Distorted frequency of dendritic cells and their associated stimulatory and inhibitory markers augment the pathogenesis of pemphigus vulgaris.

The objective of this study was to investigate the frequency and functionality of DCs and its associated stimulatory and inhibitory markers in the pathogenesis of PV Active PV patients (n = 30) having both skin and oral lesions, and 30 healthy controls were recruited in the study. The frequency of DCs was determined by flow cytometry followed by the primary culture by using recombinant IL-4 (250 IU/ml) and GM-CSF (600 IU/ml). The culture supernatant was used for ELISA. RNA was isolated from sorted DCs and used for the mRNA expression of DC-associated stimulatory (CD40 and CD80) and inhibitory (PSGL1 and ILT3) markers. Tissue localization of Langerhans cells was done by immunohistochemistry. In this study, altered frequency of myeloid DC (mDC) and plasmacytoid DC (pDC) was seen in the circulation of PV patients. The primary culture of patient-derived DCs showed anomalous cytokine profiling. In the culture supernatant of DCs, elevated levels of TNF-ɑ and IL-12 were detected in PV patients. Meanwhile, reverse trend was found in the case of IFN-ɑ and IL-10 cytokine levels. Similarly, a discrepancy in the expression of DC-associated stimulatory (CD40 and CD80) and inhibitory (PSGL1 and ILT3) markers suggested their possible involvement in the immunopathogenesis of PV. An elevated number of tissue localizing Langerhans cells was also observed in the perilesional skin. This study indicates the distorted frequency and functionality of DCs in the immunopathogenesis of PV. Targeting these functional markers in the future may generate novel therapeutic options for better management of PV.

Distinctive Treg associated CCR4-CCL22 expression profile with altered frequency of Th17/Treg cell in the immunopathogenesis of Pemphigus Vulgaris.

Pemphigus Vulgaris (PV), a relatively common autoimmune blistering disease in India, primarily mediated by anti-Desmoglein 3 (anti-Dsg3) autoantibodies. T-helper 17 (Th17) and T-regulatory (Treg) cells play significant role in regulating immune homeostasis in autoimmune disorders. To understand immunopathogenesis of PV, it is crucial to unfold the phenotypic expression and functional characteristics of these cells along with their specific homing chemokine receptor-ligand. This proposed study aims to unravel the functional expression of Th17 and Treg cells along with their specific homing chemokine receptor-ligand, transcription factors and cytokine levels to better understand the immunopathogenesis of PV. The Flow cytometry results showed decreased frequency of Treg cells and high number of Th17 cells (p<0.001) indicating immune dysregulation in PV. A significant increase (p<0.001) in the serum levels of Th17 associated molecules (IL-17A, CCL-20) and relative expression of RORγt, CCR6 and CCL20 was found in patients. For Treg cells, transcription factor FOXp3 was significantly lowered along with defective CCR4-CCL22 (p<0.05) that might be playing an ambiguous role in Treg generated immune regulation, leading to homing defect at lesional sites. This maiden study revealed the role of defective receptor-ligand interface that might have failed to suppress inflammatory milieu produced by Th17 cells thus promoting inflammation and contributing to immunopathogenesis of PV. This chemokine receptor-ligand can further be explored as potential target for development of novel therapies in PV.