Decreased In Situ Expression of Interleukin-10 Receptor Is Correlated with the Exacerbated Inflammatory and Cytotoxic Responses Observed in Mucosal Leishmaniasis

Abstract

Human infection with Leishmania braziliensis can lead to cutaneous leishmaniasis (CL) or mucosal leishmaniasis (ML). We hypothesize that the intense tissue destruction observed in ML is a consequence of an uncontrolled exacerbated inflammatory immune response, with cytotoxic activity. For the first time, this work identifies the cellular sources of inflammatory and antiinflammatory cytokines, the expression of effector molecules, and the expression of interleukin-10 (IL-10) receptor in ML and CL lesions by using confocal microscopy. ML lesions displayed a higher number of gamma interferon (IFN-␥)-producing cells than did CL lesions. In both ML and CL, CD4؉ cells represented the majority of IFN-␥-producing cells, followed by CD8 ؉ cells and CD4 ؊ CD8 ؊ cells. The numbers of tumor necrosis factor alpha-positive cells, as well as those of IL-10-producing cells, were similar in ML and CL lesions. The effector molecule granzyme A showed greater expression in ML than in CL lesions, while inducible nitric oxide synthase did not. Finally, the expression of IL-10 receptor was lower in ML than in CL lesions. Thus, our data identified distinct cytokine and cell population profiles for CL versus ML patients and provide a possible mechanism for the development of ML disease through the demonstration that low expression of IL-10 receptor is present in conjunction with a cytotoxic and inflammatory profile in ML.

Immunological and Genetic Evidence for a Crucial Role of IL-10 in Cutaneous Lesions in Humans Infected with Leishmania braziliensis

“…The role of IL-4 in LCL is not clear, as there is no report of a strong polarization toward Th2 in LCL subjects. PBMC from MCL patients produce less IL-10, respond less to IL-10 and TGF-␤ (20), and show lower IL-10 receptor expression than PBMCs from LCL subjects (23). These findings suggest that MCL might be aggravated by uncontrolled Th1 mediated inflammation due to low IL-10 and TGF-␤ production.…”

“…Studies on nonhealing lesions as a result of L. mexicana infection have shown an association with increased IL-10 and TGF-␤ production (24) in the presence of IFN-␥; this suggests that IFN-␥ is neutralized by IL-10 and/or TGF-␤. Severe and rare MCL disease was associated with low IL-10 and TGF-␤ production (20) and lower IL-10 receptor expression than that observed in LCL (23). Thus, the role of IL-10 in human CL, as a result of Lb infection, was less clear.…”

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

“…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.…”

Immunological Determinants of Clinical Outcome in Peruvian Patients with Tegumentary Leishmaniasis Treated with Pentavalent Antimonials

“…The mucosal forms are characterized by an exacerbated cell-mediated immune response and high intralesional levels of TNF-␣, IFN-␥, and IL-4, leading to extensive tissue destruction but not to parasite clearance (3,5,34,47). A defect in IL-10 receptor expression was shown to correlate with high inflammatory responses in ML (14). Finally, T reg cells and high IL-10 production potential have been described in the skin of individuals infected with L. braziliensis (10).…”