Local Increase of Arginase Activity in Lesions of Patients with Cutaneous Leishmaniasis in Ethiopia

Abstract

Background Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica . This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood. Methodology/Principal Findings We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs. Conclusion Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.

A Defective Oxidative Burst and Impaired Antigen Presentation are Hallmarks of Human Visceral Leishmaniasis

“…1a) can be attributed to a decreased expression of iNOS and/or increased activity of arginase, establishing the status of these immunomodulatory enzymes was necessary. In experimental CL and VL as also in patients with PKDL, increased arginase activity has been reported [9,[20][21][22] but differed from Indian VL where activity was unaltered. This unchanged activity of arginase tilted the axis towards decreased expression of iNOS playing a predominant role.…”

Glycyrrhizic Acid-Mediated Subdual of Myeloid-Derived Suppressor Cells Induces Antileishmanial Immune Responses in a Susceptible Host

“…Myeloid cells are a major source of T cell suppression in many diseases, including leishmaniasis (13). In the present study, we aimed to shed light on inhibition of the suppression mechanism employed by MDSCs in the context of L. donovani infection.…”

“…Besides the lymphocytic population of regulatory T cells (Tregs), MDSCs have a myeloid origin and evoke a suppressive function on T cells (11,12), dampening immunotherapy. The intrinsic susceptibility of the Ethiopian population suffering from leishmaniasis through the generation of myeloid cells indicates the significance of myeloid cells (among which MDSCs are included) from a therapeutic point of view (13). Despite suppressed T cell functions, Gr1 ϩ cells have been shown to be essential for the production of early Th1 cytokines in murine draining lymph nodes (14).…”

Serum Arginase, a Biomarker of Treatment Efficacy in Human African Trypanosomiasis

“…High arginase blood levels have been measured in sera from acute hepatitis B, resulting in T cell function suppression, and in various cancers (14,15,16). High arginase activity has been measured in cutaneous leishmaniasis lesions (17). High interleukin-10 (IL-10) levels have been measured in HAT (18).…”