Background/Purpose: Autoimmune diseases are driven by a combination of predisposing genetic and environmental factors resulting in self-perpetuating chronic inflammation and tissue damage. In granulomatosis with polyangiitis (GPA), impaired regulatory T-cell function and an expansion of circulating effector memory T-cell subsets has been reported. While expansion of circulating effector memory T-cells has been linked to disease pathogenesis and progression, the causes driving alterations of the peripheral T-cell compartment have remained poorly understood so far. To investigate mechanisms driving alterations of the peripheral T-cell compartment in GPA, we performed combined approach using phenotyping, transcriptome and functional analyses of T-cell populations.

Methods: Sorted CD4+ and CD8+ single-positive and CD4+CD8+ double-positive T-cells were subject to transcriptomic profiling in GPA and healthy controls (each n=3). To characterize functional consequences of transcriptional alterations in T cell subpopulation from GPA-patients, differentially expressed genes from GPA-patients were investigated by gene ontology (GO) analysis. 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: Transcriptome signatures from GPA-patients presented significantly GO enriched signaling pathways for nuclear factor-kB (NF-kB), toll-like receptors (TLR), cytokine/cytokine receptor interaction (interleukins IL-1b and IL-18), and chemokine cell signaling pathways. Notably, significant enrichment of pathways consistent with immune responses triggered by various pathogens and infections was found including Staphylococcus aureus and Epstein Barr virus (EBV). Grouping of patients according to presence or absence of T-cell specificity for cytomegalovirus (CMV) and EBV showed that concomitant cellular CMV- and EBV-positivity was associated with a significant increase in the percentage of CD28- T-cells in GPA whereas sole or absent CMV- or EBV-positivity was not. 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: On genetic and cellular basis, here we show that , environmental factors including concomitant CMV- and EBV-infection and inflammation impact on alterations of the T-cell compartment in autoimmune disease. We identified cellular cytokine signatures (IL-1b, IL-18) on the transcriptomic level, which could represent novel targets for anti-cytokine-based induction therapies. Our data support antiviral therapy as another supplemental disease-modifying approach to be further evaluated in autoimmune disease such as GPA. Thus, our study provides novel insights into mechanisms driving autoimmune disease and on potential therapeutic targets.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-environmental-factors-and-inflammation-on-alterations-of-the-total-peripheral-t-cell-compartment-in-granulomatosis-with-polyangiitis/