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Microenvironmental network of clonal CXCL13+CD4+ T cells and regulatory T cells in pemphigus chronic blisters

ABSTRACT: Pemphigus, a rare autoimmune bullous disease mediated by anti-desmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area, requiring long-term maintenance systemic therapy. We demonstrate the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from pemphigus patients. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T-cell receptor-mediated signaling. Regulatory T cells (Tregs) are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-β stimulation. Lastly, Intralesional corticosteroid injection improved chronic blisters and reduce skin TLSs in patients with pemphigus. This study concludes that skin TLSs are associated with the persistence of chronically recurrent blisters in pemphigus patients, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242234 | GEO | 2023/09/10

REPOSITORIES: GEO

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Project description:Background and aims: Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and the acquisition of a pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however, their role in TLS development in the context of inflammation-associated liver cancer remains unexplored. Methods: IKKβ(EE)Hep mice, exhibiting chronic liver inflammation and TLS formation followed by liver cancer, were crossed with RORc knockout mice to explore the effect of RORc on TLS and tumor formation. Transcriptional, proteomic and immunohistochemical techniques were used to analyze TLS phenotypes. CD4, CD8 and B cell depletions were used to analyze their contribution to liver TLS and tumor formation. Results: RORc expressing cells were detected within TLSs of both human patients and mice which develop intrahepatic cholangiocarcinoma. In mice, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs, revealed enrichment of exhausted CD8 cells that retained effector functions, as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor-directed antibodies. Conclusions: RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs.

Project description:Pemphigus foliaceus (PF) is a complex autoimmune disease characterized by bullous skin lesions and the presence of antibodies against desmoglein 1. In this study we sought to contribute to a better understanding of the molecular processes in endemic PF, since the identification of factors that participate in the pathogenesis is a prerequisite for understanding its biological basis and may lead to novel therapeutic interventions. CD4+ T lymphocytes are central to the development of the disease. Therefore, we compared genome-wide gene expression profiles of peripheral CD4+ T cells of various PF patient subgroups with each other and with that of healthy individuals. The patients sample was subdivided in three groups: untreated patients with the generalized form of the disease, patients submitted to immunosuppressive treatment, and patients with the localized form of the disease. Comparisons between different subgroups resulted in 135, 54 and 64 genes differentially expressed. These genes are mainly related with lymphocyte adhesion and migration, apoptosis, cellular proliferation, cytotoxicity and antigen presentation. Several of these genes were differentially expressed when comparing lesional and uninvolved skin from the same patient. The chromosomal regions 19q31 and 12p13 concentrate differentially expressed genes and are candidate regions for PF susceptibility genes and disease markers. Our results reveal genes involved in severity, potential therapeutic targets and previously unsuspected processes involved in the pathogenesis. Besides, this study adds original information that will contribute to the understanding of PFM-bM-^@M-^Ys pathogenesis and of the still poorly defined in vivo functions of most of these genes. 24 samples were analyzed, no replicates. Three groups of patients were analyzed: (1) patients with the generalized form of the disease and without treatment; (2) patients with the generalized form undergoing immunosuppressive therapy (prednisone); and (3) patients with the localized form of the disease and without treatment. A fourth group consisted of healthy control subjects.

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Microenvironmental network of clonal CXCL13+CD4+ T cells and regulatory T cells in pemphigus chronic blisters

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