Differential immune regulation of activated T cells between cutaneous and mucosal leishmaniasis as a model for pathogenesis

Abstract

Cutaneous (CL) and mucosal leishmaniasis (ML) are characterized by a predominant type 1 immune response (IFN-gamma and TNF-alpha production) and strong inflammatory response in the lesions with few parasites. This exacerbated type 1 response is more evident in ML as compared to CL. Our main hypothesis is that a differential immune regulation of T cell activation leads to over reactive T cells in ML. In the present study, we investigated immunological factors that could explain the mechanisms behind it by comparing some immune regulatory mechanisms between ML and CL patients: frequency of cells expressing co-stimulatory molecules, apoptotic markers, T cell activation markers; and ability of neutralizing antibodies to IL-2, IL-12 and IL-15 do down-regulate IFN-gamma production in leishmania antigen-stimulated peripheral blood mononuclear cells (PBMC). Interestingly, in CL anti-IL-2 and anti-IL-15 significantly suppressed antigen-specific IFN-gamma production, while in ML only anti-IL-2 suppressed IFN-gamma production. Finally, higher frequency of CD4+ T cells expressing CD28-, CD69+ and CD62L(low) were observed in ML as compared to CL. These data indicate that an exacerbated type 1 response in ML is differentially regulated and not appropriately down modulated, with increased frequencies of activated effectors T cells, maintaining the persistent inflammatory response and tissue damage observed in ML.

Cytokine profile in Montenegro skin test of patients with localized cutaneous and mucocutaneous leishmaniasis

“…The destructive lesions may occur when the high quantities of IFN-gamma are not controlled by the Th2 cytokines 7 .…”

Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis

“…The observation that there is no reduction in the time for healing of the lesion with the early introduction of treatment suggests that the pathogenesis is related more to the inflammatory process rather than to the amount of the parasite in the lesion [18]. Some data show an increased production of inflammatory modulators, such as TNF-a and IFN-g, in ML [115], which is more evident when compared with cutaneous leishmaniasis [116]. For this reason, the use of immunomodulators associated with some drugs seems appropriate and it has been tested in some patients with promising results.…”

Protective and Pathological Functions of CD8+T Cells in Leishmania braziliensis Infection

“…Human CL caused by Leishmania braziliensis is characterized by a strong Th1 response with the production of high levels of IFN-␥ and tumor necrosis factor alpha (TNF-␣) (6, 7). This exaggerated Th1 response is associated with the development of lesions and the severity of the disease (6, [8][9][10]. In patients with CL caused by L. braziliensis, there are more CD4 ϩ than CD8 ϩ T cells, but this ratio reaches an equilibrium due to the increase in CD8 ϩ T cells that occurs during the healing process (11).…”