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Abstract Number: 2112

Disease-Activity Associated Autoantibodies to Malondialdehyde-Modified Proteins Can be Isolated from Synovial B Cells in RA

Caroline Grönwall1, Khaled Amara1, Uta Hardt1, Lelise Getu2, Jeffrey D. Greenberg3, Robert M Clancy3, Vivianne Malmström4 and Gregg J. Silverman3, 1Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden, 2Department of Medicine, New York University School of Medicine, New York, NY, 3Department of Medicine, Division of Rheumatology, New York University School of Medicine, New York, NY, 4Department of Medicine, Rheumatology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: autoantibodies, autoantigens, B cells, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, November 15, 2016

Session Title: B Cell Biology and Targets in Autoimmune Disease - Poster II: Rheumatoid Arthritis and Other Rheumatic Diseases

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Malondialdehyde (MDA) is a naturally occurring reactive aldehyde that arises during apoptosis or as a consequence of elevated reactive oxygen species and lipid peroxidation. Free MDA can post-translationally modify lysine residues in a protein carbonylation process that generates neo-epitopes that can be recognized by autoantibodies.

Methods: Serum IgG anti-MDA levels were compared in 71 healthy controls, 30 OA, and 283 SLE and 162 RA patients, identified by ACR criteria. IgG anti-MDA was measured by sandwich ELISA using MDA-modified BSA. After flow cytometry sorting of RA synovial memory B cells, and single cell Ab-gene PCR, 114 mAbs were expressed and tested for MDA-reactivity. Analyses used the 2-sided Mann-Whitney test or Spearman correlation.

Results: In sera, IgG anti-MDA was significantly increased in SLE (17±21 RU/ml, p<0.0001) and RA patients (13±11 RU/ml, p<0.0001), compared to controls (5±3 RU/ml). In SLE, IgG anti-MDA correlated with disease activity by SELENA-SLEDAI (p<0.0001, R=0.34, n=219). Levels were also significantly higher in SLE patients with active disease (SLEDAI≥6, 18.9±17.3 RU/ml, p=0.001) than with low disease activity (SLEDAI<6, 11.5±16.6). In RA patients, IgG anti-MDA correlated with DAS28-ESR (p<0.0001, R=0.35, n=157). Compared to RA patients with low disease activity (DAS28<3.2, 6±3), levels were significantly increased in RA with moderate activity (DAS28 3.2-5.1, 12±11 RU/ml, p=0.005) and high activity (DAS28>5.1, 15±12 RU/ml, p=0.001). In DMARD naïve RA (n=62), IgG anti-MDA also correlated with serum TNFα (p=0.002, R=0.39), IL-6 (p=0.03, R=0.27), and CRP levels (p=0.003, R=0.37). In RA synovial mAbs, we identified four clones (3.5%) that recognized MDA-modified epitopes. The most reactive clone, 1276:01F04, showed high specific binding to MDA but was non-reactive with carbamylated or 4-HNE-modifications. Specificity was confirmed in antigen-competition studies with MDA or MDA acetaldehyde (MAA) protein adducts. This mAb also bound MDA-modified human fibrinogen and albumin. No cross-reactivity with citrullinated epitopes was detected, and mAbs with ACPA or RF reactivity did not bind MDA. Notably, 1276:01F04 originated from an IgG1-bearing B cell that was encoded by near germline variable genes (VH4-39, 1 R-mutation in HCDR3; VL1-51, 2 S-mutations in FR1).

Conclusion: IgM binding to MDA-adducts may be common in health from birth and are part of the natural antibody pool. Yet, IgG anti-MDA are associated with inflammatory conditions including increased disease activity in autoimmune patients. Importantly, MDA-autoreactive B cells could also be isolated from RA synovium, the site of disease. Further studies are merited to investigate the potential pathogenic properties of IgG anti-MDA B-cells/autoantibodies.


Disclosure: C. Grönwall, None; K. Amara, None; U. Hardt, None; L. Getu, None; J. D. Greenberg, None; R. M. Clancy, None; V. Malmström, None; G. J. Silverman, None.

To cite this abstract in AMA style:

Grönwall C, Amara K, Hardt U, Getu L, Greenberg JD, Clancy RM, Malmström V, Silverman GJ. Disease-Activity Associated Autoantibodies to Malondialdehyde-Modified Proteins Can be Isolated from Synovial B Cells in RA [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/disease-activity-associated-autoantibodies-to-malondialdehyde-modified-proteins-can-be-isolated-from-synovial-b-cells-in-ra/. Accessed July 1, 2022.
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