Immunoactivation and immunopathogeny during active visceral leishmaniasis

Abstract

SUMMARYVisceral leishmaniasis is caused by protozoan parasites of the Leishmania donovani complex. During active disease in humans, high levels of IFN-g and TNF-a detected in blood serum, and high expression of IFN-g mRNA in samples of the lymphoid organs suggest that the immune system is highly activated. However, studies using peripheral blood mononuclear cells have found immunosuppression specific to Leishmania antigens; this poor immune response probably results from Leishmania antigen-engaged lymphocytes being trapped in the lymphoid organs. To allow the parasites to multiply, deactivating cytokines IL-10 and TGF-b may be acting on macrophages as well as anti-Leishmania antibodies that opsonize amastigotes and induce IL-10 production in macrophages. These high activation and deactivation processes are likely to occur mainly in the spleen and liver and can be confirmed through the examination of organ samples. However, an analysis of sequential data from studies of visceral leishmaniasis in hamsters suggests that factors outside of the immune system are responsible for the early inactivation of inducible nitric oxide synthase, which occurs before the expression of deactivating cytokines. In active visceral leishmaniasis, the immune system actively participates in non-lymphoid organ lesioning. While current views only consider immunocomplex deposition, macrophages, T cells, cytokines, and immunoglobulins by diverse mechanism also play important roles in the pathogenesis. KEYWORDS:Visceral leishmaniasis; Human; Immunosuppression; Immunoactivation; Cytokines; Immunopathogenesis.Visceral leishmaniasis is caused by protozoa of the genus Leishmania that are transmitted to mammalian hosts, including humans, by phlebotomine sandflies. The disease is present in 66 countries in tropical and subtropical regions, and 90% of cases occur in India, Sudan, Bangladesh, Nepal, and Brazil. It is estimated that there are 500,000 new cases a year worldwide 68 , and 3,000 new cases occur each year in Brazil 48 . Until recently, the disease was thought to be caused by three species of the Leishmania donovani complex: Leishmania (Leishmania) donovani, L. (L.) infantum, and Leishmania (L.) chagasi (a species present in Brazil). There is now debate, however, over whether L. (L). infantum and Leishmania (L.) chagasi are the same 44 or different 60 species. In this review, the names of the three species will be used as in the original publications. Leishmania (Leishmania) donovani is present in East Africa, India, and parts of the Middle East, while L. (L.) infantum in Europe, North Africa, and South and Central America. Human infections can be asymptomatic or can manifest as oligosymptomatic and progressive diseases; progressive cases can involve hepatosplenomegaly, fever, pancytopenia, hypergammaglobulinemia, and serious weight loss 4 . During active visceral leishmaniasis, the parasite multiplies within the cells of the mononuclear phagocyte system in the spleen, liver, and bone marrow, and the disease is fatal if untreated.Studies...

Cytokines and visceral leishmaniasis: a comparison of plasma cytokine profiles between the clinical forms of visceral leishmaniasis

“…Here, a mixed cytokine profile (Th1 and Th2) was detected in the patients with the active disease. This mixed profile has also been reported by other investigators (Goto & Lindoso 2004, Peruhype-Magalhães et al 2005, Goto & Prianti 2009). The increase in inflammatory cytokines could be associated with the physiopathological alterations seen during the active disease, whereas the production of IL-10 has been suggested to be important for the survival and persistence of the parasite inside macrophages (PeruhypeMagalhães et al 2006.…”

“…IFN-γ is likely produced in lymphoid organs where Leishmania proliferates (Goto & Prianti 2009). However, few studies support this hypothesis because it is difficult to obtain tissue samples from patients with the active disease.…”

“…The factors that determine the development of VL have not been completely identified, but the specific cellular immune response to Leishmania seems to play a key role in the control of infection (Holaday 2000, Bacelar & Carvalho 2005, Michalick & Genaro 2005. In experimental mouse models using Leishmania major, protection against the disease is attributed to a T helper (Th)1 immune response that is characterised by the production of interferon (IFN)-γ and interleukin (IL)-12, whereas susceptibility to the disease is attributed to a Th2 type response with the production of IL-4 and IL-10 (Park et al 2000, Belkaid et al 2002, Stetson et al 2002, Goto & Prianti 2009). However, this dichotomy is not evident in mice infected with Leishmania donovani (Melby et al 2001, Peruhype-Magalhães et al 2005.…”

Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection

“…It is endemic in 88 countries and affects 12 million people worldwide. The visceral form, caused by Leishmania donovani and Leishmania chagasi, is prevalent in tropical and subtropical regions, with 90% of cases occurring in Bangladesh, Brazil, India, Nepal and Sudan (Desjeux 2001, Goto & Prianti 2009, Verma et al 2010. Leishmania infection may be asymptomatic, oligosymptomatic or progressive and the most severe cases result in splenomegalia, fever, pancytopenia, hypergammaglobulinemia and weight loss ).…”

“…Leishmania infection may be asymptomatic, oligosymptomatic or progressive and the most severe cases result in splenomegalia, fever, pancytopenia, hypergammaglobulinemia and weight loss ). During active visceral leishmaniasis, parasites replicate within mononuclear phagocytes in the spleen, liver and bone marrow; disease can be fatal if the infection is not treated (Goto & Prianti 2009). …”