Dysregulation of complement regulator CD55 in the initiation of autoimmunity

Abstract

Abstract CD21 is a complement receptor involved in B cell tolerance. CD21 low age-associated B cells (ABCs) are an autoimmune-prone population of B cells that are expanded in autoimmunity. B cell receptor (BCR) and toll-like receptor 9 (TLR9) co-stimulation poise B cells for this autoimmunity-associated cell fate. We and others have discovered that BCR and TLR9 co-stimulation also causes downregulation of CD55, a complement regulatory protein that dampens complement activation by interfering with the production of complement fragments. We posit that CD55, by controlling the generation of complement fragments, regulates BCR-TLR9-triggered B cell responses in the context of autoimmunity. Congruent with this hypothesis, CD55 deficiency has been shown to cause exaggerated experimental encephalitis and disease in the MRL/lpr mouse model of lupus. Our overarching hypothesis is that CD55 regulates B cell responses in the context of autoimmune disease. For this study, we examined CD86 upregulation, proliferation, and cytokine production in B cells after knocking out CD55. We found that CD55 did not impact the CD86 upregulation or proliferation of B cells, but did induce a proinflammatory cytokine profile with increased IL-6 production. In addition, crossing CD55 deficiency onto anti-insulin B cells, a well-studied anergic model, showed that CD55 deficiency partially abrogated anergy-mediated tolerance, increasing the ability of these B cells to proliferate when stimulated through TLR9. These findings may have implications for the future use of complement inhibitors in the treatment of autoimmune disease. Iris Lee holds a Dean’s Scholars Award from the Washington University Division of Physician-Scientists, which is funded by a Burroughs Wellcome Fund Physician-Scientist Institutional Award. The Kendall lab is supported by VA Merit I01BX002882 and R01 DK084246.