Date of Award
Doctor of Philosophy (PhD)
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Professor Basel K. al-Ramadi
Maria J 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 responses 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-+/IL-4+ and IFN+/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 to self-antigens and provide a potential mechanism for the inter-relationship between microbial infections and autoimmune disease development in humans.
It would have never been possible to complete this doctoral thesis without the help and support of the kind and compassionate people around me. I would like to express my deepest and heartfelt gratitude to my research guide, Professor Basel.K al-Ramadi for his excellent guidance, patience and providing me the opportunity to pursue this research. You have mentored me and guided me in the right direction, letting me explore my own potential. I would also like to thank my committee members Dr. Maria J Cabezudo and Professor Tibor Pal whose advice, support and assistance are well appreciated. I am very grateful to Mr.Yasser for being a pillar of support, help and encouragement through my research. I would also like to thank all my lab members for their constant support and insightful comments. I would like to thank my family in UAE and my family in Kuwait. My hearfelt thanks goes to my parents. This doctoral thesis is nothing but a reflection of the love and encouragement you have given me all my years. Thank you Karima, Rokaya, Heba, and Crystal for all the wonderful times we have spent over these years and for standing by my side through the good and bad times. Being miles apart, my sincere love goes to my husband Rewin for being my pillar of strength and for patiently waiting for me to complete my PhD.
Issac, Jincy Merin, "ROLE OF MYD88 PROTEIN IN THE MAINTENANCE OF IMMUNOLOGICAL SELF-TOLERANCE: INDUCTION OF AUTOIMMUNITY BY SALMONELLA INFECTION CONSEQUENT TO MYD88 DEFICIENCY" (2014). Dissertations. 26.