Artikel
Multiple factors drive alterations of the total T-cell compartment in granulomatosis with polyangiitis
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Veröffentlicht: | 29. August 2016 |
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Gliederung
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Background: Granulomatosis with polyangiitis (GPA) is a systemic autoimmune vasculitis associated with anti-neutrophil cytoplasmic autoantibodies to proteinase 3 (PR3-ANCA). Impaired regulatory T-cell function and expansion of circulating effector memory T-cell subsets including a Th1-type CD4+ T-cell subset lacking co-stimulatory CD28 expression suggests an imbalance of mutually regulating processes in GPA. However, the causes of these alterations of the total T cell compartment have remained poorly understood so far. Therefore, this study focused on investigating mechanisms driving alterations of the total peripheral T-cell compartment in GPA.
Methods: The transcriptomic profile of sorted CD4+ and CD8+ single-positive and CD4+CD8+ double-positive T-cells was analyzed in GPA and healthy controls (each n=3). The frequency of circulating antigen-specific T-cells and phenotype of T-cells from 20 HLA-A2-positive patients with GPA and 20 healthy controls was assessed by flow cytometry. Antigen-specificity was detected using peptide/MHC class I dextramers in HLA-A2-positive subjects.
Results: Transcriptomic profiling of sorted CD4+ and CD8+ single-positive and CD4+CD8+ double-positive T-cell populations showed major differences between GPA and healthy controls reflecting antigen-driven effects in GPA. In peripheral blood, we found increased percentages of CD4+CD28-, CD8+CD28- and CD4+CD161+ single-positive T-cell subsets and CD4+CD8+ double-positive T-cells in GPA. Concomitant cytomegalovirus (CMV)- and Epstein Barr virus (EBV)-positivity was associated with a significant increase in the percentage of CD28- T-cells in GPA-patients. In contrast, sole or absent CMV- or EBV-positivity was not associated with an expansion of CD28- T-cells. T-cell specificity for other viruses (influenza A virus, metapneumovirus, respiratory syncytial virus) and PR3 was infrequently detected in GPA. Notably, antigen-specific T-cells were not specifically enriched within any of the T-cell subsets.
Conclusion: Transcriptional dysregulation and cellular antigen-specificity suggest a multifactorial etiology of alterations in total T-cell compartment from GPA patients. Specifically, concomitant CMV- and EBV-infection, but not CMV-infection alone as previously suggested, is linked to the expansion of circulating CD28- T-cells.