Immunopathology and signalling molecules involved during experimental African trypanosomiasis

Abstract: In humans, African trypanosomiasis occurs in two forms; the chronic West African form is caused by T.b. gambiense and the acute or subacute East African form is caused by T.b. rhodiense. Trypanosomes are transmitted by tsetse flies generating an extracellular infection eventually affecting the central nervous system. Mortality is due to massive parasitosis or secondary infection as a result of trypanosome induced immunosuppression. About 60 million people residing in Africa are at risk. Experimental African trypanosomiasis was established in mice and rats to study the immunopathological mechanisms during the disease. We studied the production of cytokines and investigated a mechanism for their regulation through generation of cytokine neutralising autoantibodies (Aabs). Trypanosomiasis resulted in increased serum levels of IFN-[gamma], TN17-a and IL-4 with decreased Aabs to these cytokines during early infection. In the late stage of the disease these responses were reversed; low serum cytokine levels were associated with high serum Aabs. The scenario was different for IL-10 and TGF-[beta] with initial low cytokine and high Aabs levels. However, at later time points high IL-10 and TGF-[beta] expression was linked to low Aabs serum levels. Trypanosome-derived lymphocyte-triggering factor released by T.b. brucei triggered CD8 T-cells and dorsal root gangli cells to produce interferon-[gamma]. This cytokine supported T.b. brucei growth through intracellular STAT-1 activation. The mice infected with T.b. brucei developed CNS involvement which was associated with significantly increased cerebrospinal fluid levels of MIP-2, RANTES and MIP-1[alpha] and to a lower extent MCP-1. MIP-2, RANTES and MIP-1[alpha] were produced early by astrocytes and microglia and later by macrophages and T-lymphocytes. The chemokine production was at its peak when the animals developed CNS symptoms and was associated with significant infiltration of lymphomononuclear cells in the brain. The outcome of functional interactions between antigen presenting cells and T- and B-cells are dependent on expression of co-stimulatory molecules. Here we used computerised in situ imaging to investigate the induction of CD40-L, CD86, CD80, MHC-class 11 expression and germinal center (GC) formation in the spleen during the initial course of experimental African trypanosomiasis. Peak expression of these molecules occurred four days after infection. Initial enhanced CD86 expression was accompanied by CD80 expression indicating DC type-II signalling. At later time points we found a significant increase in novel GC formation. In addition, a significant upregulation of IgE response was found in the spleen of infected mice. Thus, African trypanosomiasis is associated with humoral immune activation without eliminating the pathogen.