Does immune dysregulation contribute towards development of hypopigmentation in Indian Post Kala-azar Dermal Leishmaniasis?

Post kala-azar dermal leishmaniasis (PKDL), a sequel of apparently cured Visceral Leishmaniasis (VL) presents with papulonodular (polymorphic) or hypopigmented lesions (macular) and is the proposed disease reservoir. As hypopigmentation appears consistently in PKDL, especially the macular form, this study aimed to delineate immune factors that singly or in combination could contribute towards this hypopigmentation. At lesional sites, the presence of melanocytes and CD8 + T-cells was assessed by immunohistochemistry and mRNA expression of melanogenic markers (Tyrosinase, Tyrosinase Related Protein-1 and MITF) by droplet digital PCR, while plasma levels of cytokines and chemokines were measured by a multiplex assay. In comparison to skin from healthy individuals, macular PKDL demonstrated a near total absence of Melan-A + cells at dermal sites, while the polymorphic cases demonstrated a 3.2 fold decrease, along with a dramatic reduction in the expression of key enzymes related to the melanogenesis signaling pathway in both forms. The levels of circulating IFNγ, IL-6, IL-2, IL-1ß, TNF-α and IFNγ-inducible chemokines (CXCL9/10/11) were elevated, and was accompanied by an increased lesional infiltration of CD8 + T-cells. The proportion of CD8 + T-cells correlated strongly with plasma levels of IFN-γ (r= 0.8), IL-6 (r=0.9, p<0.05), IL-2 (r= 0.7), TNF-α (r= 0.9, p<0.05) and IL-1ß (r= 0.7), as also with CXCL9 (r=0.5) and CXCL10 (r=0.6). Taken together, the absence/reduction of Melan-A suggested hypopigmentation in PKDL was associated with destruction of melanocytes, following impairment of the melanogenesis pathway. Furthermore, the presence of CD8 + T-cells, and an enhanced IFNγ associated immune milieu suggested generation of a pro-inflammatory landscape that facilitated melanocyte dysfunction/destruction.