Background/Purpose: While the contribution of humoral immunity to SLE is well established, the role it plays in chronic cutaneous lupus erythematosus (CCLE) is less clear. One characteristic of SLE is a breakdown of tolerance in autoreactive VH4.34 antibodies that are recognized by the rat anti-human idiotypic antibody 9G4 (9G4+). 9G4+ antibodies have germ line encoded autoreactive specificity for glycolipids found on red blood cells and B cells. Despite a high frequency of naive 9G4+ B cells, healthy control donors (HC) have low amounts of serum 9G4+ IgG. In contrast, many SLE patients have high levels of serum 9G4+ IgG that is associated with higher disease activity and highly correlated with anti-dsDNA and a substantial proportion of anti-dsDNA antibodies are 9G4+. The purpose of this study was to compare 9G4+ IgG and associated SLE auto-antibodies between CCLE patients and SLE patients.

Methods: We analyzed samples from 36 HC and 52 patients with primary CCLE, 44 SLE with CCLE, and 303 SLE without CCLE. Cases with a validated diagnosis of either discoid, panniculitis, tumidus or chilblain lupus were included as CCLE. The ACR criteria and attending rheumatologist/dermatologist judgement were used to classify CCLE cases as primary or associated with SLE. We used ELISA to measure 9G4 with the rat monoclonal 9G4, and goat anti-human IgG. Anti-dsDNA and anti-chromatin IgG were measured using commercial ELISA kits. B cell binding 9G4+ was evaluated ex-vivo by flow cytometry.

Results:

41% of SLE patients were positive for 9G4 IgG and had significantly higher serum concentration than HC (p<0.001) Surprisingly, CCLE patients also had high levels of 9G4+ IgG, 38% were positive and serum concentrations were significantly higher than HC (p<0.001) and did not statistically differ from SLE patients. In contrast, while many SLE patients had anti-dsDNA (48%) and anti-chromatin (52%), few CCLE patients were positive for these specificities (12% and 21%) and the concentration was significantly lower for both (p<0.001). Consequently, 9G4+ IgG concentration was highly correlated with both anti-dsDNA (p<0.001, r=0.48) and anti-chromatin (p<0.001, r=0.45) concentration in SLE patients but not in CCLE patients. CCLE patients, however, did have auto-reactive 9G4+, as B cell binding antibodies were similar between SLE and CCLE patients.

Conclusion: Our study confirms the correlation between 9G4+ IgG and anti-dsDNA in SLE and extends this to anti-chromatin. Surprisingly, CCLE patients had high levels of 9G4+ IgG but not anti-dsDNA. This suggests a two-step model of 9G4 tolerance in SLE, the breakdown of general tolerance of germline encoded autoreactive VH4.34 antibodies and a subsequent development of 9G4+ specific for dsDNA. CCLE patients clearly have a defect in the first step and the mechanism of this defect is potentially shared between CCLE and SLE. However, the second step is not shared, as CCLE patients with 9G4+ IgG do not have high levels of anti-dsDNA. Regulation of this step may help determine if otherwise immunologically similar patients may develop SLE or CCLE. Because the specificity of 9G4+ in CCLE is unknown, it remains to be determined whether these antibodies contribute directly to CCLE disease

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chronic-cutaneous-lupus-erythematosus-patients-have-a-breakdown-in-autoreactive-vh4-34-antibody-tolerance-while-maintaining-tolerance-to-dsdna-and-chromatin/