Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: In Myeloperoxidase (MPO) Anti Neutrophilic Cytoplasmic Antibody (ANCA)-Associated Vasculitis (MPO-AAV), murine and human studies suggest that the MPO435-465 region, which includes ANCA-binding MPO447-459, the CD4 MPO435-454 epitope and CD8 MPO457-465 epitope; is an immunogenic hotspot within the MPO heavy chain. To map the MPO peptide proliferative response in peripheral blood (PB) of MPO-AAV, we developed a T cell proliferation assay based on CFSE dilution, and assayed responses to MPO heavy chain peptides in participants with MPO-AAV, and age and sex-matched healthy controls.
Methods: MPO-AAV participants were included if they had a positive MPO-ANCA and Birmingham Vasculitis Activity Score (BVAS) ≥ 1 at diagnosis. We collected PB, isolated and froze mononuclear cells, thawed and stained them with CFSE, and cultured them for 7 days with no peptide, anti-CD3, tetanus toxoid, MPO peptides or pools of 10 overlapping 15mer MPO peptides derived from the MPO279-745 heavy chain. The % proliferating CD3+CD4+ and CD8+ T cells in response to antigen or anti-CD3 was calculated by flow cytometry. The cell division index (CDI) was calculated as % divided in peptide-stimulated relative to % divided in unstimulated samples. All were genotyped for HLA-DR, DP and DQ.
Results: Nineteen participants with MPO-AAV were included, with mean age 65.32 (95% CI: 57.36- 73.27) and 14/19 were male (11 MPA, 3 GPA, 5 renal limited disease). Five had active disease. Of the healthy participants, mean age was 56.70 (95% CI: 43.32- 70.08), and 7/9 were male. MPO-AAV patients had a significantly greater CD4+ T cell CDI to MPO447-459 than healthy controls (p=0.015), with median CDI 3.20 (95% CI: 0.96- 5.80) in MPO-AAV and 0.67 (95% CI: 0.07- 0.89) in controls. CDI was greater in patients with remitted disease (median CDI 3.93, 95% CI: 0.52- 13.00), than in patients with active disease (median CDI 1.72, 95% CI: 0.96-3.89), but CDI did not correlate with ANCA titre. Within the MPO heavy chain, there was no significant increase in CDI among MPO-AAV patients towards any epitope other than MPO447-461. CDI to MPO435-365 among MPO-AAV patients with remitted disease was increased relative to patients with active disease. No peptide stimulated a significantly increased CD8+ proliferative response. HLA-DPB1*04:01 was enriched among patients with MPO-AAV (10/13; 76.92%) relative to controls (2/6; 33.33%), odds ratio 6.67 (95% CI: 0.79- 56.21). Carriage of this allele did not influence CDI to MPO447-459.
Conclusion: CD4+ T cells from patients with MPO-AAV proliferate specifically to the MPO447-459 epitope within the MPO heavy chain, and this response is greater after remission. An increased CDI to MPO435-465 suggests that MPO447-459 can be processed in culture from the longer peptide. T cell immunomodulation may be a suitable strategy for remitted MPO-AAV.
To cite this abstract in AMA style:Terrill M, Nel H, Musthaffa Y, Richard W, Francis R, Johnson D, Keir G, Gillis D, Thomas R. The Myeloperoxidase (MPO) Anti-Neutrophilic Cytoplasmic Antibody (ANCA) Binding Epitope, MPO447-459 Induces CD4 T-cell Proliferation in Patients with MPO-ANCA-associated Vasculitis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/the-myeloperoxidase-mpo-anti-neutrophilic-cytoplasmic-antibody-anca-binding-epitope-mpo447-459-induces-cd4-t-cell-proliferation-in-patients-with-mpo-anca-associated-vasculitis/. Accessed October 19, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-myeloperoxidase-mpo-anti-neutrophilic-cytoplasmic-antibody-anca-binding-epitope-mpo447-459-induces-cd4-t-cell-proliferation-in-patients-with-mpo-anca-associated-vasculitis/