Premature Cell Senescence and T Cell Receptor‐Independent Activation of CD8+ T Cells in Juvenile Idiopathic Arthritis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99044/1/art38015.pd

T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis

T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αβT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis

Consensus Treatment Plans For Chronic Nonbacterial Osteomyelitis Refractory To Nonsteroidal Antiinflammatory Drugs And/Or With Active Spinal Lesions

Objective. To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies. Methods. Virtual and face-to-face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflanunatory drug (NSAID) monotherapy and/or with active spinal lesions. Results. Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response. Conclusion. Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.Wo