Balancing Protective Immunity and Immunopathology: A Unifying Model of Monocytotropic Ehrlichiosis

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Abstract
Interactions among pathogens, antigen-presenting cells (APCs) and lymphocytes are critical in maintaining balance in the daily challenges to the immune system. Monocytotropic ehrlichiosis, caused by Ehrlichia chaffeensis, is a multisystem inflammatory ailment. A complex interaction between Ehrlichia and the immune systems of a number of mammalian hosts, in human disease and animal models, has been described. The presence of an overwhelming ehrlichial infection in immunocompromised individuals suggests that severe tissue damage is most likely due to direct bacterial effect. However, clinical and experimental observations indicate that this is an oversimplified concept. First, immunocompetent patients with severe ehrlichiosis have a low bacterial burden. Second, severe and fatal murine ehrlichiosis in immunocompetent animals, which mimics human disease, is associated with a low bacterial burden in different organs and late systemic and local overproduction of TNF-alpha by T cells. In order to counterbalance overshooting immune responses, T cells and APCs secrete anti-inflammatory cytokines that are key for maintaining a healthy balance between protection and immunopathology. CD4+ T cell-mediated immunity and antibody responses of a Th1 phenotype play critical roles in protection against Ehrlichia. Of particular importance for the generation of protective immunity is the induction of activation programs in APCs directly by pathogens or by T cell-derived factors. In this study, we consider the roles of innate and adaptive immune responses in terms of protection from severe ehrlichiosis and their potential roles in immunopathology.