Background/Purpose:

Rheumatoid arthritis is thought to be a T cell mediated disease, based on its strong association with HLA class II alleles, clinical responsiveness to T cell directed therapies and the presence of CD4 T cells in rheumatoid joints. Understanding the character and antigen specificity of auto-reactive T cell responses in RA has been elusive, in part due to the limited identification of the most relevant epitopes and inability to interrogate responses directly ex vivo.  The presence of ACPA in the serum of patients and association of these antibodies with HLA-DR4 alleles provides a clue to the specificity of pathogenic T cells and implicates their probable importance in the development and progression of RA.

Methods:

We developed a panel of HLA-DR0401 tetramers, selecting citrullinated peptides from four different synovial antigens and verifying their immunogenicity in HLA-DR4 transgenic mice.  This panel of tetramers was used to directly examine the frequency and cell surface phenotype of T cells specific for citrullinated peptides in subjects with DR0401 haplotypes using an ex vivo magnetic enrichment procedure. 

Results:

Citrullinated-antigen specific CD4 T cells were detectable in peripheral blood samples from both healthy subjects and RA patients.  In comparison to healthy subjects, RA patients had significantly higher frequencies of citrullinated-antigen specific T cells (p=0.0069) and a greater proportion of these cells displayed a T_H1 memory phenotype (p<0.0001).  Among RA subjects the frequency of citrullinated-antigen specific T cells was significantly higher within the first 5 years after disease onset (p=0.0018) and was decreased among patients on biologic therapies (p<0.0001) and this difference was seen irrespective of disease duration, indicating an independent effect.

Conclusion:

This study represents the first evidence that the frequency and phenotype of citrullinated-antigen specific T cells vary with respect to important disease parameters and are therefore a potential biomarker in at risk individuals and subjects with RA.  These findings link the presence of ACPA in patient serum with T cells specific to citrullinated epitopes and suggest that the pathogenic T cells in established RA are of a Th1 lineage.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/citrulline-specific-cd4-t-cells-exhibit-a-th1-memory-phenotype-in-rheumatoid-arthritis-subjects-and-their-ex-vivo-frequency-is-influenced-by-both-disease-duration-and-biologic-therapy/