Intersection of Complement C4 and Interferon Alpha pathways in B cell tolerance (171.32)

Abstract Humoral autoimmunity is an important hallmark of autoimmune diseases like lupus. Factors that allow self-reactive B cells to escape negative selection stages and become activated remain poorly defined. Using a novel B cell receptor knock-in mouse strain 564Igi, we define a complement-dependent pathway by which B cell tolerance is upheld. Interestingly, the 564-autoantibody could bind SSB/La, a common lupus antigen, establishing the physiological relevance of this model. Deficiency in complement C4 caused a breakdown in the elimination of autoreactive B cell clones at the transitional stage, as demonstrated by their continued maturation, their ability to respond to a range of stimuli, entry into follicles (lack of follicular exclusion) and formation of germinal centers with a higher propensity. All results taken together indicate that the complement system must be intact for B cell tolerance to be upheld. Strikingly, the dysregulation of autoreactive B cells in C4-deficient mice was not B cell intrinsic, as a C4-sufficient myeloid compartment could re-establish efficient B cell selection. Our current model holds that poor clearance of apoptotic debris in the absence of C4 chronically activates myeloid cells to release cytokines, like IFNα, in excess and reduce the stringency of tolerance at the transitional stage. In support of our hypothesis, IFNα receptor blockade was found to restore negative selection of B cells in C4-deficient 564Igi mice.