Background/Purpose: Although the etiology of rheumatoid arthritis (RA) remains unclear, existing research suggests a complex interplay of both genetic and environmental factors. Citrullinated proteins/peptides, and immune responses to them, may lead to the breaching of immunological tolerance, and subsequent disease. While most research to date has focused on the specificity of anti-citrullinated protein antibodies (ACPAs) in RA, the role of T cell responses to citrullinated peptides remains to be further investigated. The aim of this study is to better understand the involvement of T cells in the pathogenesis of the disease, with the ultimate vision of developing therapeutic interventions for RA.

Methods: HLA-DRA/DRB1*0401 transgenic mice were immunized with two subcutaneous injections of 10 citrullinated T-cell epitopes known to bind to DRB1*0401 and derived from proteins implicated in the development of RA. After 1 week, a second boost was performed, either with citrullinated human fibrinogen protein or with an additional dose of the 10 peptides. Two months after, the mice received an intra-articular (IA) boost in the right knee with a mixture containing 5 citrullinated peptides. All immunizations were performed in complete (for the priming injection, CFA) or incomplete (for the subsequent boosts, IFA) Freund’s adjuvant.

Results: Within weeks of the initial subcutaneous immunizations, the mice developed T-cell responses that were specific for the citrullinated peptides and not for their native counterparts. Remarkably, the injection of citrullinated T cell epitopes was sufficient to induce the production of ACPA, detectable in the blood by ELISA. In addition, the IA boost led to the manifestation of clinical signs of arthritis: mice injected intra-articularly with citrullinated peptides and IFA showed prolonged articular swelling and systemic inflammation in comparison to the control groups. Such signs were even more pronounced in mice previously treated with the citrullinated human fibrinogen protein.

Conclusion: This study shows that immunization with shared epitope-binding citrullinated peptides is sufficient to induce immunological and clinical signs of RA, by triggering arthritogenic T cell responses. These results provide direct evidence of the pathogenic contribution of particular peptides to arthritis and of the pivotal role of T cells in the pathogenesis of the disease. Furthermore, these findings also introduce the possibility of using peptide immunotherapy to re-establish immunological tolerance to RA autoantigens.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-cd4-t-cells-in-the-pathogenesis-of-ra-immunization-with-citrullinated-t-cell-epitopes-is-sufficient-to-induce-immunological-and-clinical-manifestations-of-arthritis-in-dr4-transgenic-mice/