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.
Highlights
Dysregulation of a number of innate immune pathways has been associated with the onset and pathogenesis of systemic lupus erythematosus (SLE) [1,2,3]
Our findings reveal a decisive role of MAVS in autoimmune GC responses: the development of autoreactive GCs and autoantibody production in lupus susceptible R2−/− mice was nearly completely abrogated by the MAVS deficiency
It is the B cells that were mainly responsible for the protective effect in Mavs−/−R2−/− mice, arguing for a role for MAVS in B cell tolerance that goes beyond systemic expression of type I interferon
Summary
Dysregulation of a number of innate immune pathways has been associated with the onset and pathogenesis of systemic lupus erythematosus (SLE) [1,2,3]. Studies over the last decade have revealed critical roles for intracellular DNA and RNA sensing pathways in the production of type I interferons (IFNs), a double-edge sword in antiviral defense and autoimmunity [1,2,3]. Among the innate immune pathways that recognize viral RNA and have been linked to SLE are members of the RIG-I-like receptor (RLR) group. This group of RNA sensors includes RIG-I, MDA5 or LGP2 [4,5,6], which activate the downstream adaptor molecule MAVS ( known as IPS-1, VISA, and Cardif). MAVS initiates two well-characterized signaling cascades: 1) the interferon regulatory factors (IRFs) 3 and 7 pathway that leads to the expression of type I/III IFNs and 2) the NF-kB pathway that promotes the expression of proinflammatory proteins [15]
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