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Abstract Number: 666

Immunoglobulin N-Glycosylation Acquired By Somatic Hypermutation As a Potential Mechanism for Non-Specific B Cell Activation in Sjogren’s Syndrome

Kristi A. Koelsch1,2,3, Joshua Cavett4,5, Jacen Maier-Moore6, Kenneth Smith5, Christopher Lessard4,7,8, Lida Radfar9, David M. Lewis10, Biji T Kurien1,4,5, Astrid Rasmussen7, Kathy Sivils5,8, Judith A. James4,7,8, A. Darise Farris7 and R. Hal Scofield1,7,11, 1U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK, 2Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Okalahoma City, OK, 3Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 4College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 5Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 6Dept. of Clinical Laboratory Science, University of Texas at El Paso, El Paso, TX, 7Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 8Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 9Oral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, OK, 10Department of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, OK, 11College of Medicine, Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Plasmablasts

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Session Information

Date: Sunday, November 13, 2016

Session Title: Sjögren's Syndrome - Poster I: Translational Science

Session Type: ACR Poster Session A

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

Background/Purpose: Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands resulting in tissue destruction, pathological dry mouth and dry eyes and in increased risk for lymphoma. The presence of ectopic germinal centers, clonally related B cells and autoantibody production from antibody-secreting cells (ASCs) isolated from the salivary glands indicate that at least some of the ASCs arise from an antigen-driven immune response. Analyses of immunoglobulin sequences can be instrumental for determining somatic mutational patterns shaped by selective pressures, where positive selection in the Complementary Determining Regions (CDRs) and negative selection in the framework regions (FWRs) would indicate antigen-driven antibody production. An alternative would be a non-specific mode of B cell activation. Immunoglobulin variable region N-linked glycosylation acquired by somatic hypermutation (AcN-glycs) has been strongly correlated to follicular lymphoma. Bacterial lectins can bind and activate B cells via AcN-glycs – a possible non-specific mechanism for antibody production and proliferation of B cells.

Methods: To explore immunoglobulin selective pressures in our cohort, we single cell-sorted IgG+ ASCs isolated from the minor salivary glands of 4 SS patients meeting the American-European combined and ACR criteria, and 5 sicca controls. The immunoglobulin variable regions were sequenced by RT-PCR. AcN-glyc motiffs were identified using the online NetNGlyc tool. An IMGT/V-QUEST sequence analysis was performed to confirm that all identified AcN-glyc motifs were introduced by somatic mutation and not germline-encoded. To analyze for antigen-driven selection we utilized BASELINe Version 1.3, an online tool for predicting positive or negative selective pressures.

Results: We sequenced 56 variable regions from 3 SS and 21 sicca control immunoglobulins. Analysis of heavy and light chain sequences revealed SS patients had an increased frequency of AcN-glycs motifs in the FWRs and a decreased frequency in the CDRs as compared to controls (20% vs 5%; 4% vs 10%). The BASELINe analysis showed positive selection in the CDRs and negative selection in the FWRs of sequences from both SS patients and controls. When the selection strengths for immunoglobulins based on glycosylation status were compared (regardless of classification), we found that heavy chains with CDR AcN-glycs and light chains with FWR AcN-glycs had significantly less positive selection than those without AcN-glycs (p=0.05 and p=0.04, respectively).

Conclusion: Overall, immunoglobulins from ASCs infiltrating the minor salivary glands of SS patients and sicca controls in our cohort undergo positive selection in the CDRs and negative selection in the FWRs, indicating antigen-driven immune responses. Immunoglobulins with AcN-glycs have lower positive and negative selection pressures in the heavy chain CDRs and FWRs as compared to those that are non-glycosylated, indicating a potential non-specific mechanism for activation in these ASCs that could potentially give rise to autoreactive proliferations or lymphoproliferative neoplasms.


Disclosure: K. A. Koelsch, None; J. Cavett, None; J. Maier-Moore, None; K. Smith, None; C. Lessard, None; L. Radfar, None; D. M. Lewis, None; B. T. Kurien, None; A. Rasmussen, None; K. Sivils, None; J. A. James, None; A. D. Farris, None; R. H. Scofield, Eli Lilly and Company, 5,UCB, 5.

To cite this abstract in AMA style:

Koelsch KA, Cavett J, Maier-Moore J, Smith K, Lessard C, Radfar L, Lewis DM, Kurien BT, Rasmussen A, Sivils K, James JA, Farris AD, Scofield RH. Immunoglobulin N-Glycosylation Acquired By Somatic Hypermutation As a Potential Mechanism for Non-Specific B Cell Activation in Sjogren’s Syndrome [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/immunoglobulin-n-glycosylation-acquired-by-somatic-hypermutation-as-a-potential-mechanism-for-non-specific-b-cell-activation-in-sjogrens-syndrome/. Accessed January 19, 2021.
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