Abstract
BackgroundHuman Heat Shock Protein 60 (hHSP60) has been implicated in autoimmunity through molecular mimicry, based on the high degree of homology with HSP65 of micro-organisms leading to autoimmune recognition of the human protein. Additionally, sequence homology between hHSP60 and myeloperoxidase (MPO) has been described. MPO is a major autoantigen in vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). We hypothesized that infections may trigger the ANCA response against MPO through hHSP60.MethodsIn 86 consecutive patients with ANCA-associated vasculitis (AAV), anti-hHSP60 and anti-mycobacterial HSP65 were measured by ELISA. Patients were compared with 69 healthy controls (HC). Continuous data between groups were compared using Wilcoxon signed rank test and Kruskal-Wallis test with Dunn's post-test when appropriate. Correlations between data were derived using Spearman correlation. Odds ratios and 95% confidence intervals were obtained using Fisher's exact test.ResultsAt diagnosis, median anti-mHSP65 level was higher in AAV (median [range]: 42.5 [0–500]), and subsequently in MPO-ANCA (44 [7–500]), compared to HC (22 [0–430]). Anti-hHSP60 levels in AAV were not higher compared to HC (18 [0–319] and 18.5 [0–98], respectively). However, in MPO-ANCA anti-hHSP60 levels were increased (32.5 [0–319]) compared to PR3-ANCA (13 [0–79]) and HC. We could not detect cross-reactivity between hHSP60 and MPO-ANCA. There was a correlation between anti-mHSP65 and anti-hHSP60 levels (r = 0.32, P = 0.003) but not between anti-hHSP60 and MPO-ANCA (r = -0.064, P = 0.69).ConclusionAntibodies against mHSP65 are higher in AAV compared to HC, and anti-hHSP60 antibodies are higher in patients with MPO-ANCA than in patients with PR3-ANCA and HC. Although this finding may be indicative for cross-reactivity between MPO-ANCA and hHSP60, additional assays did not support this hypothesis.
Highlights
Small vessel vasculitides, such as Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), are strongly associated with antineutrophil cytoplasmic antibodies (ANCA), which are either directed to myeloperoxidase (MPO) or proteinase 3 (PR3) [1,2,3]
Results showed that antibodies against mycobacterial HSP65 (mHSP65) are higher in associated vasculitis (AAV) compared to healthy controls (HC), and anti-human Heat Shock Protein 60 (hHSP60) antibodies are higher in patients with MPO-ANCA than in patients with PR3-ANCA and HC
Anti-mycobacterial HSP65 antibodies are elevated in MPO-ANCA compared to healthy controls In patients with AAV, median anti-mHSP65 level was 42.5 arbitrary units (AU)/mL [0–500], compared to 22 AU/mL [0–430] in healthy controls (P = 0.008, figure 1)
Summary
Small vessel vasculitides, such as Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), are strongly associated with antineutrophil cytoplasmic antibodies (ANCA), which are either directed to myeloperoxidase (MPO) or proteinase 3 (PR3) [1,2,3]. These diseases can occur in any organ system but the respiratory tract and the kidneys are most frequently involved. It has been described that an autoimmune response may be induced by the presence of a peptide that is antisense or complementary to the autoantigen, for instance, PR3 [10] This immune response may induce anti-idiotypic antibodies (autoantibodies) that cross-react with the autoantigen. We hypothesized that infections may trigger the ANCA response against MPO through hHSP60
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