The research team, led by investigators including Deep Goswami and Mitali Chatterjee, analyzed skin biopsies and blood plasma from PKDL patients and compared them with samples from healthy controls. Using immunohistochemistry and immunofluorescence, they quantified the populations of immune cells infiltrating the lesions, including CD8-positive T cells, CD68-positive macrophages, CD20-positive B cells, and CD66b-positive neutrophils. In parallel, they measured the levels of chemokines and cytokines circulating in the plasma using multiplex assays and ELISA, and examined the integrity of key structural proteins in the skin, such as E-cadherin, intercellular adhesion molecule-1, fibronectin, collagen types I and IV, and laminin.

What they found was a coordinated immune invasion. PKDL lesions were densely infiltrated with immune cells, and the hierarchy was clear: monocytes and macrophages dominated, followed by CD8-positive T cells, then neutrophils, and finally B cells. This was not a random accumulation but a targeted recruitment. The researchers detected elevated levels of specific chemokines in the circulation, including CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, and IL-8, and these chemokines positively correlated with the abundance of their corresponding immune cell populations in the tissue. In other words, the chemical signals in the blood were acting as homing beacons, drawing each immune cell type into the skin lesions where they accumulated.

The structural consequences of this infiltration were equally striking. E-cadherin, a molecule that glues keratinocytes together and helps maintain the integrity of the epidermis, was significantly downregulated in the lesions, with the most pronounced reduction seen in macular lesions, the flat, pale patches characteristic of the disease. Meanwhile, intercellular adhesion molecule-1, or ICAM-1, was elevated, reflecting the inflammatory activation of the tissue. The extracellular matrix, the protein scaffold that gives skin its shape and resilience, was also significantly depleted, with reduced levels of fibronectin, collagen I, collagen IV, and laminin across both macular and polymorphic forms of PKDL.

Critically, the loss of these structural components was not independent of the immune invasion. The researchers found that the depletion of extracellular matrix proteins correlated inversely with the degree of immune cell infiltration, meaning that the more immune cells crowded into a lesion, the more the underlying scaffold was eroded. This inverse relationship suggests that the immune cells, or the inflammatory molecules they produce, are actively breaking down the tissue architecture rather than simply occupying space left behind by other processes.

To identify the molecular culprits, the team turned to the enzymes and cytokines known to degrade structural proteins. Matrix metalloproteinase 9, or MMP9, an enzyme capable of cleaving collagen and other matrix components, was elevated in the lesions. So were the pro-inflammatory cytokines TNF-alpha and IFN-gamma. Importantly, the levels of these molecules correlated inversely with E-cadherin and the extracellular matrix proteins, providing a plausible mechanism: the inflammatory milieu, rich in TNF-alpha, IFN-gamma, and MMP9, drives the breakdown of the adhesion molecules and structural proteins that hold the skin together.

The systemic picture reinforced the local one. In the plasma of PKDL patients, pro-inflammatory cytokines including TNF-alpha, IFN-gamma, IL-6, and IL-1beta were elevated, along with IL-4, a cytokine more typically associated with allergic and humoral immune responses. This combination suggests that PKDL is not a purely Th1 or Th2 inflammatory state but a mixed immune environment in which multiple signaling pathways converge on the skin. The elevated circulating chemokines, which correlated with tissue infiltration, further support the idea that the blood is carrying the instructions for immune cell homing to the lesions.

The clinical significance of these findings lies in their potential to explain the most visible and stigmatizing feature of PKDL: hypopigmentation. The researchers propose that the loss of E-cadherin and extracellular matrix components, driven by MMP9, TNF-alpha, and IFN-gamma, could cause a site-specific loss of melanocytes, the pigment-producing cells of the skin. If the structural framework that supports melanocytes is dismantled, those cells may be lost or dysfunctionally displaced, resulting in the pale patches that characterize macular PKDL. This mechanism links the immune pathology directly to the visible symptom, a connection that had remained poorly defined until now.

Beyond the mechanistic insight, the study has implications for how PKDL might be monitored and treated. The correlation between circulating chemokines and tissue infiltration suggests that blood markers could serve as non-invasive indicators of disease activity, potentially reducing the need for repeated skin biopsies. The identification of TNF-alpha, IFN-gamma, and MMP9 as central drivers of tissue remodeling also points to potential therapeutic targets. If the enzymatic and cytokine-mediated breakdown of E-cadherin and the extracellular matrix can be modulated, it may be possible to preserve skin architecture and prevent or reverse the hypopigmentation that causes so much social and psychological burden for patients.

PKDL remains a significant public health challenge in regions where visceral leishmaniasis is endemic, particularly in the Indian subcontinent and East Africa. Because PKDL patients can harbor parasites in their skin, they are thought to act as reservoirs that sustain transmission even after large-scale treatment campaigns have reduced visceral disease. Understanding the immune-mediated remodeling of skin architecture in PKDL therefore serves a dual purpose: it illuminates the biology of a neglected disease and may contribute to strategies aimed at interrupting the transmission cycle. By revealing how chemokine-driven immune infiltration, cytokine-mediated inflammation, and matrix-degrading enzymes converge to dismantle the skin’s structural integrity, this study provides a foundation for developing interventions that could improve both the clinical management and the epidemiological control of this disfiguring sequela of kala-azar.

Subject of Research: Immune-mediated tissue remodeling and hypopigmentation in Post-Kala-Azar Dermal Leishmaniasis

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

Article References: Goswami, D., Saha, S., Roy, M., Mohammad, E., Maji, R., Sengupta, R., Sengupta, S., Roy, S., Chaudhuri, S. J., Das, N. K., Chakraborty, B., Chatterjee, U., & Chatterjee, M. (2026). Immune-mediated remodelling of tissue architecture in Post-Kala-Azar Dermal Leishmaniasis (PKDL). PLOS Neglected Tropical Diseases, 20(10), e0014798. https://doi.org/10.1371/journal.pntd.0014798

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014798

Keywords: PKDL, visceral leishmaniasis, hypopigmentation, E-cadherin, MMP9, chemokines, extracellular matrix, macrophages, CD8 T cells, TNF-alpha, IFN-gamma, skin pathology