A case of paracoccidioidomycosis due to Paracoccidioides lutzii presenting sarcoid-like form

Paracoccidioidomycosis (PCM) is a fungal disease caused by Paracoccidioides spp., which can cause a systemic granulomatous infection with tegumentary and visceral involvement. Sarcoid-like skin lesions are uncommon and can be misdiagnosed due to similarities with other granulomatous diseases. We report a case of a women presenting with erythematous infiltrated plaques on her face that was treated for leprosy and rosacea with no response and was later diagnosed with PCM, presenting positive serology for Paracoccidioides lutzii.Univ Fed Espirito Santo, Med Sch, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Espirito Santo, Div Infect Dis, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Espirito Santo, Odontol Clin, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Espirito Santo, Dept Pathol, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, BR-04021001 Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, BR-04021001 Sao Paulo, BrazilWeb of Scienc

Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8⁺ T cells in human cutaneous leishmaniasis

Cytotoxic activity mediated by CD8+ T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished CD27 stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age‐matched controls. The accumulation of circulating senescent NK cells (CD56dim CD57bright) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8+ T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin‐homing potential compared with total or senescent CD8+ T cells. This was confirmed in CL skin lesions where we found a predominance of CD8+ T cells (both senescent and non‐senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56+ CD57+) in the skin and lesion size, this was less evident. Collectively our results demonstrate first‐hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8+ T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non‐specific skin damage in CL

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4^{+} and CD8^{+} T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1^{+}, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8^{+}CD45RA^{+}CD27^{-} T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis

Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis

Leishmania (Viannia) braziliensis induces American tegumentary leishmaniasis that ranges in severity from the milder form, cutaneous (CL) to severe disseminated cutaneous leishmaniasis. Patients with CL develop a cell-mediated Th1 immune response accompanied by production of inflammatory cytokines, which contribute to parasite control and pathogenesis of disease. Here, we describe the accumulation of circulating T cells with multiple features of telomere dependent-senescence including elevated expression of CD57, KLRG-1, and γH2AX that have short telomeres and low hTERT expression during cutaneous L. braziliensis infection. This expanded population of T cells was found within the CD45RA+CD27− (EMRA) subset and produced high levels of inflammatory cytokines, analogous to the senescence-associated secretory profile (SASP) that has been described in senescent non-lymphoid cells. There was a significant correlation between the accumulation of these cells and the extent of systemic inflammation, suggesting that they are involved in the inflammatory response in this disease. Furthermore, these cells expressed high level of the skin homing receptor CLA and there was a highly significant correlation between the number of these cells in the circulation and the size of the Leishmania-induced lesions in the skin. Collectively our results suggest that extensive activation during the early stages of leishmaniasis drives the senescence of T cells with the propensity to home to the skin. The senescence-related inflammatory cytokine secretion by these cells may control the infection but also contribute to the immunopathology in the disease