Can interferon-γ and interleukin-10 balance be associated with severity of human <i>Leishmania (Viannia) braziliensis</i> infection?

Gomes-Silva, Adriano; Bittar, Rita de Cássia; Nogueira, R.; Amato, Valdir Sabbaga; Mattos, Marise; Oliveira-Neto, Manoel P.; Coutinho, S.; Da‐Cruz, Alda Maria

doi:10.1111/j.1365-2249.2007.03436.x

Cited by 77 publications

(88 citation statements)

References 26 publications

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“…Although IL-10 can favor the progression of the disease in the early phase of leishmaniasis, depending on the counter balance exerted by IFN-γ, cure can be achieved due to its effector functions on parasitized macrophages (Rocha et al 1999, Bosque et al 2000. Moreover, our results strengthen the idea that the intrinsic ability to produce IL-10 in response to Leishmania infection can be a key factor in avoiding a possible harmful effect of IFN-γ, exerting an important function on regulating inflammatory responses necessary for infection control (Rocha et al 1999, Belkaid et al 2001, Gomes-Silva et al 2007.…”

Section: Discussionsupporting

confidence: 72%

T-cell responses associated with resistance to Leishmania infection in individuals from endemic areas for Leishmania (Viannia) braziliensis

Bittar

Nogueira

Vieira-Gonçalves

et al. 2007

Mem. Inst. Oswaldo Cruz

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Subclinical or asymptomatic infection is documented in individuals living in endemic areas for leishmaniasis suggesting that the development of an appropriate immune response can control parasite replication and maintain tissue integrity. A low morbidity indicates that intrinsic factors could favor resistance to Leishmania infection. Herein, leishmanial T-cell responses induced in subjects with low susceptibility to leishmaniasis as asymptomatic subjects were compared to those observed in cured cutaneous leishmaniasis (CCL) patients, who controlled the disease after antimonial therapy. All of them have shown maintenance of specific long-term immune responses characterized by expansion of higher proportions of CD4 + as compared to CD8 + Leishmania reactive T-lymphocytes. Asymptomatic subjects had lower indexes of in vitro Leishmania induced lymphoproliferative responses and interferon-gamma (IFN-γ) production in comparison to CCL patients. On the other hand, interleukin (IL-10) production was much higher in asymptomatics than in CCL, while no differences in IL-5 levels were found. In conclusion, long lived T-cell responses achieved by asymptomatic individuals differed from those who had developed symptomatic leishmaniasis in terms of intensity of lymphocyte activation (proliferation or IFN-γ) and regulatory mechanisms (IL-10). The absence of the disease in asymptomatics could be explained by their intrinsic ability to create a balance between immunoregulatory (IL-10) and effector cytokines (IFN-γ), leading to parasite destruction without producing skin tissue damage. The establishment of profiles of cell-mediated immune responses associated with resistance against Leishmania infection is likely to make new inroads into understanding the long-lived immune protection against the disease.Key words: asymptomatic infection -Leishmania (Viannia) braziliensis -cured leishmaniasis -cytokines -T-cell subsetslong term immunity (Grimaldi Jr & MacMahon-Pratt 1991). The spectrum of the clinical presentation ranges from self-healing or benign cutaneous lesions to more severe forms, such as disseminated lesions or mucosal involvement (Da-Cruz & Pirmez 2005).Studies conducted in mice and humans have unequivocally shown that a major T-cell driven component underlies the establishment of acquired immunity and protection against re-infection ( Coutinho et al. 1996, Louis et al. 1998, Bosque et al. 2000. Cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factoralpha (TNF-α) activate macrophages for killing parasites, while interleukin (IL)-4, IL-5, IL-10, and transforming grow factor-beta (TGF-β) favor intracellular parasite growth (Louis et al. 1998. In addition, IL-10 production by CD4 + CD25 + T-cells is required for maintenance of Leishmania after cure, which in turn preserves an adaptive immunity to L. (Leishmania) major (Belkaid et al. 2002).The majority of ATL patients develop cutaneous leishmaniasis (CL) (Oliveira-Neto et al. 2000), but occurrence of subclinical or asymptomatic infection strongly suggests that po...

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Section: Discussionsupporting

confidence: 72%

T-cell responses associated with resistance to Leishmania infection in individuals from endemic areas for Leishmania (Viannia) braziliensis

Bittar

Nogueira

Vieira-Gonçalves

et al. 2007

Mem. Inst. Oswaldo Cruz

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“…23,24 Therefore, it is an imbalance between pro-inflammatory and regulatory cytokines that leads to ATL pathogenesis. 23,32,33 Herein, we showed that elderly subjects have a decrease in the antigen-response of IFNγ, and thus lack the main cytokine responsible for macrophage activation and killing. Furthermore, we also observed an increase in IL-10 that may facilitate parasite growth.…”

Section: Discussionmentioning

confidence: 99%

Age Modifies the Immunologic Response and Clinical Presentation of American Tegumentary Leishmaniasis

Carvalho¹,

Amorim²,

Barbosa³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Leishmania (Viannia) braziliensis is the main causal agent of American tegumentary leishmaniasis (ATL) that may present as cutaneous, mucosal, or disseminated cutaneous leishmaniasis. The disease is highly prevalent in young males and there is a lack of studies of ATL in the elderly. Herein, we compared clinical manifestations, immunologic response, and response to antimony therapy between patients 60 years of age (N = 58) and patients who were 21-30 years of age (N = 187). The study was performed in Corte de Pedra, Bahia, Brazil, a well-known area of L. braziliensis transmission. Cytokine production by cultured peripheral blood mononuclear cells stimulated with soluble Leishmania antigen was performed. Elderly subjects more frequently had a previous history of cutaneous leishmaniasis, large lesions, or mucosal leishmaniasis, and they were less likely to have lymphadenopathy. There was no difference regarding gender and response to therapy. Peripheral blood mononuclear cells from elderly subjects produced a similar amount of tumor necrosis factor than young patients but they produced less interferon-gamma and more interleukin-10 than young subjects. We concluded that elderly patients with cutaneous leishmaniasis should be searched for mucosal or disseminated leishmaniasis. The decreased interferon-gamma production and increase in interleukin-10 observed in elderly patients may contribute to parasite persistence and L. braziliensis infection dissemination.

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“…Another explanation for the extensive tissue damage can be low expression or no modulation of IL-10 mRNA, which has been observed in the majority of tissues of all animals and leads to a decreased ability to downregulate IFN-␥ mRNA. In human leishmaniasis patients, a high IFN-␥/ IL-10 ratio is associated with more severe clinical forms of the disease, such as mucosal leishmaniasis (37,38).…”

Section: Discussionmentioning

confidence: 99%

Comparative Evaluation of Lesion Development, Tissue Damage, and Cytokine Expression in Golden Hamsters (Mesocricetus auratus) Infected by Inocula with Different Leishmania (Viannia) braziliensis Concentrations

et al. 2014

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The golden hamster (Mesocricetus auratus) is a susceptible model to Leishmania (Viannia) spp.; however, available studies employ different infection protocols, which account for clinical and pathological presentation differences. Herein, L. (V.) braziliensis preparations were standardized to contain 10 4 , 10 5 , or 10 6 parasites to determine an optimal inoculum that ensured cutaneous lesions without causing a disseminated infection in hamsters. Lesion development was followed for 105 days by size measurements, and skin, draining lymph node, spleen, and sera were investigated to check parasite load, spleen visceralization, cytokine expression, histopathological changes, and anti-Leishmania IgG levels. The lesion emergence time was inversely proportional to the parasite concentration in the inocula. Animals infected by 10 4 parasites presented nodular lesions, while those infected with 10 6 parasites often exhibited ulcerated lesions. The differences in the final lesion sizes were observed between 10 4 and 10 5 inocula or 10 4 and 10 6 inocula. High IFNG expression, anti-Leishmania IgG levels, and parasite load occurred independently of the inoculum used. A mild inflammatory skin involvement was observed in animals infected with 10 4 parasites, while extensive tissue damage and parasite spleen visceralization occurred with 10 5 and 10 6 parasites. These results indicate that inocula with different concentrations of parasites generate differences in the time of lesion emergence, clinical presentation, and systemic commitment, despite high and similar IFNG expression and parasite load. This suggests that a modulation in the immune response to different parasite numbers occurs in an early phase of the infection, which could dictate the establishment and magnitude of the chronic phase of the disease.

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Can interferon-γ and interleukin-10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?

Abstract: Summary Suitable levels of interferon (IFN)-g and interleukin (IL)-

Cited by 77 publications

References 26 publications

T-cell responses associated with resistance to Leishmania infection in individuals from endemic areas for Leishmania (Viannia) braziliensis

T-cell responses associated with resistance to Leishmania infection in individuals from endemic areas for Leishmania (Viannia) braziliensis

Age Modifies the Immunologic Response and Clinical Presentation of American Tegumentary Leishmaniasis

Comparative Evaluation of Lesion Development, Tissue Damage, and Cytokine Expression in Golden Hamsters (Mesocricetus auratus) Infected by Inocula with Different Leishmania (Viannia) braziliensis Concentrations

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