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

Abstract

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 RNAsequencing 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.

Autoantibody-Mediated Depletion of IL-1RA in Still’s Disease and Potential Impact of IL-1 Targeting Therapies

“…Yet, for sJIA, association with HLA-DRB1-11* and altered inflammatory T-lymphocyte subsets, in part driven by IL-1 signaling, were reported [ 14 – 17 ]. Beyond, recent data point to an enhanced development of inflammatory, antibody-production driving T helper cells and altered self-reactive IgG profiles in sJIA [ 18 ], supporting the concept that features adaptive immunity may drive Still’s disease progression [ 19 – 21 ]. For AOSD, certain HLA haplotypes were associated with the development and course of disease [ 22 – 25 ], and anecdotal reports suggest that individual patients with AOSD can potentially benefit from B-cell depletion [ 26 ].…”

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

“…The classification of SJIA as an autoinflammatory or autoimmune disease has been discussed in the literature, as the disease also shows signs of both disease groups [ 22 , 23 , 24 , 25 ]. In 2006, McGonagle et al proposed a disease continuum model combining the adaptive and the innate immune system with their respective disease group [ 26 ].…”