Negative regulation of autoreactive B cell activation by integrin CD11b molecule (167.13)

Abstract

Abstract The immunological hallmark of systemic lupus erythematosus (SLE) is a loss of immune 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. However, how CD11b regulates disease pathogenesis remains elusive. We found surprisingly that B cells from CD11b knock out (KO) mice exhibited hyperproliferative responsiveness to B cell receptor (BCR) cross-linking. CD11b KO autoreactive B cells had the decreased tyrosine phosphorylation including Lyn and PLCγ2 and increased p38 MAKP. Moreover, CD11b deficiency promoted B cell survival which was associated with increased BCL-xl expression. In vivo engagement of BCR by apoptotic cells resulted in significantly increased autoAb production in CD11b KO mice. Furthermore, we found that BCR cross-linking could induce CD11b activation and modulate CD11b-medited phagocytosis, suggesting ‘out-side-in’ activation of CD11b integrin by BCR crosslinking. Taken together, these results reveal the interaction between CD11b integrin and BCR signaling pathways and suggest the critical role for CD11b molecule in maintaining autoreactive B cell tolerance (This work was supported by the Alliance for Lupus Research).