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Characterization of the T cell response to hnRNP-A2 (RA33) in HLA-DR4 transgenic mice


HnRNP-A2 (RA33) is a multifunctional RNA-binding protein involved in various aspects of post-transcriptional regulation of gene expression. Autoantibodies to A2/RA33 are present in approximately 30% of rheumatoid arthritis (RA) patients whereas autoreactive T cells have been found in almost 60% of the patients.


The aim of the study was to analyze the T cell response to A2/RA33 and its possible involvement in the pathogenesis of RA.


The Tepitope programme as well as ELISAs were used to define peptide sequences within A2/RA33 that may bind to the RA associated MHC molecules HLA-DR*0401 and DR*0404. Candidate peptides were analyzed in vivo by immunizing DR*0401 transgenic (tg) mice and restimulating lymph node cells or purified CD4+ or CD8+ T cells with the peptides. The potential of A2/RA33 to induce disease was studied by immunizing arthritis-prone DBA/1 mice, a strain bearing the DR*0401 transgene on the DBA/1 background and TNF tg mice (which spontaneously develop erosive arthritis).


Immunogenic sequences were found clustered in the RNA binding domains of A2/RA33. In immunized HLA-DR4 tg mice the reaction to A2/RA33 peptides seemed to be entirely produced by CD4+ T cells showing a Th1 phenotype, with some of the peptides inducing high production of IFN-γ. However, immunization of HLA-DR4 tg or DBA/1 mice with A2/RA33 protein induced only mild swellings in some animals with no pathological findings in the histological analysis. On the other hand, immunization of TNF tg mice enhanced arthritis significantly. These mice overexpressed A2/RA33 in the joint, whereas expression was very low in wild-type mice.


A2/RA33 derived peptides can bind to RA associated HLA class II molecules and induce a proinflammmatory Th1 response. The increased arthritis observed in immunized TNF tg mice suggests that the autoimmune response to A2/RA33 may indeed be involved in the pathogenesis of RA by inducing or enhancing disease in a proinflammatory environment.

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Hoffmann, M., Trembleau, S., Hayer, S. et al. Characterization of the T cell response to hnRNP-A2 (RA33) in HLA-DR4 transgenic mice. Arthritis Res Ther 6 (Suppl 1), 33 (2004).

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