Dataset Information

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

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-?/IL-4 and IFN-?/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.

SUBMITTER: Issac JM

PROVIDER: S-EPMC6019449 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Induction of Hypergammaglobulinemia and Autoantibodies by <i>Salmonella</i> Infection in MyD88-Deficient Mice.

Issac Jincy M JM Mohamed Yassir A YA Bashir Ghada Hassan GH Al-Sbiei Ashraf A Conca Walter W Khan Taj A TA Iqbal Asif A Riemekasten Gabriela G Bieber Katja K Ludwig Ralf J RJ Cabral-Marques Otavio O Fernandez-Cabezudo Maria J MJ Al-Ramadi Basel K BK

Frontiers in immunology 20180620

Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control <i>Salmonella</i> 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 My ...[more]

PMID: 29973931

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Project description:Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of defense. Patients suffering from chronic granulomatous disease are deficient in one of the subunits of NADPH oxidase. They display a high incidence of Crohn's disease-like intestinal inflammation and are hyper-susceptible to infection with fungi and bacteria, including a 10-fold increased risk of Salmonellosis. It is not completely understood which steps of the infection process are affected by the NADPH oxidase deficiency. We employed a mouse model for Salmonella diarrhea to study how NADPH oxidase deficiency (Cybb (-/-)) affects microbe handling by the large intestinal mucosa. In this animal model, wild type S. Typhimurium causes pronounced enteropathy in wild type mice. In contrast, an avirulent S. Typhimurium mutant (S.Tm(avir); invGsseD), which lacks virulence factors boosting trans-epithelial penetration and growth in the lamina propria, cannot cause enteropathy in wild type mice. We found that Cybb (-/-) mice are efficiently infected by S.Tm(avir) and develop enteropathy by day 4 post infection. Cell depletion experiments and infections in Cybb (-/-) Myd88 (-/-) mice indicated that the S.Tm(avir)-inflicted disease in Cybb (-/-) mice hinges on CD11c(+)CX3CR1(+) monocytic phagocytes mediating colonization of the cecal lamina propria and on Myd88-dependent proinflammatory immune responses. Interestingly, in mixed bone marrow chimeras a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to ameliorate disease severity. Our data indicate that NADPH oxidase expression is of key importance for restricting the growth of S.Tm(avir) in the mucosal lamina propria. This provides important insights into microbe handling by the large intestinal mucosa and the role of NADPH oxidase in maintaining microbe-host mutualism at this exposed body surface.

Project description:Previous studies using purified toll-like receptor (TLR) ligands plus agonistic anti-CD40 antibodies showed that TLRs and CD40 can act synergistically on dendritic cells (DCs) to optimize T cell activation and Th1 differentiation. However, a synergistic effect of TLRs and CD40 during bacterial infection is not known. Here, we show that mice lacking the TLR adaptor MyD88 alone, or lacking both MyD88 and CD40 [double knockout (DKO) mice], are compromised in survival to Salmonella infection but have intact recruitment of neutrophils and inflammatory monocytes as well as unaltered abundance of DC subsets and DC activation in infected tissues. In contrast to infected wildtype and CD40(-/-) mice, both MyD88(-/-) mice and DKO mice lack detectable serum IFN-γ and have elevated IL-10. A synergistic effect of TLRs and CD40 was revealed in co-culture experiments where OT-II T cell proliferation was compromised when DKO DCs were pulsed with OVA protein and OVA323-339 peptide, but not with heat-killed Salmonella expressing OVA (HKSOVA), relative to MyD88(-/-) DCs. By contrast, MyD88(-/-) or DKO DCs pulsed with any of the antigens had a similar ability to induce IFN-γ that was lower than WT or CD40(-/-) DCs. DKO DCs pulsed with HKSOVA, but not with OVA or OVA323-339, had increased IL-10 relative to MyD88(-/-) DCs. Finally, HKSOVA-pulsed MyD88(-/-) and DKO DCs had similar and low induction of NFκB-dependent and -independent genes upon co-culture with OT-II cells. Overall, our data revealed that synergistic effects of CD40 and MyD88 do not influence host survival to Salmonella infection or serum levels of IFN-γ or IL-10. However, synergistic effects of MyD88 and CD40 may be apparent on some (IL-10 production) but not all (OT-II proliferation and IFN-γ production) DC functions and depend on the complexity of the antigen. Indeed, synergistic effects observed using purified ligands and well-defined antigens may not necessarily apply when complex antigens, such as live bacteria, challenge the immune system.

Dataset Information

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

Publications

Induction of Hypergammaglobulinemia and Autoantibodies by <i>Salmonella</i> Infection in MyD88-Deficient Mice.

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