Integrin ITGAM/CD11b negatively regulates BCR signaling to maintain autoreactive B cell tolerance (P4062)

Abstract

Abstract The hallmark of systemic lupus erythematosus (SLE) is loss of immunological tolerance and B cell hyperactivity. Recent studies demonstrated an association between the variant of the integrin-α-M (ITGAM, also called CD11b) gene and SLE susceptibility, severity of disease, and pathogenic anti-dsDNA antibody production. However, the cellular and molecular mechanism by which CD11b regulates disease pathogenesis is not understood. We found that autoreactive B cells defective of CD11b exhibited hyperproliferative responsiveness to B cell receptor (BCR) cross-linking. CD11b deficiency promoted cell cycle progression and B cell survival, which was associated with elevated anti-apoptotic gene and protein levels. In vivo engagement of BCR resulted in increased autoAb production and kidney Ig deposition in CD11b-deficient mice. CD11b-deficient autoreactive B cells had the decreased tyrosine phosphorylation including Lyn and CD22 with decreased SHP-1 recruitment but increased calcium influx. Colocalization analysis revealed that the inhibitory effect of CD11b is due to its cis-interaction with CD22. Interestingly, B cells transfected with wildtype CD11b or rs1143679 (R77H) lupus associated variant of CD11b suggest that this mutation completely impairs CD11b regulatory effect on BCR signaling. Taken together, these results reveal the negative regulatory role for CD11b in maintaining autoreactive B cell tolerance.