News and Announcements
ORIGINAL RESEARCH ARTICLE
Impact of RAG gene mutations on the length of the complementarity-determining region 3 in autoimmune diseases
Show Less
1 Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, the Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi,
China
2 Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, Guangdong,
China
†These authors contributed equally to this work.
EJMO, 025440460 https://doi.org/10.36922/EJMO025440460
Received: 31 October 2025 | Revised: 1 February 2026 | Accepted: 10 February 2026 | Published online: 15 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract
Introduction: The exact mechanisms of autoimmune diseases (ADs) remain incompletely elucidated. However, T cells are thought to play an essential role in the pathogenesis of ADs.
Objective: To investigate whether abnormal shortening of the TCR/BCR CDR3 region is a common feature in autoimmune diseases (specifically systemic lupus erythematosus and rheumatoid arthritis), and to determine the role of RAG mutations in generating this aberrant repertoire.
Methods: We analyzed the T- and B-cell receptor (TCR/BCR) repertoires in datasets of individuals with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In addition, we characterized the TCR and BCR repertoires using datasets from Rag1-mutant mice and patients with RAG mutations.
Results: Analysis of the TCR/BCR repertoires in SLE and RA revealed a common feature: the complementarity-determining region 3 (CDR3) region of the TCRβ/BCR-H chain is notably shorter than that of healthy controls. Notably, we found that TCRβ/BCR-H CDR3s display abnormal shortening in Rag1-mutant mice and patients with RAG mutations.
Conclusion: Our research shows that RAG mutations cause abnormal TCR/BCR gene rearrangements, leading to unusually short CDR3, which may contribute to the breakdown of self-tolerance. These findings offer new insights into the prevention and treatment of ADs.
Keywords
Autoimmune diseases
Systemic lupus erythematosus
Rheumatoid arthritis
T-cell receptor
Recombination-activating genes
Funding
This work was supported by grants from the Guangdong Basic and Applied Basic Research Foundation (2025A1515012661), the Guangxi Natural Science Foundation (2024GXNSFAA010096), the Shenzhen Science and Technology Program (JCYJ20230807150913027, JCYJ20240813165111016), the Guilin Science Research and Technology Development Project (20230135-4-2 and 20220139-13-2), the Guangdong Province Medical Science and Technology Research Foundation (B2025207), the Guangxi Medical and Health Appropriate Technology Development and Promotion Project (S2024075), the National Natural Science Foundation of China (82460324, 82101877), the China Postdoctoral Science Foundation (2023M740344), the Innovation Training Program for College Students (202410601013, S202410601182), the Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation (2023KF006, 3030302213, 2021KF001), the Chronic Disease Management Research Project of National Health Commission Capacity Building and Continuing Education Center (GWJJMB202510025042), and the Guangxi medical and health key cultivation discipline construction project.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
- Coronel-Restrepo N, Posso-Osorio I, Naranjo-Escobar J, Tobón GJ. Autoimmune diseases and their relation with immunological, neurological and endocrinological axes. Autoimmun Rev. 2017;16(7):684-692. doi: 10.1016/j.autrev.2017.05.002
- Gershwin LJ. Current and Newly Emerging Autoimmune Diseases. Vet Clin North Am Small Anim Pract. 2018;48(2):323-338. doi: 10.1016/j.cvsm.2017.10.010
- Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity. Nat Immunol. 2017;18(7):716- 724. doi: 10.1038/ni.3731
- Regnell SE, Lernmark Å. Early prediction of autoimmune (type 1) diabetes. Diabetologia. 2017;60(8):1370-1381. doi: 10.1007/s00125-017-4308-1
- Mehta L. The Nature of Autoimmune Diseases. J Assoc Physic India. 2021;69(7):11-12.
- Rose NR. Prediction and Prevention of Autoimmune Disease in the 21st Century: A Review and Preview. Am J Epidemiol. 2016;183(5):403-406. doi: 10.1093/aje/kwv292
- Christen U. Pathogen infection and autoimmune disease. Clin Exp Immunol. 2019;195(1):10-14. doi: 10.1111/cei.13239
- Zhang P, Lu Q. Genetic and epigenetic influences on the loss of tolerance in autoimmunity. Cell Mol Immunol. 2018;15(6):575-585. doi: 10.1038/cmi.2017.137
- Kumar P, Saini S, Khan S, Surendra Lele S, Prabhakar BS. Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells. Cell Immunol. 2019;339:41-49. doi: 10.1016/j.cellimm.2018.09.008
- Kurosaki T, Shinohara H, Baba Y. B cell signaling and fate decision. Annu Rev Immunol. 2010;28:21-55. doi: 10.1146/annurev.immunol.021908.132541
- Sherman MH, Bassing CH, Teitell MA. Regulation of cell differentiation by the DNA damage response. Trends Cell Biol. 2011;21(5):312-319. doi: 10.1016/j.tcb.2011.01.004
- Hoolehan W, Harris JC, Byrum JN, Simpson DA, Rodgers KK. An updated definition of V(D)J recombination signal sequences revealed by high-throughput recombination assays. Nucleic Acids Res. 2022;50(20):11696-11711. doi: 10.1093/nar/gkac1038
- Russell ML, Souquette A, Levine DM, et al. Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities. eLife. 2022;11:e73475. doi: 10.7554/eLife.73475
- Murugan A, Mora T, Walczak AM, Callan CG Jr. Statistical inference of the generation probability of T-cell receptors from sequence repertoires. Proc Natl Acad Sci USA. 2012;109(40):16161-16166. doi: 10.1073/pnas.1212755109
- Nemazee D. Mechanisms of central tolerance for B cells. Nat Rev Immunol. 2017;17(5):281-294. doi: 10.1038/nri.2017.19
- Sogkas G, Atschekzei F, Adriawan IR, Dubrowinskaja N, Witte T, Schmidt RE. Cellular and molecular mechanisms breaking immune tolerance in inborn errors of immunity. Cell Mol Immunol. 2021;18(5):1122-1140. doi: 10.1038/s41423-020-00626-z
- Hou X, Zeng P, Zhang X, et al. Shorter TCR β-Chains Are Highly Enriched During Thymic Selection and Antigen- Driven Selection. Front Immunol. 2019;10:299. doi: 10.3389/fimmu.2019.00299
- Liu X, Zhang W, Zhao M, et al. T cell receptor β repertoires as novel diagnostic markers for systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis. 2019;78(8):1070- 1078. doi: 10.1136/annrheumdis-2019-215442
- Liu S, Hou XL, Sui WG, Lu QJ, Hu YL, Dai Y. Direct measurement of B-cell receptor repertoire’s composition and variation in systemic lupus erythematosus. Genes Immun. 2017;18(1):22-27. doi: 10.1038/gene.2016.45
- Ott de Bruin LM, Bosticardo M, Barbieri A, et al. Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development. Blood. 2018;132(3):281-292. doi: 10.1182/blood-2017-12-820985
- Rowe JH, Stadinski BD, Henderson LA, et al. Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity. J Allergy Clin Immunol. 2017;140(6):1739-1743.e7. doi: 10.1016/j.jaci.2017.08.001
- Gomez-Tourino I, Kamra Y, Baptista R, Lorenc A, Peakman M. T cell receptor β-chains display abnormal shortening and repertoire sharing in type 1 diabetes. Nat Commun. 2017;8(1):1792. doi: 10.1038/s41467-017-01925-2
- Wu YC, Kipling D, Leong HS, Martin V, Ademokun AA, Dunn-Walters DK. High-throughput immunoglobulin repertoire analysis distinguishes between human IgM memory and switched memory B-cell populations. Blood. 2010;116(7):1070-1078. doi: 10.1182/blood-2010-03-275859
- Rosner K, Winter DB, Tarone RE, Skovgaard GL, Bohr VA, Gearhart PJ. Third complementarity-determining region of mutated VH immunoglobulin genes contains shorter V, D, J, P, and N components than non-mutated genes. Immunology. 2001;103(2):179-187. doi: 10.1046/j.1365-2567.2001.01220.x
- Lin SG, Ba Z, Alt FW, Zhang Y. RAG Chromatin Scanning During V(D)J Recombination and Chromatin Loop Extrusion are Related Processes. Adv Immunol. 2018;139:93- 135. doi: 10.1016/bs.ai.2018.07.001
- Huang Y, Giblin W, Kubec M, et al. Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability. J Exp Med. 2009;206(4):893-908. doi: 10.1084/jem.20082396
- Hirokawa S, Chure G, Belliveau NM, et al. Sequence- dependent dynamics of synthetic and endogenous RSSs in V(D)J recombination. Nucleic Acids Res. 2020;48(12):6726- 6739. doi: 10.1093/nar/gkaa418
- Castaneda-Zegarra S, Fernandez-Berrocal M, Tkachov M, Yao R, Upfold NLE, Oksenych V. Genetic interaction between the non-homologous end-joining factors during B and T lymphocyte development: In vivo mouse models. Scand J Immunol. 2020;92(4):e12936. doi: 10.1111/sji.12936
- Troshchynsky A, Dzneladze I, Chen L, Sheng Y, Saridakis V, Wu GE. Functional analyses of polymorphic variants of human terminal deoxynucleotidyl transferase. Genes Immun. 2015;16(6):388-398. doi: 10.1038/gene.2015.19