Patients with Systemic Juvenile Idiopathic Arthritis (SJIA) Show Differences in Autoantibody Signatures Based on Disease Activity.

Systemic juvenile idiopathic arthritis (SJIA) is a severe rheumatic disease in children. It is a subgroup of juvenile idiopathic arthritis (JIA; MIM #604302), which is the most common rheumatic disease in children. The diagnosis of SJIA often comes with a significant delay, and the classification between autoinflammatory and autoimmune disease is still discussed. In this study, we analyzed the immunological responses of patients with SJIA, using human proteome arrays presenting immobilized recombinantly expressed human proteins, to analyze the involvement of autoantibodies in SJIA. Results from group comparisons show several differentially reactive antigens involved in inflammatory processes. Intriguingly, many of the identified antigens had a high reactivity against proteins involved in the NF-κB pathway, and it is also notable that many of the detected DIRAGs are described as dysregulated in rheumatoid arthritis. Our data highlight novel proteins and pathways potentially dysregulated in SJIA and offer a unique approach to unraveling the underlying disease pathogenesis in this chronic arthropathy.

Aberrant Naive CD4-Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help.

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. In this study, we hypothesized that aberrant or incomplete polarization of T helper cells contributes to disease pathology. METHODS: Cells or serum samples were obtained from healthy controls (n = 72) and systemic JIA patients (n = 171). Isolated naive T helper cells were cultured under Th1, Th17, and T follicular helper (Tfh) or T peripheral helper (Tph)-polarizing conditions and were partly cocultured with allogenic memory B cells. Cell samples were then analyzed for surface marker, transcription factor, and cytokine expression, as well as plasmablast generation. Serum samples were subjected to multiplexed bead and self-antigen arrays and enzyme-linked immunosorbent assays, and all data were compared to retrospective RNA profiling analyses. RESULTS: Differentiation of systemic JIA-naive T helper cells toward Th1 cells resulted in low expression levels of interferon-γ (IFNγ) and eomesodermin, which was associated in part with disease duration. In contrast, developing Th1 cells in patients with systemic JIA were found to produce elevated levels of interleukin-21 (IL-21), which negatively correlated with cellular expression of IFNγ and eomesodermin. In both in vitro and ex vivo analyses, IL-21 together with programmed cell death 1 (PD-1), inducible T cell costimulator (ICOS), and CXCR5 expression induced naive T helper cells from systemic JIA patients to polarize toward a Tfh/Tph cell phenotype. Retrospective analysis of whole-blood RNA-sequencing data demonstrated that Bcl-6, a master transcription factor in Tfh/Tph cell differentiation, was overexpressed specifically in patients with systemic JIA. Naive T helper cells from systemic JIA patients which were stimulated in vitro promoted B cellular plasmablast generation, and self-antigen array data indicated that IgG reactivity profiles of patients with systemic JIA differed from those of healthy controls. CONCLUSION: In the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a Tfh/Tph cell phenotype may represent an echo of autoimmunity, which may indicate the mechanisms driving progression toward chronic destructive arthritis.

Systemic autoinflammatory diseases.

Systemic autoinflammatory diseases (SAIDs) are a growing group of disorders caused by a dysregulation of the innate immune system leading to episodes of systemic inflammation. In 1997, MEFV was the first gene identified as disease causing for Familial Mediterranean Fever, the most common hereditary SAID. In most cases, autoinflammatory diseases have a strong genetic background with mutations in single genes. Since 1997 more than 30 new genes associated with autoinflammatory diseases have been identified, affecting different parts of the innate immune system. Nevertheless, for at least 40-60% of patients with phenotypes typical for SAIDs, a distinct diagnosis cannot be met, leading to undefined SAIDs (uSAIDs). However, SAIDs can also be of polygenic or multifactorial origin, with environmental influence modulating the phenotype. The implementation of a disease continuum model combining the adaptive and the innate immune system with autoinflammatory and autoimmune diseases shows the complexity of SAIDs and the importance of new methods to elucidate molecular changes and causative factors in SAIDs. Diagnosis is often based on clinical presentation and genetic testing. The timeline from onset to diagnosis takes up to 7.3 years, highlighting the indisputable need to identify new treatment and diagnostic targets. Recently, other factors are under investigation as additional contributors to the pathogenesis of SAIDs. This review gives an overview of pathogenesis and etiology of SAIDs, and summarizes recent diagnosis and treatment options.