Immune-mediated remodelling of tissue architecture in Post-Kala-Azar Dermal Leishmaniasis (PKDL)

Background Post-Kala-Azar Dermal Leishmaniasis (PKDL), a dermal sequel of apparently cured visceral leishmaniasis (VL), presents with macular or polymorphic lesions. A relationship, if any, between immune cell infiltration and cytokines potentially causing tissue-remodelling remains poorly defined, and was the focus of this study. Methodology/principal findings Skin biopsies along with plasma from PKDL patients and healthy controls were analyzed. Tissue sections were assessed for immune cell subsets (CD8 ⁺ T cells, CD68 ⁺ macrophages, CD20 ⁺ B cells, CD66b⁺ neutrophils), associated cytokines/chemokines, adhesion molecules (E-cadherin, Intercellular Adhesion Molecule-1), extracellular matrix (ECM) proteins (fibronectin, collagen I/IV, laminin), matrix metalloproteinase 9 (MMP9) using immuno-histochemistry/fluorescence, while circulating cytokines/chemokines, and MMP9 were quantified using multiplex assays/ELISA. PKDL lesions exhibited increased cell infiltration, monocytes/macrophages>CD8 ⁺ T cells>> neutrophils >B cells. E-cadherin was significantly downregulated, especially in macular lesions, whereas ICAM-1 was elevated. In both PKDL forms, ECM components were significantly reduced, and correlated inversely with immune cell infiltration. The raised levels of circulating chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, IL-8) positively correlated with their corresponding immune populations; additionally, circulating pro- (TNF-α, IFN-γ, IL-6, IL-1β) inflammatory cytokines and IL-4 was elevated. Additionally, lesional TNF-α, IFN-γ and MMP9 was elevated, and correlated inversely with E-cadherin and ECM proteins. Conclusions/significance In PKDL lesions, there was an elevated presence of monocytes-macrophages/CD8 + T cells, B cells and neutrophils; the increased presence of their respective chemokines endorsed their homing to lesional sites. Furthermore, the increased presence of dermal MMP9, TNF-α and IFN-γ possibly facilitated the breakdown of E-cadherin and ECM components, which could cause a site-specific loss of melanocytes, and contribute to the hypopigmentation associated with PKDL.