Toll-like receptors 2, 4, and 9 expressions over the entire clinical and immunopathological spectrum of American cutaneous leishmaniasis due to Leishmania (V.) braziliensis and Leishmania (L.) amazonensis

Abstract

Leishmania (V. ) braziliensis and Leishmania(L. ) amazonensis are the most pathogenic agents of American Cutaneous Leishmaniasis in Brazil, causing a wide spectrum of clinical and immunopathological manifestations, including: localized cutaneous leishmaniasis (LCL ^DTH+/++), borderline disseminated cutaneous leishmaniasis (BDCL ^DTH±), anergic diffuse cutaneous leishmaniasis (ADCL ^DTH-), and mucosal leishmaniasis (ML ^DTH++++). It has recently been demonstrated, however, that while L. ( V.) braziliensis shows a clear potential to advance the infection from central LCL (a moderate T-cell hypersensitivity form) towards ML (the highest T-cell hypersensitivity pole), L. ( L.) amazonensis drives the infection in the opposite direction to ADCL (the lowest T-cell hypersensitivity pole). This study evaluated by immunohistochemistry the expression of Toll-like receptors ( TLRs) 2, 4, and 9 and their relationships with CD4 and CD8 T-cells, and TNF-α, IL-10, and TGF-β cytokines in that disease spectrum. Biopsies of skin and mucosal lesions from 43 patients were examined: 6 cases of ADCL, 5 of BDCL, and 11 of LCL caused by L. ( L.) amazonensis; as well as 10 cases of LCL, 4 of BDCL, and 6 of ML caused by L. ( V.) braziliensis. CD4 ⁺ T-cells demonstrated their highest expression in ML and, in contrast, their lowest in ADCL. CD8 ⁺ T-cells also showed their lowest expression in ADCL as compared to the other forms of the disease. TNF-α ⁺showed increased expression from ADCL to ML, while IL-10 ⁺and TGF-β ⁺ showed increased expression in the opposite direction, from ML to ADCL. With regards to TLR2, 4, and 9 expressions, strong interactions of TLR2 and 4 with clinical forms associated with L. ( V.) braziliensis were observed, while TLR9, in contrast, showed a strong interaction with clinical forms linked to L. ( L.) amazonensis. These findings strongly suggest the ability of L. ( V.) braziliensis and L. ( L.) amazonensis to interact with those TLRs to promote a dichotomous T-cell immune response in ACL.