Abstract
Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control Salmonella 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 Salmonella enterica 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 Salmonella infection. Likewise, the T cell compartment of Salmonella-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-Salmonella 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 Salmonella. Infection with other microorganisms (Acinetobacter baumanii, Streptococcus agalactiae, or Escherichia coli) 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.
Highlights
The innate immune sensing apparatus, as originally proposed by Janeway [1], serves two important functions: first, it is a means through which the host can recognize and respond rapidly to microbial pathogens; second, the innate immune machinery directs and regulates the ensuing adaptive immune responses so as to achieve maximum efficiency against the invading pathogens
We have previously demonstrated that myeloid differentiation primary response 88 (MyD88)−/− mice are susceptible to infection by an attenuated strain of S. typhimurium (BRD509E) [17, 30]
While i.p. inoculation of BRD509E resulted in high mortality rates in MyD88−/− mice, its oral administration led to the establishment of a chronic infection that lasted for more than 6 months [17]
Summary
The innate immune sensing apparatus, as originally proposed by Janeway [1], serves two important functions: first, it is a means through which the host can recognize and respond rapidly to microbial pathogens; second, the innate immune machinery directs and regulates the ensuing adaptive immune responses so as to achieve maximum efficiency against the invading pathogens. Upon binding to pathogen-associated molecular patterns, most TLRs signal through myeloid differentiation primary response 88 (MyD88), an essential cytoplasmic adaptor protein that links triggering of TLRs and IL-1/IL-18 receptors to downstream activation of IL-1 receptor-associated kinases (IRAKs) and the nuclear factor-kappa B (NF-κB) [5]. This initiates the production of various pro-inflammatory and immunoregulatory cytokines that control the subsequent development of antimicrobial B and T cell responses [6, 7]. The requirement of TLR/MyD88 pathway for antibody responses has been challenged by several studies demonstrating T-cell-dependent antibody synthesis in the absence of TLR/ MyD88 signaling [8]
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