Journal Article

Excessive CD11c + Tbet + B cells promote aberrant T FH differentiation and affinity-based germinal center selection in lupus

Huang, Chuanxin, Xu, Huji, Chen, Lei, Xiao, Hui, Kang, Zijian, Li, Fubin, Zhang, Wenqian, Zhang, Huihui, Liu, Yaoyang, Liu, Shujun, Shen, Nan, Zhang, Yan, Xia, Fucan

2019

Overview

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c + Tbet + age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c + Tbet + ABCs induce deregulated follicular T-helper (T FH ) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c + Tbet + ABCs and deregulated T FH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c + Tbet + ABC differentiation, and blocking CD11c + Tbet + ABC differentiation in ShipΔB mice by ablating MyD88 normalizes T FH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c + Tbet + ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

• Subject: Adult / Animals / Autoimmunity - immunology / B-Lymphocyte Subsets - immunology / B-Lymphocyte Subsets - metabolism / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Case-Control Studies / CD11 Antigens - metabolism / Cell Differentiation - immunology / Disease Models, Animal / Female / Germinal Center - immunology / Humans / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Lymph Nodes - cytology / Lymph Nodes - immunology / Male / Mice / Mice, Knockout / Middle Aged / Myeloid Differentiation Factor 88 - genetics / Myeloid Differentiation Factor 88 - immunology / Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - genetics / Signal Transduction - immunology / T-Box Domain Proteins - metabolism / T-Lymphocytes, Helper-Inducer - immunology