Background Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by recurrent disease activity flares, multiple organ involvement, and often with a presentation of nephritis. Malondialdehyde (MDA) post-translational modification of proteins occurs upon inflammation and oxidative stress. Natural IgM anti-MDA autoreactivity is present from birth and may be beneficial. However, both IgM and IgG anti-MDA can also be increased in autoimmune disease. Yet, the role for potentially pro-inflammatory autoreactive IgG anti-MDA in SLE remains elusive.
Objectives Here, we study the association between serum IgG anti-MDA and clinical features of SLE.
Methods This cross-sectional study included 398 SLE patients at the Karolinska University Hospital fulfilling at least four of the 1982 ACR criteria. Data was compared to the previously reported combined US east coast cohorts (1, 2). Disease activity was assessed by SLEDAI-2K. Total IgG and ANA IgGs were assessed in the clinical laboratory and sTNFR by ELISA. IgG anti-MDA was measured by a quantitative ELISA using modified BSA. As a comparison, we measured IgG anti-phosphorylcholine (PC), another oxidation-associated natural IgG. Cutoff for positivity was based on highest control quartile. Specific IgGs were normalized for total IgG levels in the analysis. Means were compared with Mann-Whitney test, correlations with Spearman's analysis, and meta-analysis used Mantel-Haenszel fixed effect model.
Results Serum IgG anti-MDA significantly correlated with SLE-associated auto-IgG (e.g. anti-dsDNA, n=398 R=0.42 p<0.0001). IgG anti-MDA correlated with higher disease activity by SLEDAI in two independent cohorts (Sweden KS, n=397 R=0.33 p<0.0001; US east coast, n=219 R=0.34 p<0.0001) and was confirmed in meta-analysis of dichotomized data showing an Odds Ratio of 3.9 (CI 2.6–5.8 p<0.0001) for IgG anti-MDA positivity in patients with active disease (SLEDAI≥6). Association of anti-MDA with disease activity was supported by an inverse correlation of IgG anti-MDA normalized for total IgG with complement (C2, n=304 R=-0.24 p<0.0001, C3 and C4, n=385 R=-0.24 p<0.0001). Furthermore, we observed elevated IgG anti-MDA/total IgG reactivity in SLE patients with current or history of nephritis compared to no history of nephritis (n=389 4.5+/-4.0 vs 3.4+/-3.3 p<0.0001) and inverse weak correlation of IgG anti-MDA/total IgG with markers of kidney function (serum cystatin C, n=283 R=0.20 p=0.0008, urine albumin, n=373 R=0.23 p<0.0001). Anti-MDA IgG/total IgG also directly correlated with serum soluble TNF receptors (sTNFR1, n=286 R=0.21 p=0.0003, sTNFR2, n=287 R=0.35, p<0.0001). IgG anti-PC either did not correlate or inversely correlated with disease measurements, consistent with its previously reported more protective properties.
Conclusions IgG to MDA-modifications correlates with other autoreactivities, disease activity and nephritis in SLE, and should be further evaluated for its potential prognostic utility. Yet, it remains unclear, if IgG anti-MDA directly contributes to pathogenesis in SLE.
Clin Immunol. 2012 Mar;142(3):390–8.
Clin Immunol. 2014 Jul;153(1):1–7.
Disclosure of Interest None declared