Co-Occurence of Anti-Ro52/TRIM21 and Anti-TRIM38 Autoantibodies Is Associated with Higher Severity of Dry Eye in Sjögren's Syndrome

Nina Wolska¹, Paulina Rybakowska¹, Arkadiusz Klopocki¹, Michael Brown¹, Courtney G. Montgomery², Kiely Grundahl¹, Astrid Rasmussen¹, Robert Hal Scofield³, Lida Radfar⁴, Donald U Stone⁵, Juan-Manuel Anaya^6,7, John Ice², Christopher Lessard³, David M. Lewis⁸, Nelson L. Rhodus⁹, Raj Gopalakrishnan¹⁰, Andrew Huang¹¹, Pamela J Hughes¹², Michael D. Rohrer¹³, Michael Weismann¹⁴, Swamy Venuturupalli¹⁵, Joel M. Guthridge³, Judith A. James¹⁶, Kathy L. Sivils³, Harini Bagavant¹⁷, Umesh S Deshmukh¹⁷ and , ¹Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ³Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁴University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁵Dean McGee Eye Institute, Oklahoma City, OK, ⁶Rheumatology, Center for Autoimmune Diseases Research (CREA), Rosario University, Bogotá, Colombia, ⁷Cell Biol and Immunogenetics, CIB-Rosario University, Medellin, Colombia, ⁸College of Dentistry, Department of Oral and Maxillofacial Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁹Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, ¹⁰Diagnostic and Biological Sciences, Division of Oral Pathology, University of Minnesota, Minneapolis, MN, ¹¹Washington University,, St Louis, MO, ¹²Division of Oral and Maxillofacial Surgery, University of Minnesota, Minneapolis, MN, ¹³Hard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, MN, ¹⁴Cedars-Sinai Medical Center, Los Angeles, CA, ¹⁵Cedars-Sinai Medical Center, West Hollywood, CA, ¹⁶Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁷Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Sjogren's syndrome and autoantibodies

Session Information

Date: Tuesday, November 10, 2015

Title: Sjögren's Syndrome: Translational Insights into Sjögren's Syndrome

Session Type: ACR Poster Session C

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

Background/Purpose: Autoantibodies reactive with Ro52/TRIM21 are detected in almost 70% of primary Sjögren’s syndrome (pSjS) patients and their presence is associated with higher severity of the disease. However, anti-TRIM21 are also present in patients with systemic lupus erythematosus, dermatomyositis, primary biliary cirrhosis, and in mothers of children with congenital heart block. How immune responses to Ro52 exert pathogenic effects in such a diverse group of autoimmune disorders is not clear. TRIM21 belongs to a large and structurally conserved C-IV family of the tripartite motif containing (TRIM) proteins. Two other proteins within this family, TRIM38 and TRIM68, have been previously reported to be autoantigens in pSjS. This study investigates the hypothesis that auto-reactivity against multiple TRIM proteins is associated with the pathogenesis of pSjS. In this study, the frequency and clinical relevance of autoantibodies reactive with TRIM38 was investigated in pSjS patients.

Methods: Serum samples from pSjS patients (n=225) and controls (n=50) were analyzed for reactivity to in vitrotranscribed and translated TRIM38 and TRIM21 proteins. The association of anti-TRIM38 with different clinical parameters of disease such as: anti-Ro/SSA, van Bijsterveld scores, Schirmer’s test scores, minor labial salivary gland biopsy scores, and unstimulated whole saliva volume were evaluated. To analyze antibody cross-reactivity, affinity purified anti-TRIM38 antibodies were used to immunoprecipitate TRIM21. To analyze cross-reactivity at T cell epitope level, TRIM21 reactive T cell hybridomas generated in HLA-DR3 transgenic mice were used.

Results: TRIM38 reactive autoantibodies were detected in the sera of 24/225 pSjS patients and in 2/50 controls. The presence of anti-TRIM38 was significantly associated with the presence of anti-Ro/SSA. Almost 20% of anti-TRIM21 positive patients had anti-TRIM38 and all patients with anti-TRIM38 were positive for anti-TRIM21. Clinically, the co-occurrence of anti-TRIM38 and anti-TRIM21 was significantly associated with higher van Bijsterveld scores and reciprocally lower Schirmer’s test scores. In contrast, anti-TRIM38 did not worsen the clinical measures of salivary gland disease. Despite the structural homology between TRIM38 and TRIM21, affinity purified anti-TRIM38 antibodies did not immunoprecipitate TRIM21. Interestingly, a T cell hybridoma reactive with TRIM21_300-312 peptide was stimulated by TRIM38_138-150peptide.

Conclusion: Our data demonstrate that the co-occurrence of anti-TRIM38 and anti-TRIM21 is specifically associated with higher severity of dry eye in pSjS patients. Anti-TRIM38 is a distinct autoantibody specificity arising in a subset of pSjS patients and T cell cross-reactivity might be involved in the diversification of autoantibody responses from TRIM21 to TRIM38. Our data also suggests that the heterogeneity of clinical manifestations accompanying anti-TRIM21 in different rheumatic disorders might be associated with the co-existence of autoantibodies reactive with other TRIM proteins.

Disclosure: N. Wolska, None; P. Rybakowska, None; A. Klopocki, None; M. Brown, None; C. G. Montgomery, None; K. Grundahl, None; A. Rasmussen, None; R. H. Scofield, None; L. Radfar, None; D. U. Stone, None; J. M. Anaya, None; J. Ice, None; C. Lessard, None; D. M. Lewis, None; N. L. Rhodus, None; R. Gopalakrishnan, None; A. Huang, None; P. J. Hughes, None; M. D. Rohrer, None; M. Weismann, None; S. Venuturupalli, None; J. M. Guthridge, None; J. A. James, None; K. L. Sivils, None; H. Bagavant, None; U. S. Deshmukh, None.

To cite this abstract in AMA style:

Wolska N, Rybakowska P, Klopocki A, Brown M, Montgomery CG, Grundahl K, Rasmussen A, Scofield RH, Radfar L, Stone DU, Anaya JM, Ice J, Lessard C, Lewis DM, Rhodus NL, Gopalakrishnan R, Huang A, Hughes PJ, Rohrer MD, Weismann M, Venuturupalli S, Guthridge JM, James JA, Sivils KL, Bagavant H, Deshmukh US. Co-Occurence of Anti-Ro52/TRIM21 and Anti-TRIM38 Autoantibodies Is Associated with Higher Severity of Dry Eye in Sjögren’s Syndrome [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/co-occurence-of-anti-ro52trim21-and-anti-trim38-autoantibodies-is-associated-with-higher-severity-of-dry-eye-in-sjogrens-syndrome/. Accessed .

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