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Amebic liver abscess (ALA) is a focal destruction of the liver tissue due to infection with the protozoan parasite Entamoeba histolytica (E. histolytica). So far, it is generally accepted that pathogenicity factors of the parasite contribute to tissue damage. However, epidemiological studies as well as data that evolve from respective murine models suggest a contribution of host factors as well. Independent from the infection rates, men have a higher risk to develop ALA compared to women. The mouse model for ALA exhibits the same sex difference and based on this model, we found that IFNγ provided by Natural Killer T cells confers the female resistance towards ALA. This specific immune response is clearly modulated by androgens. Hence, female mice which were substituted with testosterone develop larger abscesses and are less able to control E. histolytica viability in the liver compared to males. In male mice, on the other side, an enhanced CCL2-dependent recruitment of inflammatory Ly6Chi monocytes via the IL-23/IL-17 immune pathological axis is responsible for tissue destruction during ALA development. Furthermore, TNFα, that exhibits a pivotal role in cytotoxicity, is an effector molecule also responsible for increased liver damage in this case. Interestingly, in human asymptomatically infected with E. histolytica, men exhibit higher CCL2 serum levels compared to women, suggesting a similar mechanism to mice underlying the immune response to the parasite. Indeed, there are a variety of phenotypical similarities within the inflammatory monocyte subsets between humans and mice including sex-dependent differences in the expression of the surface receptor for CCL2 as well as a male bias in the production of specific cytokines involved in the recruitment of innate immune cells. In summary, we assume that the host immune response is considerably involved in liver tissue damage due to the strong reactivity of inflammatory monocytes, which is significantly more distinct in male individuals. |
