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Immune dysregulation in immunoglobulin G4-related disease.

ABSTRACT: (IgG4-RD) is an immune-mediated fibrotic disorder characterized by severe resolution of inflammation and dysregulation of wound healing. IgG4-RD has been considered a unique disease since 2003, and significant progress has been achieved in the understanding of its essential features. The central role of B cells in IgG4-RD has been demonstrated by the robust clinical responsiveness of IgG4-RD to B cell depletion and the identification of multiple self-antigens that promote B cell expansion. Studies have increasingly revealed critical roles of these B cells and T cells in the pathogenesis of IgG4-RD, and we and other authors further identified CD4⁺ cytotoxic T lymphocytes as the main tissue-infiltrating CD4⁺ T cell subset in IgG4-RD tissues. Additionally, T follicular helper cell subsets that play a role in IgG4 isotype switching have been identified. In this review, we discuss research on IgG4-RD and the roles of B cell and T cell subsets, as well as the functions of CD4⁺ cytotoxic T cells in IgG4-RD pathogenesis. We highlight our findings from ongoing research using single-cell analysis of infiltrating CD4⁺ cytotoxic T cells, CD4⁺ follicular helper T cells, and infiltrating B cells in IgG4-RD and propose a model for the pathogenesis of IgG4-RD.

SUBMITTER: Maehara T

PROVIDER: S-EPMC9841035 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Immune dysregulation in immunoglobulin G4-related disease.

Maehara Takashi T Koga Risako R Nakamura Seiji S

The Japanese dental science review 20230109

(IgG4-RD) is an immune-mediated fibrotic disorder characterized by severe resolution of inflammation and dysregulation of wound healing. IgG4-RD has been considered a unique disease since 2003, and significant progress has been achieved in the understanding of its essential features. The central role of B cells in IgG4-RD has been demonstrated by the robust clinical responsiveness of IgG4-RD to B cell depletion and the identification of multiple self-antigens that promote B cell expansion. Studi ...[more]

PMID: 36654676

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Project description:Background and Objectives: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory, multiorgan disease with an obscure pathogenesis. Findings indicating excessive platelet activation have been reported in systemic sclerosis, which is another autoimmune, multisystemic fibrotic disorder. The immune-mediated, inflammatory, and fibrosing intersections of IgG4-RD and systemic sclerosis raised a question about platelets' role in IgG4-RD. Materials and Methods: By borrowing transcriptomic data from Nakajima et al. (GEO repository, GSE66465) we sought a platelet contribution to the pathogenesis of IgG4-RD. GEO2R and BRB-ArrayTools were used for class comparisons, and WebGestalt for functional enrichment analysis. During the selection of differentially expressed genes (DEGs), the translationally active but significantly low amount of platelet mRNA was specifically considered. The platelet-specific gene signature derived was used for cluster analysis of patient and control groups. Results: When IgG4-RD patients were compared with controls, 268 DEGs (204 with increased and 64 with decreased expression) were detected. Among these, a molecular signature of 22 platelet-specific genes harbored genes important for leukocyte-platelet aggregate formation (i.e., CLEC1B, GP1BA, ITGA2B, ITGB3, SELP, and TREML1) and extracellular matrix synthesis (i.e., CLU, PF4, PPBP, SPARC, and THBS1). Functional enrichment analysis documented significantly enriched terms related to platelets, including but not limited to "platelet reactivity", "platelet degranulation", "platelet aggregation", and "platelet activation". During clustering, the 22 gene signatures successfully discriminated IgG4-RD and the control and the IgG4-RD before and after treatment groups. Conclusions: Patients with IgG4-RD apparently display an activated platelet phenotype with a potential contribution to disease immunopathogenesis. If the platelets' role is validated through further carefully designed research, the therapeutic potentials of selected conventional and/or novel antiplatelet agents remain to be evaluated in patients with IgG4-RD. Transcriptomics and/or proteomics research with platelets should take into account the relatively low amounts of platelet mRNA, miRNA, and protein. Secondary analysis of omics data sets has great potential to reveal new and valuable information.

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Immune dysregulation in immunoglobulin G4-related disease.

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Immune dysregulation in immunoglobulin G4-related disease.

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