The Rheumatoid Arthritis-Associated Autoantigen hnRNP-A2 (RA33) Is a Major Stimulator of Autoimmunity in Rats with Pristane-Induced Arthritis

Abstract

A single intradermal injection of the mineral oil pristane in susceptible DA.1F rats induces erosive arthritis closely mimicking rheumatoid arthritis (RA). Pristane-induced arthritis (PIA) is driven by autoreactive T cells but no autoantigen has been identified to date. We therefore analyzed B and T cell responses to autoantigens potentially involved in the pathogenesis of RA, including IgG, citrullinated proteins, stress proteins, glucose-6-phosphate isomerase, and heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (RA33). IgG and IgM autoantibodies to hnRNP-A2 were detectable in sera of pristane-primed DA.1F rats already 1 wk before disease onset, reached maximum levels during the acute phase, and correlated with arthritis severity. Apart from rheumatoid factor, autoantibodies to other Ags were not observed. CD4+ lymph node cells isolated 10 days after pristane injection produced IFN-γ but not IL-4 in response to stimulation with hnRNP-A2, whereas none of the other candidate Ags elicited cytokine secretion. Surprisingly, hnRNP-A2 also stimulated lymph node cells of naive animals to produce inflammatory cytokines in a MyD88-dependent manner. Furthermore, hnRNP-A2 was highly overexpressed in the joints of rats injected with pristane. Overexpression coincided with the appearance of anti-RA33 Abs and preceded the onset of clinical symptoms of PIA by several days. Taken together, these data suggest hnRNP-A2 to be among the primary inducers of autoimmunity in PIA. Therefore, this Ag might play a pivotal role in the pathogenesis of PIA and possibly also human RA.

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

“…Further studies are planned to understand the molecular aspect of the differential presentation by various HLA molecules. Such studies, together with recent findings obtained in two different animal models of RA, in which autoimmunity to hnRNP-A2 spontaneously developed prior to or concomitant with clinical signs of arthritis [11,12], will help to further elucidate the role of hnRNP-A2 in the pathogenesis of RA.…”

“…The four peptides 10-26, 50-70, 120-133, and 152-170 were found to fulfill this criterium, although 10-26 bound weakly to DR Ã 0101, 120-133 weakly to DR Ã 0404, and 152-170 weakly to DR Ã 0401. Therefore, these epitopes, followed by peptides [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193], and 289-306, were considered best candidates to detect hnRNP-A2 specific T cells in patients with RA.…”

“…Furthermore, also T cells from peripheral blood and synovial fluid of RA patients were found to react to hnRNP-A2, in about 60% of the patients [8]. Interestingly, autoimmunity to hnRNP-A2 has been observed in TNF-transgenic (Tg) mice [11], which develop arthritis spontaneously, and is a dominant immunological event in pristane-induced arthritis in rats [12]. Altogether, the results suggest that this protein is an important and potentially pathogenic autoantigen in animal models of arthritis and in RA.…”

The Roles of B Cells and Their Interactions with Fibroblast-Like Synoviocytes in the Pathogenesis of Rheumatoid Arthritis

“…Recently, a number of anticitrullinated protein antibodies (ACPAs) have been described, such as antikeratin antibody, antiperinuclear factor, antiprofillagrin/fillagrin antibody, anticyclic citrullinated peptide (anti-CCP), anti-Sa antibodies, and antimutated citrullinated vimentin [7,8,9]. Many other autoantibodies have also, to our knowledge, been associated with the disease, including antibodies to type II collagen, immunoglobulin-binding protein, rheumatoid arthritis-associated autoantigen hnRNP-A2 (RA33), glucose-6-phosphate isomerase (GPI), and calp statin, among others [10,11,12,13]. These autoantibodies may contribute to the pathological processes of RA directly and indirectly by immune complex formation and complement fixation in the joint [14].…”

Expressão de microRNAs e suas interações com genes envolvidos com a resistência ou susceptibilidade à artrite induzida por pristane.

“…No entanto, alguns trabalhos mostram que apesar dessas células serem importantes no início da doença, a destruição das junções e inflamação no período crônico, deve ser independente dessas células (COMBE, 1998;LUBBERTS, 2010). As células T medeiam suas funções artritogênicas pela secreção de citocinas pró-inflamatórias nas junções (HOFFMANN et al, 2007). Alguns trabalhos descrevem que citocinas liberadas por células Th1 contribuem para a inflamação e destruição das articulações, enquanto que um perfil Th2 é mais protetor (VERVOORDELDONK; TAK, 2002).…”