Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-γ and interleukin-10 and low frequency of tumour necrosis factor-α+ monocytes are hallmarks of active human visceral Leishmaniasis due to<i>Leishmania chagasi</i>infection

Peruhype-Magalhães, Vanessa; Martins‐Filho, Olindo Assis; Prata, A; Silva, L. De A.; Rabello, Ana; Teixeira-Carvalho, A.; Figueiredo, Rosângela Maria; Guimarães-Carvalho, Sílvio Fernando; Ferrari, Teresa Cristina Abreu; Weyenbergh, Johan Van; Corrêa-Oliveira, Rodrigo

doi:10.1111/j.1365-2249.2006.03171.x

Cited by 105 publications

(123 citation statements)

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“…Although some studies evaluating cytokines in serum samples have either not detected or found low concentrations of 69,70 , other studies have produced conflicting results. IFN-g was detected in 17 of 44 patients in Iran 2 and in 13 of 15 patients in Brazil 20 ; in addition, high levels have been confirmed in patients in Asia, Europe, Africa, and Brazil 9,15,31,32,50,52 . These differing results are most likely not related to the selected patient groups or to the Leishmania species involved, but rather to the samples that were analyzed.…”

Section: Immunoactivation In Lymphoid Organsmentioning

confidence: 93%

“…It has also been found to be important in susceptibility to visceral leishmaniasis 30,49 . It has been detected in different samples of human visceral leishmaniasis: as mRNA in bone marrow 36 , lymph node 27 , and spleen 38 aspirates and at high levels in serum 1,2,15,40,50,52,63,69 ; for further information see 51 . As mentioned earlier, the possible effect of IL-10 on the production of, or proliferation of IFN-g producing cells 11,28 may not be important given the high activation of the immune response in lymphoid organs during active disease.…”

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confidence: 99%

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Immunoactivation and immunopathogeny during active visceral leishmaniasis

Goto

Prianti

2009

Rev. Inst. Med. trop. S. Paulo

101

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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...

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Section: Immunoactivation In Lymphoid Organsmentioning

confidence: 93%

mentioning

confidence: 99%

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Goto

Prianti

2009

Rev. Inst. Med. trop. S. Paulo

101

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Section: Discussionmentioning

confidence: 99%

“…It has also been postulated that gut parasitization by Leishmania amastigotes accelerates the mucosal damage associated with HIV-1 infection, increasing the levels of microbial translocation into the bloodstream, causing a systemic proinflammatory response and increasing immune activation [17][18][19][20][21][22][23][24]. Furthermore, higher T-helper type 2 (Th2) cytokine production has been observed in peripheral blood mononuclear cells (PBMCs) from coinfected patients [12,25].To date, most studies of VL/HIV coinfection have been carried out in patients with active HIV-1 replication and/or active VL, and there are no studies comparing VL/HIVcoinfected patients and other HIV-1-infected patients with similar immunological alterations but without Leishmania coinfection, such as immunodiscordant patients [26,27]. Thus, we designed a study to investigate how VL could alter immunological parameters in HIV-1-infected patients with virological suppression, and to determine the factors that could explain the impaired immune response and frequent relapses in coinfected patients, in comparison with HIV-1-infected patients with IDR and also patients who had an adequate, concordant immunological response (CR) to cART.…”

mentioning

confidence: 99%

Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

Casado¹,

Abad-Fernández²,

Moreno³

et al. 2015

HIV Medicine

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ObjectivesDifferent immune alterations have been described in HIV-infected patients with visceral leishmaniasis (VL). We aimed to identify the immunological factors involved in the lack of immunological recovery and VL relapses in HIV-infected patients with VL, by comparison with other HIV-infected patients. MethodsWe carried out a cross-sectional study of 55 patients receiving suppressive combination antiretroviral therapy (cART) for at least 1 year: nine with previous relapsing VL, 20 with an immunodiscordant response (IDR) to cART (CD4 count < 200 cells/μL) and no previous VL, and 26 with a concordant response (CR) to cART (CD4 count > 350 cells/μL) without VL. Immunosenescence was investigated by analysing CD57 + CD28− levels, immune activation by analysing CD38 + HLA-DR + levels, inflammation by analysing interleukin (IL)-6 levels, and microbial translocation by analysing lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels. ResultsIn VL patients, the median time since VL diagnosis was 42 months, and all patients had had at least one relapse despite suppressive cART for a median time of 43 months. Patients with previously diagnosed VL had a higher CD8 T-cell activation level (P < 0.001) than those with IDR. Also, levels of IL-6, LPS and especially sCD14, associated with bacterial translocation and additional monocyte activation, were significantly increased in patients with previous VL compared with patients with IDR (P = 0.048, P = 0.049 and P < 0.001, respectively). In addition, patients with previous VL had higher levels of CD8 T-cell senescence. Notably, the levels of immune activation and inflammation in patients with previous VL were not related to the time of VL diagnosis, the number of VL relapses, or hepatitis C virus (HCV) coinfection. ConclusionsOur data demonstrate that VL patients had an even worse immunological status than patients with IDR, which was probably associated with increased microbial translocation and additional monocyte/macrophage activation. These data explain the observed lack of immunological recovery and the occurrence of VL relapses in HIV-infected patients with previous VL. Specifically, visceral leishmaniasis (VL) is an infectious disease caused mainly by Leishmania donovani and Leishmania infantum (Leishmania chagasi), intracellular protozoans that infect macrophage cell lineages from lymphoid organs. It is a common coinfection in HIV-1-infected individuals in the Mediterranean basin, including Spain, with a prevalence of up to 9%. VL/HIV-1 coinfection is characterized by significantly lower cure rates, higher drug toxicity, higher relapse rates, and higher mortality rates (nearly 50%) than those for non-HIV-1-infected individuals with VL [5,6].While cART has been shown to decrease the incidence of leishmaniasis in HIV-1-infected patients, it does not seem to prevent the appearance of frequent relapses in patients previously diagnosed and largely pretreated with antiretrovirals [7][8][9], demonstrating the persistence of the parasite in different cell lines. Moreover, ...

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“…However, the basal levels of these cytokines have been detected in asymptomatic cases from Brazil, a finding that requires Key words: cytokines -visceral leishmaniasis -clinical forms further investigation (Peruhype-Magalhães et al 2006). A significant reduction in these cytokines, particularly a decline in IFN-γ, which has been indicated to be a reliable marker of the cured disease, has been observed in patients after treatment of VL (Caldas et al 2005, Ansari et al 2006.…”

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confidence: 99%

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

Costa

Aquino

et al. 2012

Mem. Inst. Oswaldo Cruz

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It is not well established whether cytokine production differs in response to different clinical forms of visceral leishmaniasis (VL). In this work, we performed a cross-sectional study to investigate the plasma levels of cytokines [interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-10 and IL-12] involved in the pathogenesis of VL in 80 subjects from VL endemic areas, including subjects with active VL, subjects with asymptomatic infection, subjects with cured VL and uninfected controls. The patients were recruited by sampling from a referral hospital and by random selection from a population-based cohort study. The results showed significant differences in the plasma concentration of all cytokines between the groups (p < 0.05). Patients with the active disease had higher plasma levels of IL-10, IL-4, INF-γ and TNF-α relative to the other groups and they produced more IL-12 than asymptomatic and cured subjects. Only the IL-2 concentration was higher in the asymptomatic and cured subjects relative to the patients with active disease (p < 0.05). Our results suggest that these cytokines can be used as markers in epidemiological studies conducted in endemic areas to distinguish between different clinical forms of VL. However, their usefulness should be confirmed in investigations conducted in other endemic areas

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Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-γ and interleukin-10 and low frequency of tumour necrosis factor-α+ monocytes are hallmarks of active human visceral Leishmaniasis due toLeishmania chagasiinfection

Abstract: Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-g and interleukin-10 and low frequency of tumour necrosis factor-a + monocytes are hallmarks of active human visceral Leishmaniasis due to Leishmania chagasi infection

Cited by 105 publications

References 27 publications

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

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

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