Regulation of lupus-antigen specific B cells by follicular dendritic cells (BA12P.113)

Abstract

Abstract Humoral responses are central to many autoimmune diseases such as systemic lupus erythematosus (SLE). Yet little is known about the cells and factors that are vital for maturation and sustenance of autoreactive B cells. In this study, we used a B cell receptor (specific for RNP complexes) knock-in strain 564Igi to demonstrate an important role of follicular dendritic cells (FDCs) in loss of tolerance of autoreactive B cells. Breeding the lupus-prone strain to a C4-deficient background resulted in escape of tolerance of auto-reactive idiotype+ (Id+) B cells. Total ablation or in vivo de-differentiation of FDCs in the C4-/- 564Igi mice resulted in a dramatic decrease in auto-reactive B cells and germinal centers suggesting their role in promoting loss of tolerance. Gene expression analysis of FDCs isolated from C4 -/- 564Igi mice show an increased expression of IFN-alpha (IFN-a) and downstream response genes. Treatment of the mice with anti-IFN-a receptor (IFNAR) resulted in restoration of tolerance. Blockade of myeloid cell IFNAR was identified as the critical pathway as mixed marrow chimeras of C4-/- 564Igi and IFNAR- deficient bone marrow into C4-/- recipients have a significantly lower frequency of auto-reactive B cells, which underlines the importance of IFN-a signaling in myeloid cells. Hence, we propose a model in which IFN-a secreted by activated FDCs act on dendritic cells, which in turn supports auto-reactive B cells by producing factors like IFN-a and BAFF.