Hao Wang

Summary: Anti-CD19 chimeric antigen receptor (CAR)-T therapy induces profound remissions in lupus by depleting B cells, challenging the longstanding view that treatment-resistant disease is sustained by long-lived plasma cells. Additionally, emerging relapses highlight the need to understand how pathogenic autoantibodies arise. Using molecular antibody tagging in mice with human monogenic lupus variants, we reveal that autoantibody-producing cell cohorts are long-lived but plasma cells are short-lived, requiring continuous replenishment from proliferating precursors. The spleen acts as a major plasma cell reservoir, with perivascular localization conserved in mice and lupus patients. Relapse after anti-CD19 CAR-T occurred through newly-generated B cells rather than treatment-resistant clones. Plasma cell depletion by anti-BCMA CAR-T failed to eliminate some precursors that become autoantibody-secreting. These findings demonstrate that continuous B cell-to-plasma cell differentiation, not intrinsic plasma cell longevity, sustains pathogenic antibody responses in lupus, supporting a potential benefit of adjunctive therapies after CAR-T, particularly in genetically predisposed patients.

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.

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 ( CTLA4 ) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (T _reg ) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor–β. Consistent with DECTIN-1’s T _reg -boosting ability, partial DECTIN-1 deficiency exacerbated the T _reg defect conferred by CTL4-4h. DECTIN-1/ CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.

In antibody responses, mutated germinal center B (B _GC ) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of B _GC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T _FH ) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the T _FH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B _GC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B _GC cells, compared with non-B _GC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B _GC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in B _GC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.