Immunity to helminths is characterized by a stereotyped host immune response that is believed to reflect orchestration by Th2 cells. These cells produce IL-4 and IL-13, cytokines which are required to produce this phenotype in many animal models, and which are also elevated in human infections. Involved tissues become infiltrated by eosinophils, basophils and Th2 cells, and macrophages assume an alternatively activated phenotype. Mast cell hyperplasia occurs, epithelial changes involve increases in numbers of mucus-secreting cells and serum IgG1 and IgE are elevated. Similar changes occur in allergic and atopic diseases. Despite elucidation of many of the pathways downstream of IL-4 and IL-13 that mediate these cellular and tissue responses, almost nothing is known regarding the upstream determinants that elicit this stereotyped response. Increasingly, contributions from the innate immune system have been demonstrated to be required for the elicitation of downstream adaptive immune responses. This has been best shown for the Toll-like receptors, which are required to establish cellular responses to many types of viruses, bacteria and fungi. Identification of molecular constituents from helminths that activate innate myeloid cells will be crucial in understanding the nature of Th2 differentiation and the subsequent unusual constellation of myeloid cells that are present in these diseases. Using mice engineered to report each of the cell types involved during tissue responses to the nematode, Nippostrongylus brasiliensis, including Th2 cells, eosinophils, basophils, mast cells and alternatively activated macrophages, we have identified an evolutionarily conserved constituent of helminths that evokes an innate immune response characterized by infiltration of tissues by alternatively activated macrophages, eosinophils and basophils. When co-injected with an unrelated protein, we have documented antigen-specific IgG1 and IgE responses, consistent with activation of Th2-mediated immunity. This proposal seeks to localize this constituent in the helminth and host during infection; to establish the pathway by which Th2 adaptive immunity is activated; and to elucidate the mechanism by which activation of the innate cells occurs.
Helminths infect over 2.9 billion humans and are estimated to cause morbidity approaching those of diabetes and lung cancer. New insights regarding the pathogenesis of these infections are greatly needed. ? ? ?
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