ANCA patients have T cells responsive to complementary PR-3 antigen

Abstract

Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3138-169-peptide; while only a third of the patients had HI-PR3 protein responsive T cells. A significant number of T cells from patients responded to cPR3138-169 peptide and to HI-PR3 protein by proliferation and/or secretion of IFN-γ, compared to healthy controls while there was no response to scrambled peptide. Cells responsive to cPR3138-169-peptide were not detected in MPO-ANCA patients suggesting that this response is specific. The HLADRB1* 15 allele was significantly overrepresented in our patient group and is predicted to bind cPR3138-169 peptide with high affinity. Regression analysis showed a significant likelihood that anti-cPR3 antibodies and cPR3-specific T cells coexist in individuals, consistent with an immunological history of encounter with a PR3-complementary protein. We suggest that the presence of cells reacting to potential complementary protein pairs might provide an alternative mechanism for auto-immune diseases.

DRB1*15 Allele Is a Risk Factor for PR3-ANCA Disease in African Americans

“…21,23 Moreover, from our previous work we know that PR3 146 -161 peptide was presented as an antigen in PR3-ANCA patients who carry a DRB1*15 allele, as evidenced by the presence of CD4 ϩ T H 1 memory cells reactive with this peptide. 8 In conclusion, African Americans with PR3-ANCA disease are far more likely to have the DRB1*15 genotype than African Americans in the local population (odds ratio of 35.9). The strength of this association is unparalleled.…”

“…8 The studies herein determine whether the DRB1*15 allele predisposes African Americans to develop ANCA disease, or more to the point, if it is a significant factor in ANCA disease regardless of race. If not, then are there other DRB1 alleles associated with ANCA disease in our patient cohort.…”

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

“…106,[154][155][156] Consistent with this hypothesis are persistent activation of T cells and elevation of soluble T cell products that correlate with disease activity, 127,157,158 the prominence of traditional Th1 delayed-type hypersensitivity markers like T cells, macrophages, fibrin, and occasional granulomas in ANCA-positive GN 156 and T cell reactivity to ANCA antigens in some patients. [159][160][161][162] T cells alone, including Th17 cells, induce focal necrotizing and crescentic GN when sensitized to a planted glomerular antigen as might occur with planted cationic MPO. 28,161 A recent study used combinations of mice selectively deficient in T cells, B cells, or MPO to demonstrate that active immunization with human MPO (in mice with subclinical glomerular injury) induces crescentic GN without immune deposits that requires the presence of endogenous MPO and T cell reactivity to MPO, but does not require B cells or anti-MPO antibody.…”

Recent Aspects of Vasculitis and Future Direction

“…Interestingly, they noticed that cPR3 shows homology with several microbe proteins including peptide-derived S. aureus. More recently, Yang et al described T-cells in the peripheral blood of patients with PR3-ANCA AAV reacting with cPR3 (11,66,81,82).…”