Induction of Hypergammaglobulinemia and Autoantibodies by Infection in MyD88-Deficient Mice.

Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control infection due to defective toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) signaling has linked the development of persistent infections to a breakdown in B cell tolerance. However, the extent of immune dysregulation in the absence of TLR-MyD88 signaling remains poorly characterized. Here, we show that MyD88 mice are unable to eliminate attenuated serovar Typhimurium, even when challenged with a low-dose inoculum (200 CFUs/mouse), developing a persistent and progressive infection when compared to wild-type (MyD88) animals. The splenic niche of MyD88 mice revealed increased counts of activated, Sca-1-positive, myeloid subpopulations highly expressing BAFF during persistent infection. Likewise, the T cell compartment of -infected MyD88 mice showed increased levels of CD4 and CD8 T cells expressing Sca-1 and CD25 and producing elevated amounts of IL-4, IL-10, and IL-21 in response to CD3/CD28 stimulation. This was associated with increased Tfh cell differentiation and the presence of CD4 T cells co-expressing IFN-γ/IL-4 and IFN-γ/IL-10. Noteworthy, infected MyD88 mice had enhanced serum titers of both anti- antibodies as well as autoantibodies directed against double-stranded DNA, thyroglobulin, and IgG rheumatoid factor, positive nuclear staining with HEp-2 cells, and immune complex deposition in the kidneys of MyD88 mice infected with live but not heat-killed . Infection with other microorganisms (, or ) was unable to trigger the autoimmune phenomenon. Our findings suggest that dysregulation of the immune response in the absence of MyD88 is pathogen-dependent and highlight potentially important genotype-environmental factor correlations.