Background and aims Systemic Lupus Erythematosus (SLE) is a highly complex, heterogeneous autoimmune disease characterised by circulating self-reactive antibodies that deposit in tissues including skin, kidneys and brain, alongside a chronic inflammatory response that leads to progressive tissue damage and impaired function. Genome-wide association studies have identified a number of receptors and signal transduction molecules specific for the immune system that predispose to the development of SLE. A loss-of-function single nucleotide polymorphism (SNP) in the Itgam gene encoding CD11b (rs1143679) has been identified which associates with an increased incidence of SLE, implicating CD11b as a protective factor against disease development. To understand the role that CD11b plays in controlling autoimmune disease, we crossed CD11b deficient mice (CD11b-/-) with Lyn deficient (Lyn-/-) mice, a well-studied, robust model of human SLE.
Methods Double knockout Lyn-/-CD11b-/- mice were analysed over time for development of autoimmune disease and inflammation.
Results While CD11b-/- mice presented with mild splenomegaly and lymphadenopathy, immune cell compartments were unchanged and pathogenic IgG anti-dsDNA autoantibody titres and glomerulonephritis were undetected suggesting that CD11b deficiency alone is insufficient to drive autoimmune disease. Conversely, deficiency of CD11b on the Lyn-deficient autoimmune-prone background exacerbated disease, driving splenomegaly and lymphadenopathy, extramedullary haematopoiesis, autoantibody production and glomerulonephritis, which heavily impacted survival.
Conclusions These findings confirm that CD11b is an autoimmune susceptibility gene that when mutated can exacerbate the severity of disease on a susceptible genetic background. This work highlights an important role for CD11b in regulating and controlling the progression of inflammation and autoimmune disease.
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