Hypergammaglobulinemia sustains the development of regulatory responses during chronic Leishmania donovani infection in mice

Visceral leishmaniasis, a chronic, potentially fatal disease, is characterized by high production of low-affinity antibodies. In humans, hypergammaglobulinemia is prediction of disease progression. Nevertheless, the contribution of hypermutated and/or class-switched immunoglobulins to disease pathogenesis has never been studied. Using Aicda(-/-) mice and the experimental model of Leishmania donovani infection, we demonstrate that the absence of hypermutated and/or class-switched antibodies was associated with increased resistance to disease, stronger protective Th1 responses, and a lower frequency of regulatory IFN gamma+IL-10(+) CD4 T cells. Interestingly, stronger Th1 responses and the absence of IFN gamma+IL-10(+) CD4 T cells during chronic infection in infected Aicda(-/-) mice were not caused by a T-cell intrinsic effect of AID, but by changes in the cytokine environment during chronic disease. Indeed TNF, IL-10 and IFN-ss expressions were only upregulated in the presence of hypermutated, class-switched antibodies and hypergammaglobulinemia at later stages of infection. Taken together, our results suggest that hypergammaglobulinemia sustains inhibitory responses during chronic visceral leishmaniasis.