcription of proinflammatory genes leading to inflammation and tissue damage. […] Disorders of innate and adaptive immunity most likely represent a spectrum of immune dysfunction, with many rheumatologic conditions being polygenic in nature. […] Autoinflammatory disease involving a predominant abnormality of the innate immune system. […] The multi-system inflammation seen in this subtype is due to complex underlying interactions of immune cells, and the host of cytokines they produce. […] Early in the disease process, cells of the innate immune system (monocytes, macrophages and neutrophils) are activated, and secrete pro-inflammatory cytokines and proteins (such as IL-1 , IL-6, IL-8, IL-18, TNF-a, and macrophage colony-stimulating factor).

• #57 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  In early stages of rheumatoid arthritis, IL-23 is a crucial cytokine that leads to inflammation through IL-17 and tumor necrosis factor (TNF), and new bone formation through interleukin (IL)-22. […] In contrast, the critical immunopathophysiology of systemic arthritis is persistent activation of innate immunity, including monocytes, macrophages, and neutrophils. […] As a result, innate proinflammatory cytokines such as IL-1 beta, IL-6, and IL-18 contribute to symptoms and signs of systemic arthritis.

• #58 Implications of juvenile idiopathic arthritis genetic risk variants for disease pathogenesis and classification

  https://ouci.dntb.gov.ua/en/works/7XLGoM07/

  Juvenile idiopathic arthritis (JIA) exhibits prominent genetic associations with the human leukocyte antigen (HLA) region, extending perhaps surprisingly even to the hyperinflammatory systemic JIA category. […] Genetic data indicate a continuity between JIA and adult arthritis poorly reflected in current nomenclature. Advancing methodologies will help to identify new pathogenic mechanisms that inform the understanding of biologic subdivisions within JIA. […] Despite significant improvements over the past decade, the aetiology and molecular mechanisms of JIA remain unclear. It has been suggested that the immunopathogenesis is characterised by complex interactions between genetic background and environmental factors that may differ between JIA subtypes. Human leukocyte antigen (HLA) haplotypes and non-HLA genes play a crucial role in the abnormal activation of both innate and adaptive immune cells that cooperate in causing the inflammatory process. This results in the involvement of proinflammatory cytokines, including tumour necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-10, IL-17, IL-21, IL-23, and others. These mediators, interacting with the surrounding tissue, cause cartilage stress and bone damage, including irreversible erosions.

• #59 IL-10 in the pathogenesis of systemic juvenile idiopathic arthritis and regulation of its production by IFN-y in TLR-triggered inflammation

  https://lirias.kuleuven.be/2000743

  Systemic juvenile idiopathic arthritis (sJIA) is a rare but severe childhood immune disorder and is a subtype of JIA, a heterogeneous group of arthritic diseases. […] The aetiology of sJIA remains largely unknown. One hypothesis is that sJIA results from the inappropriate control of the immune response to an initially harmless trigger in predisposed children. […] In the first part of this thesis, we investigated whether a defective IL-10 production underlies the pathogenesis of sJIA. […] Together, our data show that a decreased IL-10 production may underlie sJIA development. […] The defective IL-10 production in sJIA mice which genetically lack IFN-γ came as a surprise considering the traditional paradigm of IL-10 and IFN-γ as each other’s antagonists. […] Further research into the mechanisms involved revealed that the increase of TLR9-induced IL-10 by IFN-γ was restricted to B cells. […] Together, these data may represent a novel anti-inflammatory property of the traditionally considered pro-inflammatory IFN-γ, by stimulating TLR-induced IL-10 production in B cells.

• #60 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. […] The most well-established genetic factors for JRA are the HLA genes. […] Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. […] TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. […] The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type and the absence of autoantibodies and autoreactive T cells. […] Recent data indicate that IL-1 has a prominent role in systemic onset disease. […] The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement. […] The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4.

• #61 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  At the same time, regulatory T cells (CD4+ and CD25+) seem to be inhibited by the milieu of inflammatory factors; TNF and 1L-6, for example, inhibit their activity. […] Treg cells normally function to maintain immunologic self-tolerance and negative control in both physiological and pathological immune responses. […] In JIA their function appears to be inhibited, and the inflammatory balance is disrupted in favour of inflammation. […] The complex balance between pro- and anti-inflammatory mediators in the arthritic joint determines progression and outcome of disease. […] ERA encompasses Ankylosing Spondylitis, Reactive Arthritis, and Arthritis associated with IBD (though the term spondyloarthropathies also includes psoriatic arthritis when sacroiliitis or spondylitis is present). […] Traditionally considered to be an autoimmune disease triggered by GI or GU infections in HLA-B27 positive individuals (i.e. infection induces CD8T-cell clones that react against bacterial antigens and auto-antigens in joint tissue).

• #62 Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis | Pediatric Research

  https://www.nature.com/articles/pr2013187

  Systemic juvenile idiopathic arthritis (s-JIA) is clinically distinct from other types of JIA. […] Recent investigations have highlighted dysregulation of the innate immune system as the critical pathogenic driver of s-JIA. Key innate immune mediators of s-JIA are the macrophage-derived cytokines interleukin-1 (IL-1) and IL-6. […] Recent evidence supports the idea that s-JIA arises due to dysregulation of the innate immune system. This is in contrast with other forms of JIA, which are driven primarily by the adaptive immune system. Dysregulation of the innate immune system in s-JIA results in increased production of inflammatory cytokines, leading to the distinctive clinical features of the disease. […] The macrophage-derived cytokines IL-6, IL-1, and IL-18 predominate the inflammatory milieu in s-JIA.

• #63 Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.68

  The contribution of innate immunity to systemic juvenile idiopathic arthritis (sJIA) is prominent, supporting the classification of sJIA as an autoinflammatory disorder. […] Available data suggest that sJIA is a multigenic disease, and that sJIA with macrophage activation syndrome (MAS) could represent a genetically distinct disease subtype. […] IL-1 is a critical proinflammatory cytokine in early sJIA, whereas arthritis in chronic persistent sJIA is possibly driven by other mediators. […] During active disease, mediators of both inflammatory and anti-inflammatory pathways are detected; among the latter are monocyte/macrophages with features of 'alternative activation’. […] It is possible that clinically inactive disease (with no medication) represents a state of compensated inflammation rather than the absence of immune activity.

• #64 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  In early stages of rheumatoid arthritis, IL-23 is a crucial cytokine that leads to inflammation through IL-17 and tumor necrosis factor (TNF), and new bone formation through interleukin (IL)-22. […] In contrast, the critical immunopathophysiology of systemic arthritis is persistent activation of innate immunity, including monocytes, macrophages, and neutrophils. […] As a result, innate proinflammatory cytokines such as IL-1 beta, IL-6, and IL-18 contribute to symptoms and signs of systemic arthritis.

• #65 Juvenile Idiopathic Arthritis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK554605/

  In early stages of rheumatoid arthritis, IL-23 is a crucial cytokine that leads to inflammation through IL-17 and tumor necrosis factor (TNF), and new bone formation through interleukin (IL)-22. […] In contrast, the critical immunopathophysiology of systemic arthritis is persistent activation of innate immunity, including monocytes, macrophages, and neutrophils. […] As a result, innate proinflammatory cytokines such as IL-1 beta, IL-6, and IL-18 contribute to symptoms and signs of systemic arthritis.

• #66 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  IL-1 binds to its receptor (IL-1R type I) and thus induces the transcription of proinflammatory genes leading to inflammation and tissue damage. […] Disorders of innate and adaptive immunity most likely represent a spectrum of immune dysfunction, with many rheumatologic conditions being polygenic in nature. […] Autoinflammatory disease involving a predominant abnormality of the innate immune system. […] The multi-system inflammation seen in this subtype is due to complex underlying interactions of immune cells, and the host of cytokines they produce. […] Early in the disease process, cells of the innate immune system (monocytes, macrophages and neutrophils) are activated, and secrete pro-inflammatory cytokines and proteins (such as IL-1 , IL-6, IL-8, IL-18, TNF-a, and macrophage colony-stimulating factor).

• #67 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  The genetic basis of JRA is complex, but it has been estimated that the sibling recurrence risk of developing the disease is around 15. […] The most well-established genetic factors for JRA are the HLA genes. […] Antigen-specific T cells appear to play a central role in the pathogenesis of arthritis subtypes within JRA. […] TNF- and IL-1 produced by activated monocytes, macrophages, and synovial fibroblasts likely have primary roles in the pathogenesis of JRA. […] The pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, such as the lack of association with HLA type and the absence of autoantibodies and autoreactive T cells. […] Recent data indicate that IL-1 has a prominent role in systemic onset disease. […] The circulating concentration of IL-6 is noticeably increased in patients with systemic onset disease and correlates with the extent of joint involvement. […] The two most well-known anti-inflammatory cytokines associated with JRA are IL-10 and IL-4.

• #68 Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.68

  The contribution of innate immunity to systemic juvenile idiopathic arthritis (sJIA) is prominent, supporting the classification of sJIA as an autoinflammatory disorder. […] Available data suggest that sJIA is a multigenic disease, and that sJIA with macrophage activation syndrome (MAS) could represent a genetically distinct disease subtype. […] IL-1 is a critical proinflammatory cytokine in early sJIA, whereas arthritis in chronic persistent sJIA is possibly driven by other mediators. […] During active disease, mediators of both inflammatory and anti-inflammatory pathways are detected; among the latter are monocyte/macrophages with features of 'alternative activation’. […] It is possible that clinically inactive disease (with no medication) represents a state of compensated inflammation rather than the absence of immune activity.

• #69 Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.68

  The contribution of innate immunity to systemic juvenile idiopathic arthritis (sJIA) is prominent, supporting the classification of sJIA as an autoinflammatory disorder. […] Available data suggest that sJIA is a multigenic disease, and that sJIA with macrophage activation syndrome (MAS) could represent a genetically distinct disease subtype. […] IL-1 is a critical proinflammatory cytokine in early sJIA, whereas arthritis in chronic persistent sJIA is possibly driven by other mediators. […] During active disease, mediators of both inflammatory and anti-inflammatory pathways are detected; among the latter are monocyte/macrophages with features of 'alternative activation’. […] It is possible that clinically inactive disease (with no medication) represents a state of compensated inflammation rather than the absence of immune activity.

• #70 Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3012271/

  Juvenile rheumatoid arthritis (JRA) is the most common rheumatic childhood disease; its onset is before 16 years of age and it persists for at least 6 weeks. […] The first 2 types of JRA are regarded as T helper 1 (Th1) cell-mediated inflammatory disorders, mainly based on the abundance of activated Th1 cells in the inflamed synovium and the pathogenetic role of proinflammatory cytokines that are mainly produced by Th1 cell-stimulated monocytes. […] Although the precise mechanism that leads to JRA remains unclear, proinflammatory cytokines are thought to be responsible for at least part of the clinical symptoms in all JRA types. The effectiveness of biologic therapy in blocking the action of these cytokines in JRA patients provides strong evidence that they play a fundamental role in JRA inflammation.

• #71 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  These cytokines amplify the inflammatory process and generate clinical signs and symptoms. […] Oligo-/polyarticular JIA are understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells, but with emerging evidence for a component of innate immune system dysfunction. […] It is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance. […] Auto-antigen(s) (which are not known) in joint tissue activate autoreactive T cells (T helper cells, Th1 and Th17), which produce pro-inflammatory cytokines, namely IFN- and IL-17. […] Large numbers of autoreactive T cells can be found in the arthritic joint, clustered around antigen-presenting cells.

• #72 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  These cytokines amplify the inflammatory process and generate clinical signs and symptoms. […] Oligo-/polyarticular JIA are understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells, but with emerging evidence for a component of innate immune system dysfunction. […] It is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance. […] Auto-antigen(s) (which are not known) in joint tissue activate autoreactive T cells (T helper cells, Th1 and Th17), which produce pro-inflammatory cytokines, namely IFN- and IL-17. […] Large numbers of autoreactive T cells can be found in the arthritic joint, clustered around antigen-presenting cells.

• #73 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  These cytokines amplify the inflammatory process and generate clinical signs and symptoms. […] Oligo-/polyarticular JIA are understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells, but with emerging evidence for a component of innate immune system dysfunction. […] It is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance. […] Auto-antigen(s) (which are not known) in joint tissue activate autoreactive T cells (T helper cells, Th1 and Th17), which produce pro-inflammatory cytokines, namely IFN- and IL-17. […] Large numbers of autoreactive T cells can be found in the arthritic joint, clustered around antigen-presenting cells.

• #74 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  At the same time, regulatory T cells (CD4+ and CD25+) seem to be inhibited by the milieu of inflammatory factors; TNF and 1L-6, for example, inhibit their activity. […] Treg cells normally function to maintain immunologic self-tolerance and negative control in both physiological and pathological immune responses. […] In JIA their function appears to be inhibited, and the inflammatory balance is disrupted in favour of inflammation. […] The complex balance between pro- and anti-inflammatory mediators in the arthritic joint determines progression and outcome of disease. […] ERA encompasses Ankylosing Spondylitis, Reactive Arthritis, and Arthritis associated with IBD (though the term spondyloarthropathies also includes psoriatic arthritis when sacroiliitis or spondylitis is present). […] Traditionally considered to be an autoimmune disease triggered by GI or GU infections in HLA-B27 positive individuals (i.e. infection induces CD8T-cell clones that react against bacterial antigens and auto-antigens in joint tissue).

• #75 Early Identification of Juvenile Idiopathic Arthritis

  https://www.hcplive.com/view/early-identification-juvenile-idiopathic-arthritis

  The cause of JIA remains unknown, but it seems to result from a complex genetic trait with an immunoinflammatory pathogenesis, possibly influenced by external antigens. Abnormalities both cell-mediated (via inflammatory cells, cytokines, and activated T cells) and humoral (via autoantibodies) are implicated. The various phenotypes of the disease point toward interactions of multiple genes affecting immunity and inflammation. […] There are HLA associations for each JIA subtype, the strongest in children with oligoarticular disease. HLA-B27 may contribute to the disease pathogenesis via molecular mimicry among patients with enthesitis-related arthritis (ERA). […] Immune dysfunction in JIA is evident with the presence of autoantibodies, such as antinuclear antibodies (ANAs)-present in 40% of patients-and rheumatoid factor (RF)-present in 5% to 10% of patients. Although undoubtedly there are genetic predispositions to JIA, other contributing factors have been suggested, such as environmental agents, infectious vectors, trauma, psychological stress, and hormonal abnormalities.

• #76 Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation | RMD Open

  https://rmdopen.bmj.com/content/9/3/e002901

  Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation. […] Our results suggest a potential role and/or activation profile of B and Th17-like Tfh cells in the pathogenesis of extended oligo JIA and poly JIA, but not persistent oligo JIA. […] Evidence from the literature suggests that B cells might have a relevant role in the pathogenesis of JIA. […] Our study suggests that alterations in circulating B cells and follicular T cell subsets, particularly Th17-like T follicular helper cells, might be associated to the pathogenesis of extended oligoarticular JIA and polyarticular JIA. […] These results suggest a potential role of these cytokines in JIA pathogenesis, considering their relevance in B cell activation, differentiation and function and, therefore, reinforce B cell contribution in JIA pathophysiology. […] Overall, this study suggests that B cells, Tregs and follicular T cell subsets, particularly Th17-like Tfh cells, might be associated to the pathogenesis of extended oligo JIA and poly JIA.

• #77 Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches | Pediatric Rheumatology | Full Text

  https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-021-00629-8

  Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. […] This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. […] The heterogeneity of JIA disease subtypes adds complexity to the investigation of cause and mechanism of pathogenesis, and the initiating factors of JIA remain unresolved. […] Environmental factors, including infectious agents, vaccinations, antibiotics, vitamin D deficiency, stress and trauma have been proposed as risk factors. […] The pathogenesis of ERA is driven by HLA-B27-mediated presentation of arthritogenic peptide following T-cell activation and IL23 and IL17 secretion.

• #78 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. […] Specifically, the HLA-B27 molecule may be prone to misfolding within the cells endoplasmic reticulum, activating the innate immune system. […] Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. […] A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohns disease. […] Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. […] Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

• #79 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. […] Specifically, the HLA-B27 molecule may be prone to misfolding within the cells endoplasmic reticulum, activating the innate immune system. […] Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. […] A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohns disease. […] Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. […] Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

• #80 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. […] Specifically, the HLA-B27 molecule may be prone to misfolding within the cells endoplasmic reticulum, activating the innate immune system. […] Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. […] A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohns disease. […] Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. […] Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

• #81 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. […] Specifically, the HLA-B27 molecule may be prone to misfolding within the cells endoplasmic reticulum, activating the innate immune system. […] Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. […] A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohns disease. […] Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. […] Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

• #82 Juvenile idiopathic arthritis – McMaster Pathophysiology Review

  https://www.pathophys.org/jia/

  Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. […] Specifically, the HLA-B27 molecule may be prone to misfolding within the cells endoplasmic reticulum, activating the innate immune system. […] Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. […] A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohns disease. […] Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. […] Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

• #83 THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/79/Suppl_1/483.2

  Juvenile idiopathic arthritis (JIA) is a well-known chronic rheumatic disease of childhood characterised by progressive joint destruction and severe systemic complications. […] Immune cells are known to trigger the pathophysiological cascade in JIA, but there is little information regarding the contribution made by Mesenchymal stem cells (MSCs). These cells are able to modulate the immune response and decrease the level of pro-inflammatory cytokines. […] The growth kinetics of JIA-MSCs were different from healthy controls. JIA-MSCs divided slowly and appeared disorganised with large cytoplasm and loads of outgrowth. They demonstrated a decrease in cell proliferation (negative PDD) and metabolic activity. […] Considering this difference, it was hypothesised that cytokines obtained in a high amount in PB and SF of JIA patients may influence MSCs viability.

• #84 THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/79/Suppl_1/483.2

  Juvenile idiopathic arthritis (JIA) is a well-known chronic rheumatic disease of childhood characterised by progressive joint destruction and severe systemic complications. […] Immune cells are known to trigger the pathophysiological cascade in JIA, but there is little information regarding the contribution made by Mesenchymal stem cells (MSCs). These cells are able to modulate the immune response and decrease the level of pro-inflammatory cytokines. […] The growth kinetics of JIA-MSCs were different from healthy controls. JIA-MSCs divided slowly and appeared disorganised with large cytoplasm and loads of outgrowth. They demonstrated a decrease in cell proliferation (negative PDD) and metabolic activity. […] Considering this difference, it was hypothesised that cytokines obtained in a high amount in PB and SF of JIA patients may influence MSCs viability.

• #85 THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/79/Suppl_1/483.2

  Cell cycle analysis revealed that JIA-MSCs were arrested in G0/G1 phase with low number of mitotic cells. In addition, the number of senescence-associated SA–gal-positive cells was notably higher in JIA-MSCs. Furthermore, JIA-MSCs expressed high level of immunofluorescence for p16, p21 and p53 which played an important role in regulating the senescence progress of MSCs. […] Taken together current research has demonstrated that under the influence of proinflammatory cytokines JIA-MSCs suffered from oxidative stress and disruption of metabolic activity acquire senescent morphology, shorten of telomere length, arrest in G0 phase of cell cycle and finally loss of immune regulation.

• #86 THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/79/Suppl_1/483.2

  Cell cycle analysis revealed that JIA-MSCs were arrested in G0/G1 phase with low number of mitotic cells. In addition, the number of senescence-associated SA–gal-positive cells was notably higher in JIA-MSCs. Furthermore, JIA-MSCs expressed high level of immunofluorescence for p16, p21 and p53 which played an important role in regulating the senescence progress of MSCs. […] Taken together current research has demonstrated that under the influence of proinflammatory cytokines JIA-MSCs suffered from oxidative stress and disruption of metabolic activity acquire senescent morphology, shorten of telomere length, arrest in G0 phase of cell cycle and finally loss of immune regulation.

• #87 THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/79/Suppl_1/483.2

  Cell cycle analysis revealed that JIA-MSCs were arrested in G0/G1 phase with low number of mitotic cells. In addition, the number of senescence-associated SA–gal-positive cells was notably higher in JIA-MSCs. Furthermore, JIA-MSCs expressed high level of immunofluorescence for p16, p21 and p53 which played an important role in regulating the senescence progress of MSCs. […] Taken together current research has demonstrated that under the influence of proinflammatory cytokines JIA-MSCs suffered from oxidative stress and disruption of metabolic activity acquire senescent morphology, shorten of telomere length, arrest in G0 phase of cell cycle and finally loss of immune regulation.

• #88 THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/79/Suppl_1/483.2

  Cell cycle analysis revealed that JIA-MSCs were arrested in G0/G1 phase with low number of mitotic cells. In addition, the number of senescence-associated SA–gal-positive cells was notably higher in JIA-MSCs. Furthermore, JIA-MSCs expressed high level of immunofluorescence for p16, p21 and p53 which played an important role in regulating the senescence progress of MSCs. […] Taken together current research has demonstrated that under the influence of proinflammatory cytokines JIA-MSCs suffered from oxidative stress and disruption of metabolic activity acquire senescent morphology, shorten of telomere length, arrest in G0 phase of cell cycle and finally loss of immune regulation.

• #89

  https://insight.jci.org/articles/view/85633

  Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatological condition. […] Although it has been proposed that JIA has an autoimmune component, the autoantigens are still unknown. […] Our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and to oxidation and aggregation as a mechanism facilitating TTR autoimmunity. […] Some evidence supports the notion that JIA is an antigen-driven, lymphocyte-mediated autoimmune disease, including the known association with certain HLA haplotypes and the high numbers of infiltrating T cells within arthritic joints. […] Additionally, transcriptional analysis of PBMCs from patients with oligo-JIA has shown increased markers for B cell activation. […] Recently, reports identified transthyretin (TTR) as one of the proteins upregulated in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis and as a possible target of their autoantibody response.

• #90 Is Juvenile Idiopathic Arthritis an Autoimmune Disease?

  https://www.thermofisher.com/blog/proteomics/is-juvenile-idiopathic-arthritis-an-autoimmune-disease-copy/

  Juvenile idiopathic arthritis (JIA) is a common rheumatological condition. While past research suggests JIA is an autoimmune disease, the autoantigens driving this supposed T cell-mediated immune response are still unknown. […] Some well-established research indicating a connection with B cells and autoantibodies in JIA pathogenesis; however, these mechanisms are unknown. […] It also revealed several metalloproteases and other proteases, including plasmin kallikrein and cathepsins, in addition to tissue inhibitors of metalloproteinase. […] To investigate TRR as a target antigen, the researchers used enzyme-linked immunosorbent assay (ELISA) to detect anti-TTR antibodies on both synovial fluid and sera of JIA patients and controls. […] After further examination of the synovial fluid, the researchers saw misfolding, aggregation and oxidation of TTR, which is known to stimulate a signaling cascade to induce B cell differentiation and IgG secretion in a T cell-dependent and/or independent manner. […] Clement et al. recommend that future experiments should focus on mapping additional TTR peptides with different HLA restriction and on finding an immunodominant peptide driving the T cell immune response in different HLA-susceptible haplotypes.

• #91 Is Juvenile Idiopathic Arthritis an Autoimmune Disease?

  https://www.thermofisher.com/blog/proteomics/is-juvenile-idiopathic-arthritis-an-autoimmune-disease-copy/

  Juvenile idiopathic arthritis (JIA) is a common rheumatological condition. While past research suggests JIA is an autoimmune disease, the autoantigens driving this supposed T cell-mediated immune response are still unknown. […] Some well-established research indicating a connection with B cells and autoantibodies in JIA pathogenesis; however, these mechanisms are unknown. […] It also revealed several metalloproteases and other proteases, including plasmin kallikrein and cathepsins, in addition to tissue inhibitors of metalloproteinase. […] To investigate TRR as a target antigen, the researchers used enzyme-linked immunosorbent assay (ELISA) to detect anti-TTR antibodies on both synovial fluid and sera of JIA patients and controls. […] After further examination of the synovial fluid, the researchers saw misfolding, aggregation and oxidation of TTR, which is known to stimulate a signaling cascade to induce B cell differentiation and IgG secretion in a T cell-dependent and/or independent manner. […] Clement et al. recommend that future experiments should focus on mapping additional TTR peptides with different HLA restriction and on finding an immunodominant peptide driving the T cell immune response in different HLA-susceptible haplotypes.

• #92

  https://insight.jci.org/articles/view/85633

  Our findings provide evidence of a role for TTR as an autoantigen potentially involved in the pathogenesis of JIA and suggest a role for protein oxidation or other posttranslational modifications (PTMs) in stimulating autoimmune responses targeting this protein. […] TTR has a natural tendency to misfold, aggregate, and precipitate. […] The finding of TTR aggregates in the SF, synovial membrane, and eye and the finding that JIA affects young children led us to hypothesize that JIA could be another manifestation of a familial amyloidosis. […] Altogether, our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and oxidation/aggregation of TTR as an important mechanism that facilitates TTR immunogenicity.

• #93

  https://insight.jci.org/articles/view/85633

  Our findings provide evidence of a role for TTR as an autoantigen potentially involved in the pathogenesis of JIA and suggest a role for protein oxidation or other posttranslational modifications (PTMs) in stimulating autoimmune responses targeting this protein. […] TTR has a natural tendency to misfold, aggregate, and precipitate. […] The finding of TTR aggregates in the SF, synovial membrane, and eye and the finding that JIA affects young children led us to hypothesize that JIA could be another manifestation of a familial amyloidosis. […] Altogether, our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and oxidation/aggregation of TTR as an important mechanism that facilitates TTR immunogenicity.

• #94 Juvenile Idiopathic Arthritis: Practice Essentials, Background, Etiology and Pathophysiology

  https://emedicine.medscape.com/article/1007276-overview

  Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. T lymphocytes have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factoralpha [TNF-], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A disordered interaction between type 1 and type 2 T-helper cells has been postulated. […] Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for synovial nonself antigens. Evidence for abnormalities in the humoral immune system include the increased presence of autoantibodies (especially antinuclear antibodies), increased serum immunoglobulins, the presence of circulating immune complexes, and complement activation. […] Chronic inflammation of synovium is characterized by B-lymphocyte infiltration and expansion. Macrophages and T-cell invasion are associated with the release of cytokines, which evoke synoviocyte proliferation. A study by Scola et al found synovium to contain messenger ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin 1, as well as for their receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease.

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