Date Published: March 21, 2013
Publisher: Public Library of Science
Author(s): Claudia Gonzalez-Lombana, Ciara Gimblet, Olivia Bacellar, Walker W. Oliveira, Sara Passos, Lucas P. Carvalho, Michael Goldschmidt, Edgar M. Carvalho, Phillip Scott, Jean Langhorne.
Leishmaniasis, resulting from infection with the protozoan parasite Leishmania, consists of a wide spectrum of clinical manifestations, from healing cutaneous lesions to fatal visceral infections. A particularly severe form of cutaneous leishmaniasis, termed mucosal leishmaniasis, exhibits decreased IL-10 levels and an exaggerated inflammatory response that perpetuates the disease. Using a mouse model of leishmaniasis, we investigated what cytokines contribute to increased pathology when IL-10-mediated regulation is absent. Leishmania major infected C57BL/6 mice lacking IL-10 regulation developed larger lesions than controls, but fewer parasites. Both IFN-γ and IL-17 levels were substantially elevated in mice lacking the capacity to respond to IL-10. IFN-γ promoted an increased infiltration of monocytes, while IL-17 contributed to an increase in neutrophils. Surprisingly, however, we found that IFN-γ did not contribute to increased pathology, but instead regulated the IL-17 response. Thus, blocking IFN-γ led to a significant increase in IL-17, neutrophils and disease. Similarly, the production of IL-17 by cells from leishmaniasis patients was also regulated by IL-10 and IFN-γ. Additional studies found that the IL-1 receptor was required for both the IL-17 response and increased pathology. Therefore, we propose that regulating IL-17, possibly by downregulating IL-1β, may be a useful approach for controlling immunopathology in leishmaniasis.
Cutaneous leishmaniasis is caused by the protozoan parasite Leishmania where the severity of the disease is a function of both parasite replication and the immune response. These obligate intracellular parasites infect phagocytes, such as macrophages, and are controlled when macrophages become activated by IFN-γ. Thus, a Th1 response is a required component in controlling the disease. However, the immune response itself can contribute to the pathology associated with this infection. The most extreme example of this is in mucosal or mucocutaneous leishmaniasis, although it is important to point out that even in localized cutaneous leishmaniasis the immune response is largely responsible for the lesions that develop –. Thus, it is the inflammatory response, rather than uncontrolled parasite growth, that often perpetuates the disease. For this reason, regulatory mechanisms that dampen the immune response are critical for controlling the disease. Indeed, cells from patients with mucosal leishmaniasis produce less IL-10 than those with localized cutaneous disease, and cells within the mucosal lesions exhibit a reduced expression of the IL-10 receptor (IL-10R) , –. These observations suggest that the lack of IL-10 or responsiveness to IL-10 may be an important contributing factor in the immunopathology observed in this disease.
Leishmaniasis is a disease that exhibits a wide spectrum of clinical manifestations, from healing to non-healing cutaneous lesions to fatal visceral infections. The immune response is critical in controlling these parasites, but can also promote increased pathology. This is most evident in patients from South America, some of whom develop secondary lesions in the nasopharyngeal region that leads to severe disease. This disease, termed mucosal (or mucocutaneous) leishmaniasis is often non-responsive to therapy, and patients may have the disease for years. The hallmark of the infection is a very strong immune response as indicated by high IFN-γ and TNF-α production, but very few parasites present within the lesions –. Importantly, cells from these patients appear to produce less IL-10 when stimulated with leishmanial antigens than cells from self-healing patients, and within the lesions there is low expression of the IL-10 receptor , –. Thus, it is presumed that a lack of regulatory mechanisms in these individuals leads to the development of an over exuberant Th1 response. In order to study the factors that contribute to the immunopathology associated with an unregulated immune response to Leishmania, we treated L. major infected C57BL/6 mice with anti-IL-10R mAb (IL10SD) and monitored the course of infection with L. major. Using this model we are the first to demonstrate that IL-10 can play a critical role in controlling pathology in cutaneous leishmaniasis.