Immunodominant T‐cell epitopes of hnRNP‐A2 associated with disease activity in patients with rheumatoid arthritis

Abstract

The heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) has been described as an important autoantigen in rheumatoid arthritis (RA) since it is targeted by autoantibodies, autoreactive T cells, and is aberrantly expressed in synovial cells in patients. To identify hnRNP-A2-specific T-cell epitopes possibly associated with pathogenicity, we used an innovative approach. We first scanned 280 overlapping hnRNP-A2 peptides for binding to the RA-associated class II molecules HLA-DR4 and HLA-DR1, leading to a comprehensive selection of binders. The selected peptides were tested in IFN-c-specific ELISPOT assay: PBMC from 18% of RA patients showed a significant IFN-c response to hnRNP-A2 peptides, 15% to the overlapping sequences 117-133 and/or 120-133, whereas PBMC from healthy individuals tested negative. We measured proliferative responses to these two peptides in another cohort of patients with RA or osteoarthritis: positive responses were found in 28% of RA, but also in 11% of osteoarthritis patients and these responses could be blocked by anti-MHC class II Ab. Remarkably, the presence of 117/120-133-specific T cells was significantly associated with active disease in RA patients, and bone erosion appeared to be more common in T-cell positive patients. These data suggest involvement of hnRNP-A2 specific cellular autoimmune responses in RA pathogenesis.

Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism

“…20 Self-peptides that are derived from other potential self-antigens, including type II collagen and nuclear ribonucleoprotein A2 can also be presented to the susceptible DR or DQ allele products and are involved in the pathogenesis of RA. [21][22][23][24][25] The binding affinity of DR4 with class II-associated invariant chain peptide (CLIP) may also affect RA risk. 26 The presentation of misfolded immunoglobulin G heavy chain by DR protein is also shown to contribute to the susceptibility to RA.…”

Autoreactive T cells to citrullinated HSP90 are associated with interstitial lung disease in rheumatoid arthritis

“…In the study by Fritsch et al ., in vitro stimulation of PBMC derived from RA patients with nuclear ribosomal protein A2 (hnRNP‐A2) yielded significant T cell proliferation and augmented expression of IFN‐γ . Complementing these results, another study demonstrated that hnRNP‐A2 peptides capable of binding relevant major histocompatibility complex‐II molecules (HLA‐DR4/DR1) could stimulate the secretion of IFN‐γ by PBMC . Beyond hnRNP‐A2, cryptic/neo‐epitopes generated as a result of apoptosis and caspase cleavage are likely involved in the pathogenesis of RA through stimulation of antigen‐specific CD8+ T cell populations.…”

Inhibition of Inflammation and Bone Erosion by RNA Interference–Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis

“…Our data appear to support these findings and suggest a new and important role of this multifunctional protein in immune regulation as well as involvement in the pathogenesis of inflammatory diseases. The pronounced autoimmune responses to anti–hnRNP A2/B1 repeatedly observed in RA and several arthritis models indicate a dual role of this protein in the pathogenesis of autoimmune arthritis, acting on the one hand as a proinflammatory immune regulator, and on the other hand as an autoantigen inducing potentially arthritogenic autoimmune responses. Hence, specific targeting of hnRNP A2/B1 in cells of the mononuclear phagocyte system might constitute an interesting novel concept for the treatment of RA and other chronic inflammatory conditions, a notion deserving further investigation.…”