Balancing immunity and pathology in visceral leishmaniasis.
Experimental visceral leishmaniasis (VL) caused by infection with Leishmania donovani results in the development of organ-specific immunity in the two main target tissues of infection, the spleen and the liver. The liver is the site of an acute resolving infection associated with the development of inflammatory granulomas around infected Kupffer cells, and resistance to reinfection. Paradoxically, the spleen is an initial site for the generation of cell-mediated immune responses, but ultimately becomes a site of parasite persistence with associated immunopathological changes. These include splenomegaly and a breakdown in tissue architecture that is postulated to contribute to the immunocompromized status of the host. The progressive development of splenic pathology is largely associated with high levels of TNF and interleukin (IL)-10. Follicular dendritic cell (DC) networks are lost, whereas TNF mediates the destruction of marginal zone macrophages and gp38(+) stromal cells, and IL-10 promotes impaired DC migration into T-cell areas with consequent ineffective T-cell priming. Splenic stromal cell function is also altered, promoting the selective development of IL-10-producing DC with immunoregulatory properties. Ultimately, a fine immunological balance determines responses that effectively promote parasite clearance in the liver and those that promote pathology in the spleen, and future investigation aims to separate these responses to offer further means of parasite control in chronically infected VL patients.
Stanley
Amanda C
AC
Immunology & Infection Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia.
Engwerda
Christian R
CR
D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D006099:Granuloma / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007893:Leishmania donovani / Q000276:immunology / Q000472:pathogenicity*; D018314:Leishmania infantum / Q000276:immunology / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology; D008103:Liver Cirrhosis / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D013154:Spleen / Q000276:immunology
D018925:Chemokines