Deregulated phenotype of autoreactive Th17 and Treg clone cells in pemphigus vulgaris after in-vitro treatment with desmoglein antigen (Dsg-3)

• Published in: Immunobiology (1979) 2023-03, Vol.228 (2), p.152340-152340, Article 152340
• Main Authors: Ansari, Mohammad Ahmad, Singh, Praveen Kumar, Dar, Sajad Ahmad, Rai, Gargi, Akhter, Naseem, Pandhi, Deepika, Gaurav, Vishal, Bhattacharya, Sambit Nath, Banerjee, Basu Dev, Ahmad, Abrar, Das, Shukla
• Format: Article
• Language: English
• Subjects: Autoantibodies; Clone Cells - metabolism; Cytokines - metabolism; Desmoglein-3; Desmogleins - metabolism; Forkhead Transcription Factors - metabolism; FoxP3; Humans; Interleukin-10 - metabolism; Interleukin-17 - metabolism; Leukocytes, Mononuclear - metabolism; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Pemphigus - metabolism; Phenotype; RNA, Messenger - metabolism; RORγt; T-Lymphocytes, Regulatory; Th17 Cells; Treg cells
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2023.152340

[Display omitted] •Desmoglein-3 affects Th17 and Tregs cells, leading to immune dysregulation.•High HLA-DR, IL-23R and CD45RO suggests a persistent inflammatory response in PV.•Reduced FoxP3 and high RORγt represents low Treg and high Th17 cells in PV.•Raised Th17 cytokines indicate their predominant role in PV immunopathogenesis.•Impaired Treg functions leads to low TGF-β and IL-10. The loss of balance between regulatory T (Treg) and T helper 17 (Th17) causes loss of tolerance against desmoglein (Dsg)-3 leading to pemphigus vulgaris (PV), an autoimmune bullous skin disorder associated with autoantibodies against Dsg-3. We aimed to elucidate the complex relationship of Th17 and Treg cells, their molecules, and the underlying mechanism in the development of PV disease. Using cytokine secretion assays, Th17 and Treg cells were sorted by FACS Aria-III within Dsg-3-responsive PBMC population and homogeneous T cell clones were generated in-vitro. Different cell surface molecules like CD25, GITR, CD122, CD152, CD45RO, IL-23R, STAT3, STAT5, CD127, HLA-DR, CCR4, CCR5, CCR6 and CCR7 were studied. The functional response of Th17 and Treg cells were elucidated by measuring the levels of various cytokines released by IL-10 and IL-17 T cells. The mRNA expression of transcription factors (FoxP3 and RORγt) was also analyzed. IL-17 secreting (Th17) cells with phenotype CD4+IL-17+ were greatly increased and IL-10 secreting (Treg) cells with phenotype CD4+IL-10+ were reduced in PV cases than healthy controls. The qPCR analysis showing high expression of retinoic acid receptor-related orphan receptor gamma (RORγt) mRNA in comparison to forkhead box P3 (FoxP3) mRNA confirmed the development of pro-inflammatory Th17 response in PV. Further, the cytokine profile of pro-inflammatory and anti-inflammatory cytokines suggested defective suppressive functions in Treg cells with high inflammatory response. Our findings indicate that autoantigen Dsg-3 specifically allows the proliferation of IL-17 secreting T cells though has a negative effect on IL-10 secreting T cells leading to dysregulation of immunity in PV patients. This antagonistic relationship between Dsg-3-specific Th17 and Treg cells may be critical for the onset and persistence of inflammation in PV cases.