Antiviral Adaptor MAVS Promotes Murine Lupus With a B Cell Autonomous Role

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by increased production of autoantibodies, which commonly target nuclear antigens, and concomitant deposition of immune complexes that cause inflammation in tissues. SLE is often associated with increased systemic expression of type I interferons, in some cases due to dysregulation in nucleic acid-sensing innate pathways. There is strong genetic evidence for a link between cytoplasmic RNA sensing pathways (RIG-I/MDA5) and SLE, both in human patients and murine models, however questions still remain regarding pathway initiation, cell types involved and downstream effects. Here we show that MAVS, an essential adaptor for RIG-I/MDA5 signaling, is necessary for all symptoms of autoimmune disease that develop spontaneously in the lupus model FcγRIIB−/− mice. This effect was independent of type I interferon signaling, TLR7 expression or STING, all three factors that have been connected to autoimmunity. Mixed bone marrow reconstitution experiments showed reduced occurrence in autoimmune germinal centers and diminished autoantibody production by MAVS-deficient B cells. Thus, MAVS plays a B cell intrinsic role in autoreactive B cell activation that is independent of its anti-viral functions and independent of elevated type I interferon expression.

Innate Immune Sensing by Cells of the Adaptive Immune System

“…The formation of spontaneous germinal centers (Spt-GCs), whose dysregulation is associated with SLE and other autoimmune diseases, was shown to be dependent on MAVS and TLR7 expression in mice, and TLR7 ligation could only partially reinstate the Spt-GC development (26). Another study not only confirmed that MAVS in B cells is required for the formation of autoreactive GCs and autoantibody production in lupus-susceptible mice, but additionally linked its expression to the development of proteinuria and glomerulonephritis (27).…”

Mitochondria in innate immunity signaling and its therapeutic implications in autoimmune diseases

“…In non-synonymous single nucleotide polymorphisms (SNPs) screening analysis identifies a loss-of-function variant of MAVS is associated with an uncommon subset of SLE patients and correlates with lowered expression of type I IFN ( 116 ). Intriguingly, a recent study has shown that MAVS is critical in promoting B cell activation besides their impact on promoting type I IFN production ( 117 ). Meanwhile, aberrant RLR activation has also been proven to be associated with the pathogenesis of various autoimmune or inflammatory diseases such as SLE ( 118 ), type 1 diabetes ( 119 ), and dermatomyositis ( 120 ), due to their ability to induce proinflammatory cytokine production and autoantibody generation ( 121 ).…”

Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases

“…An autoantibody to MDA5 was detected in a subpopulation of ADM patients, and the level of autoantibody was strongly correlated with disease severity [ 99 , 100 ]. MDA5 was also reported to be associated with type 1 diabetes [ 88 , 101 , 102 ]. Several polymorphisms in IFIH1 , which encodes MDA5, were found to be associated with resistance to type 1 diabetes, such as T946A, E627*, I923V, R843H, IVS8 + 1, and IVS14 + 1 [ 103 – 106 ].…”