Campylobacter jejuni is an enteric bacterium present ubiquitously in food animals and is one of the top two etiologic agents of gastroenteritis worldwide. While many healthy individuals can be colonized asymptomatically or experience self-limiting gastroenteritis, serious autoimmune disease sequelae can also follow infections with C. jejuni. Inflammatory Bowel Disease, Reactive Arthritis and acute neuropathies Guillain Barré Syndrome and Miller Fisher Syndrome, have also been demonstrated to be strongly associated with antecedent C. jejuni infection. GBS is now the world's leading cause of acute neuromuscular paralysis, with up to 10,000 cases annually in the USA. Yet very little is known about how Campylobacter jejuni interacts with the immune system to establish asymptomatic colonization, induce gastroenteritis and/or lead to autoimmune sequelae. Lack of functional IL-10 is a predisposing factor to IBD, and thus the IL-10 deficient mice reiterate human disease by developing colitis after C. jejuni infection, making it a useful model for studying colon inflammation. In these studies, we have demonstrated that C. jejuni mediated colitis in specific pathogen free C57BL/6IL-10-/- mice was IFN- and IL-17 cytokine dependent. We also showed that both Innate Lymphoid Cells and T cells participate in IFN- and IL-17 elicitation, albeit with different kinetics. We also showed that T cells are essential for C. jejuni induced colitis. These results yield new cytokine and cellular targets for immunomodulatory therapy against IBD. This work also provides the first demonstration of a time-dependent role of Innate Lymphoid Cells and T cells in mediating Type1 (IFN-) and Type17 (IL-17) cytokine responses following infection with a human pathogen. Furthermore, we demonstrated that depleting IFN- and/or IL-17 pivots the immune response away from sustaining inflammation in the colon to inducing a contrasting Type2 (IL-4) cytokine response. Following infection with C. jejuni isolates from GBS patients, this T helper cell dependent IL-4 cytokine response lead to elicitation of circulating autoantibodies. These autoantibodies caused histological and phenotypic changes in IL-10 deficient mice that were consistent with this syndrome's manifestation in humans. We further demonstrated that Siglec-1 is a central antigen presenting cell-expressed receptor that mediates uptake of C. jejuni and subsequent TH2 maturation in a sialylation dependent manner. Therefore, IL-4 and Siglec-1 are novel and rational therapeutic targets against this peripheral autoimmunity, against which only invasive, non-specific and inefficient therapies like plasmapheresis exist.
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