Autoimmune B Cell Repertoire in a Mouse Model of Sjögren’s Syndrome

Abstract

In genetically prone individuals, chronic immune activation may lead to expansion of autoreactive lymphocyte clones that can induce organ damage developing autoimmune disorders. Sjögren’s Syndrome (SjS) is a systemic chronic autoimmune disease that primarily affects exocrine glands. Despite the accumulated evidences of profound B-cell alterations of humoral immunity, the repertoire and development of B-cell autoreactivity in SjS remains to be determined. We hypothesize that SjS mice will have an increased frequency of self-reactive B cells with a progressive evolution to antigen-driven oligoclonality. Here, we study the B cell repertoire of NOD.H-2h4 mice, a mouse model of spontaneous autoimmunity mimicking SjS without developing diabetes. A library of 168 hybridomas from NOD.H-2h4 mice and 186 C57BL/6J splenocytes at different ages was created. The presence of mono or polyreactive autoantibodies to several antigens was evaluated by ELISA, and their staining patterns and cellular reactivity were tested by IFA and FACS. We observed a higher frequency of autoreactivity among B-cell clones from NOD.H-2h4 mice as compared to wild-type mice. The presence of polyreactive and autoreactive IgG clones increased with mice age. Strikingly, all anti-Ro52 autoantibodies were polyreactive. No loss of polyreactivity was observed upon antibody class switching to IgG. There was a progression to oligoclonality in IgG B cells with mice aging. Our results indicate that in the NOD.H-2h4 mouse model of SjS, IgG+ B cells are mainly polyreactive and might expand following an unknown antigen-driven positive selection process.

CD6 deficiency impairs early immune response to bacterial sepsis

“…Due to the complex composition of whole serum, such a protective effect cannot be unequivocally attributed to the NAbs fraction. So, additional transfer experiments were performed using a previously reported polyreactive mAb (H2h4-7-50) of the IgG2b subclass ( Sáez Moya et al., 2021 ). As illustrated in Figures 6 B–6D, H2h4-7-50 mAb transfer improved CLP-induced Cd6 −/− mouse survival in a dose-dependent manner, together with a trend to reduced total peritoneum and spleen bacterial burdens and IL-6 systemic levels.…”

“…15 h before CLP-induction. In parallel experiments, affinity-purified polyreactive H2h4-7-50 (IgG2b) mAb ( Sáez Moya et al., 2021 ) was also injected (0.2 or 0.5 mg/mouse, i . p .)…”

Effect of BAFF blockade on the B cell receptor repertoire and transcriptome in a mouse model of systemic lupus erythematosus

“…The comprehensive characterization of the BCR repertoire has improved our knowledge of autoimmune disease pathogenesis ( 43 , 44 ). The presence of abnormal specific clonotype expansion and diversity as well as the abnormal usage of IGHV genes in SLE indicate a broad dysregulation of the BCR repertoire ( 45 , 46 ).…”

Proteogenomic analysis of the autoreactive B cell repertoire in blood and tissues of patients with Sjögren’s syndrome

“…It features activated B cells in affected tissues, aberrancies in circulating B cell populations and circulating autoantibodies (AutoAbs), including antinuclear antibodies (ANAs) anti-Ro60/SSA, anti-Ro52/SSA, anti-La/SSB and rheumatoid factors (RFs) 1–3. Although the precise role of autoreactive B cells in the pathogenesis of SjS is less well defined, the pathogenic role of these AutoAbs is suggested by animal experiments4 5 and clinical observations 6. Antibodies produced by lymphomas that develop in up to 10% of patients with SjS, most commonly mucosa-associated lymphoid tissue (MALT) lymphomas, express immunoglobulins (Igs) with RF activity 7–10…”