Rheumatoid arthritis is more than cytokines: Autoimmunity and rheumatoid arthritis

Smolen, Josef S.; Steiner, Günter

doi:10.1002/1529-0131(200110)44:10<2218::aid-art382>3.0.co;2-c

Cited by 28 publications

(21 citation statements)

References 43 publications

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“…In addition, there has been controversy for several decades about the major pathogenic cell type(s); many candidates have been implicated (47)(48)(49). After an initial focus on B cells and Abs (47), Th cells became prime suspects largely because of the HLA-DR associations in RA (1).…”

Section: Are Cii-specific T Cells Relevant To Ra Pathogenesis?mentioning

confidence: 99%

Tracking of Proinflammatory Collagen-Specific T Cells in Early and Late Collagen-Induced Arthritis in Humanized Mice

Svendsen

Andersen

Willcox

et al. 2004

The Journal of Immunology

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Rheumatoid arthritis is a chronic inflammatory disease associated with certain HLA-DR4 subtypes. The target autoantigen(s) is unknown, but type II collagen (CII) is a candidate, with a single immunodominant DR4-restricted 261–273 T cell epitope (CII(261–273)). In the present study, we have prepared HLA-DR4:CII(261–273) tetramers and analyzed peripheral blood, lymph node, and synovial fluid cells from DR4-transgenic mice with early and late collagen-induced arthritis to draw a fuller picture of the role of CII-reactive Th cells in disease development. Their frequencies increased ∼20-fold in blood 1–2 wk postimmunization, and even more in acutely arthritic joints. Our data strongly suggest that CII-specific Th cells are necessary, but not sufficient for collagen-induced arthritis. The CII-specific Th cells displayed an activated proinflammatory Th1 phenotype, and their expansion correlated with onset and severity of arthritis and also with anti-CII Ab levels. Surprisingly, shortly after the first clinical signs of arthritis, activated HLA-DR4:CII tetramer+ cells became undetectable in the synovial fluid and rare in the blood, but persisted in lymph nodes. Consequently, future human studies should focus on patients with early arthritis, and on their synovial cells, to re-evaluate the occurrence and pathogenic importance of CII-specific or other Th cells in rheumatoid arthritis.

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Section: Are Cii-specific T Cells Relevant To Ra Pathogenesis?mentioning

confidence: 99%

Tracking of Proinflammatory Collagen-Specific T Cells in Early and Late Collagen-Induced Arthritis in Humanized Mice

Svendsen

Andersen

Willcox

et al. 2004

The Journal of Immunology

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“…These mice spontaneously developed an autoantibody to hnRNP-A2, and immunization with recombinant hnRNP-A2 aggravated the disease, suggesting that autoimmune reactions to hnRNP-A2 may contribute to the inflammatory and destructive processes in PIA in a similar way. The aberrant expression of hnRNP-A2 under inflammatory conditions may lead to the creation of neoepitopes that may form the molecular basis for recognition by autoreactive T and B cells (22,(42)(43)(44)(45)(46)(47). To date it is unknown to what degree the joint protein is posttranslationally modified, and it will be a challenging task for the future to identify novel inflammation-induced modifications in hnRNP-A2 isolated from the arthritic joint.…”

Section: Discussionmentioning

confidence: 99%

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

Hoffmann

Tuncel

Skriner

et al. 2007

The Journal of Immunology

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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.

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“…Dies gilt in noch höherem Maße für autoreaktive T-Zellen, denen bei Organ-spezifischen Autoimmunerkrankungen entscheidende pathogenetische Bedeutung zukommt. Allerdings geben gerade die in jüngster Zeit gewonnenen neuen Erkenntnisse über Autoantigene, Autoantikörper und autoreaktive T-Zellen Anlass zur Hoffnung, dass schon in naher Zukunft sowohl die Diagnostik als auch unser Verständnis der Pathogenese der RA bedeutende Fortschritte machen werden (37). …”

Section: Abschließende Bemerkungenunclassified

Neue Autoantikörper in der Diagnostik der rheumatoiden Arthritis

Steiner¹,

Smolen²

2002

Zeitschrift f�r Rheumatologie

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The diagnosis of rheumatoid arthritis has been hampered by the lack of a truly disease-specific serologic marker. Thus, despite its moderate specificity rheumatoid factor (RF) is still the only established marker antibody for RA and among the diagnostic criteria of the American College of Rheumatology the only serologic one. However, in recent years, several newly characterized autoantibodies have been described that may have the potential to become diagnostic indicators for RA. In particular, antibodies to citrullinated targets (anti-keratin or anti-filaggrin antibodies, respectively, antibodies to synthetic citrullinated peptides) appear to be highly specific for RA. Other potentially useful antibodies include anti-RA33 autoantibodies and antibodies to the stress protein BiP which seem to have higher specificity for RA than RF. Apart from being promising diagnostic markers these autoantibodies or the underlying cellular autoimmune reactions, respectively, may also play a role in the pathogenesis of RA.

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Rheumatoid arthritis is more than cytokines: Autoimmunity and rheumatoid arthritis

Cited by 28 publications

References 43 publications

Tracking of Proinflammatory Collagen-Specific T Cells in Early and Late Collagen-Induced Arthritis in Humanized Mice

Tracking of Proinflammatory Collagen-Specific T Cells in Early and Late Collagen-Induced Arthritis in Humanized Mice

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

Neue Autoantikörper in der Diagnostik der rheumatoiden Arthritis

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