Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.

Coaches of youth field sports as delivery agents of injury prevention programmes: how are we training the trainers? A scoping review.

OBJECTIVE: To systematically map the coach education (CE) component of injury prevention programmes (IPPs) for youth field sports by identifying and synthesising the design, content and facilitation strategies used to address competency drivers and behaviour change. DESIGN: Scoping review. DATA SOURCES: PubMed, PsycInfo, EMBASE, CINAHL, SportDiscus and Google Scholar electronic databases were searched using keywords related to IPPs and youth field sports. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies of IPPs in youth field sports, that provided 'train-the-trainer' education to coaches as designated delivery agents. RESULTS: 20 studies from two field sports (soccer/football; n=17, Rugby Union; n=3) fulfilled the eligibility criteria. Eleven CE interventions occurred in the preseason and 18 occurred at one time-point (single day). Five studies cited use of a behavioural change theory or model in the design of their CE, most frequently the Health Action Process Approach model (n=5); and use of behavioural change techniques varied. Twelve of twenty studies (60%) reported some form of ongoing support to coaches following the CE primary intervention concurrent with IPP implementation. CONCLUSION: CE that occurs on 1 day (one time-point) is most popular for preparing coaches as delivery agents of IPPs in youth field sports. While recognising pragmatic barriers, more expansive in-service training, support and feedback may enhance the effective implementation of IPPs. TRIAL REGISTRATION NUMBER: https://doi.org/10.17605/OSF.IO/FMHGD.