Date of Award
Doctor of Philosophy (PhD)
Bael K. al-Ramadi
Maria J. Femandez-Cabezudo
Activation of the innate immune system is a prerequisite for the induction of adaptive immune responses to both infectious and non-infectious agents. Toll-like receptors (TLRs) are a family of proteins important for recognizing pathogen associated molecular patterns. MyD88 is an adaptor molecule whose function is critical in TLR signaling. MyD88-deficient (MyD88-/-) mice exhibit heightened susceptibility to infections, even by attenuated strains of Salmonella enterica serovar Typhimurium. Paradoxically, despite their hypersusceptibility, infected MyD88-/- mice produce elevated serum levels of anti-Salmonella antibodies regardless of the route of infection. This hypergammaglobulinemia was observed with both Th1-driven (IgG2c and IgG3) and Th2-driven (IgG1) antibody isotypes. The dysregulated antibody response also led to the production of autoantibodies as demonstrated by reactivity to dsDNA and thyroglobulin, positive nuclear staining with HEp2 cells, and immune complex deposition in the kidneys of MyD88-/- mice. Utilizing intracellular cytokine staining, real time PCR and 6-color flowcytometric analysis, we demonstrated that these autoimmune responses correlate with the activation of distinct populations of IFN-y+/IL-4+ and IFNy+/IL-10+ T helper lymphocytes. Further analysis revealed that these most likely represent a specialized family of cells known as follicular helper T cells (TFH cells) which function to promote B cell activation and antibody production. The aberrant expansion of these TFH-like cells could underlie the activation of autoreactive B cells leading to humoral autoimmunity. Our findings highlight a critical role for TLR-MyD88 pathway in controlling reactivity of self-antigens and provide a potential mechanism for the inter-relationship between microbial infections and autoimmune disease development in humans.
Merin Issac, Jincy, "Role of MYD88 Protein in the Maintenance of Immunological Self-Tolerance: Induction of Autoimmunity by Salmonella Infection Consequent to MYD88 Deficiency." (2014). Theses. 229.