TCR Motifs Identify Unique Clones in African Americans with Systemic Sclerosis

Urvashi Kaundal¹, Chloe Borden², Devin Teehan², Brittany Dulek³, Justin Lack⁴, Ami Shah⁵, Maureen Mayes⁶, Daniel Shriner⁷, Ayo P. Doumatey⁷, Amy Bentley⁷, Robyn Domsic⁸, Thomas Medsger, Jr⁹, Paula Ramos¹⁰, Richard Silver¹¹, Virginia Steen¹², John Varga¹³, Vivien Hsu¹⁴, Lesley Ann Saketkoo¹⁵, Dinesh Khanna¹³, Elena Schiopu¹⁶, Jessica Gordon¹⁷, Lindsey Criswell¹⁸, Heather Gladue¹⁹, Chris Derk²⁰, Elana Bernstein²¹, S. Louis Bridges¹⁷, Victoria Shanmugam²², Lorinda Chung²³, Suzanne Kafaja²⁴, Reem Jan²⁵, Marcin Trojanowski²⁶, Avram Goldberg²⁷, Benjamin Korman²⁸, Faiza Naz²⁹, Stefania Dell'Orso³⁰, Adebowale Adeyemo⁷, Elaine Remmers³¹, Charles Rotimi⁷, Fredrick Wigley³², Francesco Boin³³, Daniel Kastner³⁴ and Pravitt Gourh²⁹, ¹Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Chevy Chase, MD, ²Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ³Integrated Data Science Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, ⁴Integrated Data Science Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, Bethesda, MD, ⁵Division of Rheumatology, Johns Hopkins University, Ellicott City, MD, ⁶UTHealth Houston Division of Rheumatology, Houston, TX, ⁷Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, ⁸Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, ⁹Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Verona, PA, ¹⁰Medical University of South Carolina, Charleston, SC, ¹¹Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, ¹²Georgetown University School of Medicine, Washington, DC, ¹³University of Michigan, Ann Arbor, MI, ¹⁴Department of Medicine, Rheumatology Division, Rutgers-RWJ Medical School, South Plainfield, NJ, ¹⁵New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Louisiana State University and Tulane University Medical Schools, New Orleans, LA, ¹⁶Division of Rheumatology, Medical College of Georgia at Augusta University, Martinez, GA, ¹⁷Division of Rheumatology, Weill Cornell Medical College, New York, NY, ¹⁸Genomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, Bethesda, MD, ¹⁹Arthritis & Osteoporosis Consultants of the Carolinas, Charlotte, NC, ²⁰Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, ²¹Division of Rheumatology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, ²²NIH Office of Autoimmune Disease Research in the Office of Research on Women's Health, National Institutes of Health, Bethesda, MD, Bethesda, MD, ²³Stanford University, Woodside, CA, ²⁴Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA, ²⁵Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, ²⁶Department of Rheumatology, Boston University School of Medicine, Boston, MA, ²⁷NYU Langone Health - NYU Hospital for Joint Diseases, Lake Success, NY, ²⁸University of Rochester, Rochester, NY, ²⁹National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, Bethesda, MD, ³⁰Genomic Technology Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ³¹Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, ³²Johns Hopkins University, Division of Rheumatology, Baltimore, MD, Baltimore, MD, ³³Cedars-Sinai Medical Center, Los Angeles, CA, ³⁴National Human Genome Research Institute, Bethesda, MD

Meeting: ACR Convergence 2024

Keywords: Disparities, genomics, Systemic sclerosis, T Cell

Session Information

Date: Sunday, November 17, 2024

Title: Systemic Sclerosis & Related Disorders – Basic Science Poster I

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Systemic sclerosis (SSc) is a rare multisystem autoimmune disease that disproportionately affects African Americans (AA). Previous work from our lab has suggested a pivotal role of HLA-II genes in SSc pathogenesis. These HLA alleles encode variations in the antigen-binding grooves of the HLA molecules that determine their binding affinity for specific antigens. Antigenic peptides presented by the HLA molecules are recognized by T cell receptors (TCRs) leading to an antigen-specific response. We hypothesized that for a rare disease like SSc, where HLA genes play an important role, there must exist a unique set of TCRs that lead to SSc pathogenesis. In this study, we examined the TCRb sequences of AA subjects with SSc and identified groups of patients who share a TCR motif that defines a unique clone in each patient.

Methods: TCRb region was deep sequenced for 132 AA subjects with SSc and 49 AA control subjects using the immunoSEQ assay (Adaptive Biotechnologies, USA). The SSc subjects were enrolled at the 24 academic centers participating in the Genome Research in African American Scleroderma Patients (GRASP) consortium. Data were analyzed using Immunarch software for repertoire analysis. TCRb clones were identified as “unique” if they were found in only one individual. GLIPH2 (Grouping of Lymphocyte Interactions by Paratope Hotspots) software was used to identify motifs that cluster the TCRs into shared antigen specificity groups.

Results: We identified a total of 3,321,168 TCRb clones and using GLIPH2 (Figure 1) prioritized 228 motifs found exclusively in SSc patients and not in control subjects with significant GLIPH2 scores. Next, we identified motifs that comprised at least 10% of the samples and narrowed down to three motifs. These three motifs included TCRb clones seen in 47 SSc patients (36%) out of a total of 132 patients (Figure 2). We observed that greater than 90% of SSc patients carrying these unique clones also carried the previously reported HLA risk alleles in SSc. These unique TCRb clones were of shorter lengths (10-16 amino acids), as observed in our overall cohort analysis. There was also a preferred usage of the amino acid Glycine at position 114 in the “G%GR” motif and patients with this motif had a higher prevalence (75%) of interstitial lung disease (ILD), compared to 63% in overall SSc cohort. Motif “G%RSGNT” had Asparagine at position 114 and patients with this motif had a higher prevalence (38%) of pulmonary arterial hypertension (PAH), compared to 28% in overall SSc cohort.

Conclusion: We have identified unique TCR clones forming a motif in groups of SSc patients. The presence of these TCRb clones and skewing in the phenotype of these patients suggests a pathogenic role for these clones. Further studies are needed to understand the role of these clones in loss of tolerance.

Figure 1. Strategy used for analyzing GLIPH2 output to identify Scleroderma (SSc)-specific T-Cell Receptor (TCR) motifs comprising of unique clones.

Figure 2. Scleroderma (SSc) patient specific unique TCRs with GLIPH2 score, TCRb sequence, length, V and J gene usage, HLA-II risk alleles and prevalence of interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), anti-topoisomerase_1 antibodies (ATA).
Y indicates Yes; Blank indicates No or missing information.

Disclosures: U. Kaundal: None; C. Borden: None; D. Teehan: None; B. Dulek: None; J. Lack: None; A. Shah: Arena Pharmaceuticals, 5, Kadmon, 5, Medpace LLC, 5; M. Mayes: AstraZeneca, 5, Atyr, 5, Boehringer-Ingelheim, 1, 5, Horizon Therapeutics, 5, Merck/MSD, 5; D. Shriner: None; A. Doumatey: None; A. Bentley: None; R. Domsic: AstraZeneca, 2; T. Medsger, Jr: None; P. Ramos: None; R. Silver: None; V. Steen: None; J. Varga: None; V. Hsu: None; L. Saketkoo: None; D. Khanna: AbbVie/Abbott, 2, Amgen, 2, AstraZeneca, 2, Boehringer-Ingelheim, 2, Bristol-Myers Squibb(BMS), 2, Cabaletta, 2, Certa Therapeutics, 2, GlaxoSmithKlein(GSK), 2, Janssen, 2, MDI Therapeutics, 8, Merck/MSD, 2, Novartis, 2, Zura Bio, 2; E. Schiopu: None; J. Gordon: None; L. Criswell: None; H. Gladue: None; C. Derk: None; E. Bernstein: AstraZeneca, 5, aTyr, 5, Boehringer-Ingelheim, 1, 2, 5, Bristol-Myers Squibb(BMS), 5, Cabaletta, 1, 5, Kadmon, 5; S. Bridges: None; V. Shanmugam: None; L. Chung: Boehringer-Ingelheim, 5, Eicos, 1, 2, Eli Lilly, 2, Genentech, 2, IgM Biosciences, 2, Janssen, 1, Kyverna, 2, Mitsubishi Tanabe, 1, 2; S. Kafaja: None; R. Jan: None; M. Trojanowski: None; A. Goldberg: None; B. Korman: None; F. Naz: None; S. Dell'Orso: None; A. Adeyemo: None; E. Remmers: None; C. Rotimi: None; F. Wigley: None; F. Boin: Adicet Bio, 2; D. Kastner: None; P. Gourh: None.

To cite this abstract in AMA style:

Kaundal U, Borden C, Teehan D, Dulek B, Lack J, Shah A, Mayes M, Shriner D, Doumatey A, Bentley A, Domsic R, Medsger, Jr T, Ramos P, Silver R, Steen V, Varga J, Hsu V, Saketkoo L, Khanna D, Schiopu E, Gordon J, Criswell L, Gladue H, Derk C, Bernstein E, Bridges S, Shanmugam V, Chung L, Kafaja S, Jan R, Trojanowski M, Goldberg A, Korman B, Naz F, Dell'Orso S, Adeyemo A, Remmers E, Rotimi C, Wigley F, Boin F, Kastner D, Gourh P. TCR Motifs Identify Unique Clones in African Americans with Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/tcr-motifs-identify-unique-clones-in-african-americans-with-systemic-sclerosis/. Accessed .

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