Inducing Experimental Arthritis and Breaking Self-Tolerance to Joint-Specific Antigens with Trackable, Ovalbumin-Specific T Cells

Maffia, Pasquale; Brewer, James M.; Gracie, J. Alastair; Ianaro, Angela; Leung, Bernard P.; Mitchell, Paul J.; Smith, Karen; McInnes, Iain B.; Garside, Paul

doi:10.4049/jimmunol.173.1.151

Cited by 58 publications

(93 citation statements)

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“…Th1 cells have been described to be more susceptible to Fas-mediated apoptosis than Th2 [14][15][16][17] and Th17 cells [18][19][20]. However, Th1 cells can be long lived and drive chronic inflammation [6][7][8][9][10][11][12][13], and can persist as effector/memory cells efficiently [24][25][26]65]. Obviously, compensatory regulatory mechanisms have to exist in those cells.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20].…”

Section: Supporting Information Available Onlinementioning

confidence: 99%

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Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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Section: Discussionmentioning

confidence: 99%

Section: Supporting Information Available Onlinementioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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“…Lymph nodes from DO11.10 mice were pooled, and CD4ϩ T cells were purified by negative selection, as described previously (24,28). Th1 cell differentiation was induced by culturing CD4ϩ T cells with antigen-presenting cells in the presence of OVA 323-339 (Genosys), interleukin-12 (IL-12; PeproTech), and anti-IL-4 monoclonal antibody (R&D Systems), as described previously (24,28).…”

Section: Animalsmentioning

confidence: 99%

“…A model of experimental arthritis has been established in which autoimmunity is spontaneous and elicited by antigen-specific T cells (24). In this model, transgenic T cells specific for the antigen ovalbumin (OVA) mediated the development of arthritis and the production of RF, anti-CCP, and anti-CII antibodies, resembling the histologic and humoral features of human disease (24)(25)(26).…”

mentioning

confidence: 99%

“…In this model, transgenic T cells specific for the antigen ovalbumin (OVA) mediated the development of arthritis and the production of RF, anti-CCP, and anti-CII antibodies, resembling the histologic and humoral features of human disease (24)(25)(26). However, a limitation of this model was that the arthritis was acute, self-limiting, and localized in the ankle joint.…”

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confidence: 99%

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Characterization of the anticollagen antibody response in a new model of chronic polyarthritis

Conigliaro¹,

Benson²,

Patakas³

et al. 2011

Arthritis & Rheumatism

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Objective. Type II collagen (CII)-specific B cell responses have been recognized in human rheumatoid arthritis (RA) and in collagen-induced arthritis (CIA). An important limitation of the CIA model is that the CII response and the disease are stimulated by exogenously injected collagen. A model of experimental ovalbumin (OVA)-mediated acute arthritis has been established in which autoimmunity is spontaneous and elicited by antigen-specific T cells. This study was undertaken to create a new model of chronic autoimmune polyarthritis and characterize the associated CII-specific B cell response.Methods. Secondary challenge with OVA or CII in adjuvant was used to elicit chronic disease. CII-specific B cell responses against the epitopes U1, J1, C1, and citrullinated C1, together with the antibody affinity, were investigated in OVA-mediated arthritis.Results. Chronic autoimmune polyarthritis was induced and was dependent on the antigen used in the secondary challenge. U1 was the major CII epitope recognized, and antibodies showed the same affinity as those in CIA.Conclusion. Our findings indicate that the development and severity of chronic disease is dependent on the antigen and is associated with an increased autoreactive B cell response directed against a specific CII epitope (U1). OVA-mediated chronic arthritis exhibits anti-CII antibodies (against U1), resembling human RA and murine CIA.

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Animal models of rheumatoid arthritis

et al. 2009

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Animal models have been used extensively in studies of rheumatoid arthritis pathogenesis. Despite the inherent limitations of all animal models, several rodent models have significantly progressed our understanding of the fundamental mechanisms underpinning rheumatoid arthritis and contributed to several current major advances in treatment. These models include the induced arthritis models such as collagen‐induced arthritis, collagen‐antibody‐induced arthritis, zymosan‐induced arthritis, and the methylated BSA model, and the genetically manipulated or spontaneous arthritis models such as the TNF‐α‐transgenic mouse, K/BxN mouse, and the Skg mouse. Here, we describe these animal models and discuss their advantages and limitations. Note added after publication: For an update on this topic, please see the latest https://doi.org/10.1002/eji.201746938

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Inducing Experimental Arthritis and Breaking Self-Tolerance to Joint-Specific Antigens with Trackable, Ovalbumin-Specific T Cells

Cited by 58 publications

References 31 publications

Persistence of effector memory Th1 cells is regulated by Hopx

Persistence of effector memory Th1 cells is regulated by Hopx

Characterization of the anticollagen antibody response in a new model of chronic polyarthritis

Animal models of rheumatoid arthritis

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