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- Title
Induction of Hypergammaglobulinemia and Autoantibodies by <italic>Salmonella</italic> Infection in MyD88-Deficient Mice.
- Authors
Issac, Jincy M.; Mohamed, Yassir A.; Bashir, Ghada Hassan; Al-Sbiei, Ashraf; Conca, Walter; Khan, Taj A.; Iqbal, Asif; Riemekasten, Gabriela; Bieber, Katja; Ludwig, Ralf J.; Cabral-Marques, Otavio; Fernandez-Cabezudo, Maria J.; al-Ramadi, Basel K.
- Abstract
Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control <italic>Salmonella</italic> 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 <italic>Salmonella enterica</italic> 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 <italic>Salmonella</italic> infection. Likewise, the T cell compartment of <italic>Salmonella</italic>-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-<italic>Salmonella</italic> 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 <italic>Salmonella</italic>. Infection with other microorganisms (<italic>Acinetobacter baumanii, Streptococcus agalactiae</italic>, or <italic>Escherichia coli</italic>) 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.
- Subjects
HYPERGAMMAGLOBULINEMIA; AUTOANTIBODIES; SALMONELLA diseases
- Publication
Frontiers in Immunology, 2018, pN.PAG
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2018.01384