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

<div><p><i>Leishmania (V</i>.<i>) braziliensis</i> and <i>Leishmania(L</i>.<i>) amazonensis</i> 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 <i>L</i>. (<i>V</i>.) <i>braziliensis</i> 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), <i>L</i>. (<i>L</i>.) <i>amazonensis</i> drives the infection in the opposite direction to ADCL (the lowest T-cell hypersensitivity pole). This study evaluated by immunohistochemistry the expression of <i>Toll-like</i> receptors (<i>TLRs</i>) 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<i>L</i>. (<i>L</i>.) <i>amazonensis</i>; as well as 10 cases of LCL, 4 of BDCL, and 6 of ML caused by<i>L</i>. (<i>V</i>.) <i>braziliensis</i>. 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 <i>TLR</i>2, 4, and 9 expressions, strong interactions of <i>TLR</i>2 and 4 with clinical forms associated with <i>L</i>. (<i>V</i>.) <i>braziliensis</i> were observed, while <i>TLR</i>9, in contrast, showed a strong interaction with clinical forms linked to <i>L</i>. (<i>L</i>.) <i>amazonensis</i>. These findings strongly suggest the ability of <i>L</i>. (<i>V</i>.) <i>braziliensis</i> and <i>L</i>. (<i>L</i>.) <i>amazonensis</i> to interact with those <i>TLRs</i> to promote a dichotomous T-cell immune response in ACL.</p></div