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1.  Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice 
Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in diarthrodial joints. We have previously established that mice transgenic for the human DR genes associated with RA are susceptible to collagen-induced arthritis (CIA) and we have identified a determinant of type II collagen (CII263–270) that triggers T-cell immune responses in these mice. We have also determined that an analog of CII263–270 would suppress disease in DR1 transgenic mice. Because the immunodominant determinant is the same for both DR1 transgenic and DR4 transgenic mice, we attempted to determine whether the analog peptide that was suppressive in DR1 transgenic mice would also be effective in suppressing CIA in DR4 transgenic mice. We treated DR4 transgenic mice with two analog peptides of CII that contained substitutions in the core of the immunodominant determinant: CII256–276 (F263N, E266D) and CII256–270 (F263N, E266A). Mice were observed for CIA, and T-cell proliferative responses were determined. Either peptide administered at the time of immunization with CII significantly downregulated arthritis. Binding studies demonstrated that replacement of the phenylalanine residue in position 263 of the CII peptide with asparagine significantly decreased the affinity of the peptide for the DR4 molecule. In contrast, replacement of the glutamic acid residue in position 266 with aspartic acid or with alanine had differing results. Aspartic acid reduced the affinity (35-fold) whereas alanine did not. Both peptides were capable of suppressing CIA. With the use of either peptide, CII256–276 (F263N, E266D) or CII256–270 (F263N, E266A), the modulation of CIA was associated with an increase in T-cell secretion of IL-4 together with a decrease in IFN-γ. We have identified two analog peptides that are potent suppressors of CIA in DR4 transgenic mice. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of HLA-DR4 that can suppress autoimmune arthritis.
doi:10.1186/ar2043
PMCID: PMC1779432  PMID: 16982003
2.  T Cells Stimulated by an Analog Peptide of Type II Collagen Require FcRγ to Secrete IL-4 and Suppress Autoimmune Arthritis 
Arthritis and rheumatism  2011;63(9):2661-2670.
Objective
Using the collagen-induced arthritis (CIA) model, we explored the characteristics of the T cell population which responds to an analog peptide (A9) of type II collagen (CII) and regulates autoimmunity.
Methods
A9 is a 26 amino acid peptide analogous to the sequence of a segment of CII (CII 245-270) but with substitutions made at amino acid positions 260 (alanine for isoleucine), 261 (hydroxyproline for alanine), and 263 (asparagine for phenylalanine). We have previously shown that A9 profoundly suppresses immunity to CII and CIA. In order to determine the mechanism of suppression, we used a transgenic mouse whose T cells express a CII specific receptor (TCR) and performed passive cell transfer experiments.
Results
The results demonstrate that suppression of CIA by the A9 is dependent upon T cells. Using multiparameter flow cytometry, we determined that the cells responsible for suppression were CD4+ and expressed high levels of FcεRIγ(FcRγ). To establish the significance of this finding, we obtained mice genetically deficient in FcRγ to perform passive transfer experiments. The resulting FcRγ-/- CD4+ T cells when primed by culture with A9 could not transfer the suppression of arthritis nor secrete cytokines in response to A9.
Conclusion
Taken together, these data suggest that the suppression of arthritis and the Th2 cytokine profile elicited by A9 is dependent upon the presence of FcRγ in the T cells. These findings are novel and may have therapeutic potential for patients with autoimmune arthritis.
doi:10.1002/art.30454
PMCID: PMC3575180  PMID: 21590683
3.  T Cell Receptor-Signaling Induced by an Analog Peptide of type II Collagen Requires Activation of Syk 
Clinical immunology (Orlando, Fla.)  2009;133(1):145-153.
We have previously described an analog peptide of type II collagen (CII) that can suppress collagen-induced arthritis (CIA). This analog peptide represents CII245-270, the immunodominant epitope of CII, but with substitutions at 260, 261, and 263 - CII245-270 (A260, B261, and N263) (A9). To elucidate the mechanisms responsible for suppression, we used mice transgenic for a collagen-specific T cell receptor (TCR). When we found that APCs pulsed with A9 failed to induce T cell phosphorylation of TCR-? and ZAP-70, we explored alternative signaling pathways. We determined that A9 instead induced phosphorylation of spleen tyrosine kinase (Syk). The importance of Syk was confirmed by the use of chemical Syk inhibitors, which blocked both cytokine secretion and activation of GATA-3 mediated by peptide A9. In summary, T cells use an alternative pathway in response to A9 that involves Syk. This novel T cell pathway may represent an important means for altering T cell phenotypes.
doi:10.1016/j.clim.2009.06.006
PMCID: PMC2756788  PMID: 19596610
Collagen II; T cells; altered peptide ligands; T cell signaling; Syk (spleen tyrosine kinase); autoimmunity
4.  T cells that are naturally tolerant to cartilage-derived type II collagen are involved in the development of collagen-induced arthritis 
Arthritis Research  2000;2(4):315-326.
The immunodominant T-cell epitope that is involved in collagen-induced arthritis (CIA) is the glycosylated type II collagen (CII) peptide 256-270. In CII transgenic mice, which express the immunodominant CII 256-270 epitope in cartilage, the CII-specific T cells are characterized by a partially tolerant state with low proliferative activity in vitro, but with maintained effector functions, such as IFN-γ secretion and ability to provide B cell help. These mice were still susceptible to CIA. The response was mainly directed to the glycosylated form of the CII 256-270 peptide, rather than to the nonglycosylated peptide. Tolerance induction was rapid; transferred T cells encountered CII within a few days. CII immunization several weeks after thymectomy of the mice did not change their susceptibility to arthritis or the induction of partial T-cell tolerance, excluding a role for recent thymic emigrants. Thus, partially tolerant CII autoreactive T cells are maintained and are crucial for the development of CIA.
Introduction:
A discussion is ongoing regarding the possible role of cartilage-directed autoimmunity as a part of the pathogenesis of rheumatoid arthritis (RA). One possibility is that the association of RA with shared epitope-expressing DR molecules reflects a role for major histocompatibility complex (MHC) class II molecules as peptide receptors, and that the predilection of the inflammatory attack for the joint indicates a role for cartilage as a source of the antigenic peptides. A direct role for CII in the development of arthritis is apparent in the CIA model, in which a definite role for MHC class II molecules and a role for CII-derived peptides have been demonstrated [1,2,3]. Remarkably, it was found that the identified MHC class II molecule in the CIA model Aq has a structurally similar peptide binding pocket to that of the shared epitope, expressing DR4 molecules [4]. In fact, DR4 (DRB1*0401) and DR1 (DRB1*0101) transgenic mice are susceptible to CIA because of an immune response to a peptide that is almost identical to that which is involved in Aq-expressing mice [5,6]. They are both derived from position 260-273 of the CII molecule; the peptide binds to the Aqmolecule with isoleucine 260 in the P1 pocket, but with phenylalanine 263 in the P1 pocket of the DR4 and DR1 molecules.
Although these findings do not prove a role for CII in RA, they show that such recognition is possible and that there are structural similarities when comparing mouse with human. However, there are also strong arguments against such a possibility. First, arthritis can evolve without evidence for a cartilage-specific autoimmunity, as seen with various adjuvant-induced arthritis models [7,8] and in several observations using transgenic animals with aberrant immunity to ubiquitously expressed proteins [9,10,11]. Moreover, the MHC association in the adjuvant arthritis models correlates with severity of the disease rather than susceptibility [7,8], as has also been observed in RA [12]. Second, it has not been possible to identify the CII-reactive T cells from RA joints, or to achieve a strong and significant CII proliferative response from T cells derived from RA joints. Most recently these negative observations were corroborated using DR4+CII peptide tetramer reagents [13]. On the other hand, it has also been difficult to isolate autoreactive CII-specific T cells from CIA, and it can be anticipated that, even in the CIA model, T cells that are specific for CII will be hard to find in the joints [4].
We believe that the explanations for these observations in both experimental animals and humans are related to tolerance. The CIA model in the mouse is usually induced with heterologous CII, and is critically dependent on an immune response to the glycosylated CII peptide 256-270, which is bound to the MHC class II Aq molecule. In CII transgenic mice, expressing the heterologous (rat) form of the immunodominant CII 256-270 epitope in cartilage, we observed partial T-cell tolerance. This tolerance is characterized by a low proliferative activity, but with maintained effector functions such as production of IFN-γ and the ability to give help to B cells to produce anti-CII IgG antibodies [14]. Interestingly, these mice were susceptible to arthritis. However, a possibility was that T cells that had newly emerged from the thymus and that were not yet tolerized when the mice were immunized with CII led to the induction of arthritis. We have now addressed this possibility and found that induction of tolerance occurs within a few days, and that mice lacking recent thymic emigrants (ie thymectomized mice) display partially tolerant T cells and susceptibility to arthritis to the same extent as nonthymectomized mice. In addition we found that T cells that are reactive with the nonmodified peptides are relatively more affected by tolerance than T cells that are reactive with the more immunodominant glycosylated variants.
Objectives:
To investigate the possibility that T cells that are naturally tolerant to the cartilage protein CII are involved in the development of arthritis, and to exclude a role for nontolerized recent thymic T-cell emigrants in the development of arthritis.
Materials and methods:
A mutated mouse CII, expressing glutamic acid instead of aspartic acid at position 266, was expressed in a transgenic mouse called MMC (mutated mouse collagen) that has been described earlier [14]. The mice were thymectomized, or sham-operated, at 7 weeks of age and allowed to recover for 4 weeks before being immunized with rat CII in complete Freund's adjuvant. Arthritis development was recorded and sera analyzed for anti-CII IgG, IgG1 and IgG2a levels. To assay T-cell effector functions, other MMC and control mice were immunized in the hind footpads with rat CII in complete Freund's adjuvant, and the draining popliteal lymph nodes were taken 10 days later. The lymph node cells (LNCs) were used for proliferation assay, IFN-γ enzyme-linked immunosorbent assay (ELISA) and B-cell enzyme-linked immunospot (ELISPOT). For the proliferation assay, 106 cells were put in triplicate cultures in microtitre wells together with antigen and incubated for 72h before thymidine-labelling and harvesting 15-18h later. For IFN-γ ELISA analysis, supernatant from the proliferation plates was removed before harvesting and used in an ELISA to quantify the amount of IFN-γ produced [15]. B-cell ELISPOT was performed to enumerate the number of cells producing anti-CII IgG [16].
T-cell lines that were reactive towards rat CII were established by immunization with rat CII. An established T-cell line that was reactive with CII and specific for the CII 256-270 peptide was restimulated with freshly collected, irradiated, syngenic spleen cells and rat CII for 3 days followed by 2 weeks of IL-2 containing medium. Immediately before transfer, the cells were labelled with the cytoplasmic dye 5 (and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) [17]. Labelled cells (107) were injected intravenously into transgenic MMC mice and nontransgenic littermates. The mice were killed 4 days after cell transfer, and the concentration of CFSE-labelled cells was determined by flow cytometry.
Results and discussion:
To investigate whether and how quickly CII-reactive T cells will encounter CII in vivo, an established T-cell line that is reactive towards rat CII was labelled with the cytoplasmic dye CFSE and transferred into MMC-QD and control mice. Four days later the mice were killed, and it was found that MMC-transgenic mice had dramatically fewer CFSE-labelled cells in the spleen than did nontransgenic littermates (0.11% compared with 0.57%). Similarly, reduced numbers of CFSE-positive cells were observed in blood. This indicates that the T cells encountered the mutated CII that was present in the cartilage of MMC mice, but not in the nontransgenic littermates. Presumably, CII from cartilage is spread by antigen-presenting cells (APCs) to peripheral lymphoid organs. This observation also suggests that newly exported T cells from the thymus will be tolerized to CII in the periphery within less than 4 days.
To further investigate whether the MMC mice harbours naïve or tolerized T cells, the mice were immunized with CII at different time points after thymectomy that were well in excess of the times required for their encounter with CII. After 10 days, the response was analyzed in vitro towards both the nonglycosylated and the glycosylated CII 256-270 peptides as well as towards purified protein derivative. The galactosylated form of the peptide (Fig. 1) was used because this is the most immunodominant modification [18]. In contrast to control mice, LNCs from transgenic mice did not proliferate significantly towards the nonglycosylated peptide, indicating that these cells have been specifically tolerized, which is in accordance with earlier observations [14]. A reduced, but still significant proliferation was also observed toward the immunodominant glycosylated CII peptide. Most important, however, was that the proliferative response in the MMC mice did not decrease after thymectomy. Similarly, a significant IFN-γ production towards the glycosylated CII peptide was observed in the MMC mice. The response was somewhat reduced compared with that observed in nontransgenic littermates, and this was especially true for the response toward the nonglycosylated peptide. Again, no decrease in the MMC response by thymectomy was observed. Taken together, the T-cell response in transgenic mice was reduced in comparison with that in the nontransgenic littermates. Furthermore, the response in transgenic animals did not decrease by thymectomy (4 or 8 weeks before immunization), showing that autoreactive T cells are still maintained (and partially tolerized) with significant effector functions at least up to 8 weeks after thymectomy, excluding a exclusive role for recent thymic emigrants in the autoimmune response towards CII. To investigate whether thymectomized mice, lacking recent CII-specific thymic emigrants, were susceptible to CIA, mice were immunized with CII 4 weeks after thymectomy and were observed for arthritis development during the following 10 weeks. Clearly, the thymectomized MMC mice were susceptible to arthritis (five out of 18 developed arthritis; Fig. 2), and no significant differences in susceptibility between thymectomized and sham-operated mice, or between males and females, were seen. In accordance with earlier results [14], MMC transgenic mice had a significantly reduced susceptibility to arthritis as compared with the nontransgenic littermates (P < 0.0001 for arthritic scores, disease onset and incidence). All mice were bled at 35 days after immunization, and the total levels of anti-CII IgG were determined. Transgenic mice developed levels of anti-CII IgG significantly above background, but the antibody titres were lower than in nontransgenic littermates (P < 0.0001). No effect on the antibody levels by thymectomy was observed, nor did thethymectomy affect the distribution of IgG1 versus IgG2a titres,indicating that the observed tolerance is not associated with a shift from a T-helper-1- to a T-helper-2-like immune response. These findings show that T cells that are specific for a tissue-specific matrix protein, CII, are partially tolerized within a few days after thymus export and that these tolerized cells are maintained after thymectomy. Most important, mice that lack newly exported CII reactive T cells are still susceptible to CIA, suggesting that the partially tolerant T cells are involved in development of arthritis.
In the light of these data it is possible to explain some of the findings in RA. T-cell reactivity to CII has been shown in RA patients, but with a very weak proliferative activity [19,20]. This is fully compatible with observations in mouse and rat CIA when autologous CII, and not heterologous CII, are used for immunization. This is particularly true if the responses are recorded during the chronic phase of disease, in which the antigen-specific T-cell responses seem to be suppressed in both humans and experimental animals. These observations were confirmed in a recent report [21] in which it was shown that CII-reactive T-cell activity could be detected in RA patients if IFN-γ production but not proliferation was measured. In the present studies in mice the strongest response is seen towards post-translational modifications of the peptide. Because the T-cell contact points are the same whether the peptide is bound to DR4 or to Aq, it is fully possible that post-translational modifications of the peptide also plays a significant role in humans [22]. The fact that IgG antibodies specific for CII are found in many RA patients could be explained by maintained B-cell helper functions of CII-reactive T cells. In fact, it has been reported [23,24] that the occurrence of IgG antibodies to CII is associated with shared epitope DR4 molecules. These observations are thus compatible with a role for CII reactivity in RA. To avoid any confusion, it needs to be stressed that RA is a heterogeneous syndrome in which not only CII, but also other cartilage proteins and other mechanisms are of importance. Such a pathogenic heterogeneity is reflected by the multitude of experimental animal models that have demonstrated how many different pathways may lead to arthritis [25].
PMCID: PMC17814  PMID: 11056672
autoimmunity; rheumatoid arthritis; T lymphocytes; tolerance; transgenic
5.  T cell responses to a non‐glycosylated epitope predominate in type II collagen‐immunised HLA‐DRB1*0101 transgenic mice 
Annals of the Rheumatic Diseases  2006;66(5):599-604.
Aim
To study collagen‐induced arthritis in human leucocyte antigen (HLA)‐DR1 transgenic mice lacking endogenous major histocompatibility complex class II molecules (MHC‐II) and to determine T cell specificity against the arthritogenic CII259–273 epitope of type II collagen either unmodified or post‐translationally glycosylated at Lys264.
Methods
Arthritis was induced by immunisation with human type II collagen in complete Freund's adjuvant and measured by footpad swelling, clinical score and histology. T cell responses were assessed by proliferation of spleen and lymph node cells and in antigen presentation assays, using T cell hybridomas specific for the glycosylated and non‐glycosylated CII259–273 epitope.
Results
The incidence of arthritis was 50% in DR1‐transgenic mice lacking endogenous MHC‐II molecules. Recall T cell responses in draining lymph nodes and spleen were consistently greater against the non‐glycosylated epitope than to the glycosylated CII259–273. Most of the T cell hybridomas generated from CII‐immunised mice recognised the non‐glycosylated CII epitope and this form of the epitope was also presented with 100‐fold higher efficiency and 1 h faster kinetics by both macrophages and dendritic cells.
Conclusion
This study shows that T cell responses to the non‐glycosylated epitope of heterologous (human) CII are dominant in HLA‐DR1 transgenic mice lacking MHC‐II, which could contribute to the pathogenicity of autoimmune arthritis.
doi:10.1136/ard.2006.061945
PMCID: PMC1954639  PMID: 17114189
6.  Design of Glycopeptides Used to Investigate Class II MHC Binding and T-Cell Responses Associated with Autoimmune Arthritis 
PLoS ONE  2011;6(3):e17881.
The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.
doi:10.1371/journal.pone.0017881
PMCID: PMC3058040  PMID: 21423632
7.  Characterization of the T cell receptor repertoire causing collagen arthritis in mice 
Collagen type II-induced arthritis (CIA) is generated in susceptible rodent strains by intradermal injections of homologous or heterologous native type II collagen in complete Freund's adjuvant. Symptoms of CIA are analogous to those of the human autoimmune disease, rheumatoid arthritis. CIA is a model system for T cell-mediated autoimmune disease. To study the T cell receptor (TCR) repertoire of bovine type II-specific T cells that may be involved in the pathogenesis of CIA in DBA/1Lac.J (H-2q) mice, 13 clonally distinct T cell hybridomas specific for bovine type II collagen have been established and the alpha and beta chains of their TCRs have been analyzed. These T cell hybridomas recognize epitopes that are shared by type II collagens from distinct species and not by type I collagens, and exhibit a highly restricted TCR-alpha/beta repertoire. The alpha chains of the TCRs employ three V alpha gene subfamilies (V alpha 11, V alpha 8, and V alpha 22) and four J alpha gene segments (J alpha 42, J alpha 24, J alpha 37, and J alpha 32). The V alpha 22 is a newly identified subfamily consisting of approximately four to six members, and exhibits a high degree of polymorphism among four mouse strains of distinct V alpha haplotypes. In addition, the beta chains of the TCRs employ three V beta gene subfamilies (V beta 8, V beta 1, and V beta 6), however the V beta 8.2 gene segment is preferentially utilized (58.3%). In contrast, the J beta gene segment usage is more heterogeneous. On the basis of the highly limited TCR-alpha/beta repertoire of the TCRs of the panel of bovine type II-specific T cell hybrid clones, a significant reduction (60%) of the incidence of arthritis in DBA/1Lac.J mice is accomplished by the use of anti-V beta 8.2 antibody therapy.
PMCID: PMC2190910  PMID: 8381155
8.  MHC Class II Derived Recombinant T Cell Receptor Ligands Protect DBA/1LacJ Mice from Collagen-Induced Arthritis1 
We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the α1 and β1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-Aq-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257–270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-Aq-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-Aq/bCII257–270 molecule could systemically reduce proinflammatory IL-17 and IFN-γ production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257–270 molecule could also selectively inhibit IL-1β, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.
PMCID: PMC3457790  PMID: 18178865
9.  IFNγ deficient C57BL/6 (H-2b) mice develop collagen induced arthritis with predominant usage of T cell receptor Vß6 and Vß8 in arthritic joints 
Annals of the Rheumatic Diseases  2003;62(10):983-990.
Background: Transgenic deficiency in interferon γ (IFNγ) or IFNγ receptor makes resistant strains of mice bearing H-2b or H-2d susceptible to collagen induced arthritis (CIA).
Objective: To determine whether the escape from regulation of disease susceptibility at the major histocompatibility complex level involves a new use of autoimmune T cells expressing T cell receptor (TCR) Vß that vary from the cell populations previously identified within arthritic joints.
Methods: Arthritis was induced by a standard protocol with type II bovine collagen (CII) in complete Freund's adjuvant. Clinical features, histopathology, immunological responses, and TCR profile in arthritic joints in IFNγ knockout C57BL/6 (B6.IFNγ KO) mice (H-2b) were compared directly with those in DBA/1 mice (H-2q).
Results: 60–80% of B6.IFNγ KO mice developed a progressive arthritis with a similar clinical course to classical CIA in DBA/1 mice. The affected joints in B6.IFNγ KO mice had an erosive form of arthritis with similar features to joint disease in DBA/1 mice. B6.IFNγ KO mice produced significantly higher levels of IgG2b and IgG1 autoantibodies to murine CII and showed increased proliferative response to CII compared with B6 mice. Comparable levels of interleukin 1ß and tumour necrosis factor α expression were detected in arthritic joints from ß6.IFNγ KO and DBA/1 mice. B6.IFNγKO mice used predominantly TCR Vß6 and Vß8 in arthritic joints. This TCR Vß profile is similar to that found in DBA/1 mice with CIA.
Conclusions: C57BL/6 mice deficient in IFNγ production can develop arthritis that resembles classical CIA. These data suggest that IFNγ is a key factor mediating susceptibility to CIA.
doi:10.1136/ard.62.10.983
PMCID: PMC1754310  PMID: 12972478
10.  Visualization and phenotyping of proinflammatory antigen-specific T cells during collagen-induced arthritis in a mouse with a fixed collagen type II-specific transgenic T-cell receptor β-chain 
Arthritis Research & Therapy  2010;12(4):R155.
Introduction
The Vβ12-transgenic mouse was previously generated to investigate the role of antigen-specific T cells in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. This mouse expresses a transgenic collagen type II (CII)-specific T-cell receptor (TCR) β-chain and consequently displays an increased immunity to CII and increased susceptibility to CIA. However, while the transgenic Vβ12 chain recombines with endogenous α-chains, the frequency and distribution of CII-specific T cells in the Vβ12-transgenic mouse has not been determined. The aim of the present report was to establish a system enabling identification of CII-specific T cells in the Vβ12-transgenic mouse in order to determine to what extent the transgenic expression of the CII-specific β-chain would skew the response towards the immunodominant galactosylated T-cell epitope and to use this system to monitor these cells throughout development of CIA.
Methods
We have generated and thoroughly characterized a clonotypic antibody, which recognizes a TCR specific for the galactosylated CII(260-270) peptide in the Vβ12-transgenic mouse. Hereby, CII-specific T cells could be quantified and followed throughout development of CIA, and their phenotype was determined by combinatorial analysis with the early activation marker CD154 (CD40L) and production of cytokines.
Results
The Vβ12-transgenic mouse expresses several related but distinct T-cell clones specific for the galactosylated CII peptide. The clonotypic antibody could specifically recognize the majority (80%) of these. Clonotypic T cells occurred at low levels in the naïve mouse, but rapidly expanded to around 4% of the CD4+ T cells, whereupon the frequency declined with developing disease. Analysis of the cytokine profile revealed an early Th1-biased response in the draining lymph nodes that would shift to also include Th17 around the onset of arthritis. Data showed that Th1 and Th17 constitute a minority among the CII-specific population, however, indicating that additional subpopulations of antigen-specific T cells regulate the development of CIA.
Conclusions
The established system enables the detection and detailed phenotyping of T cells specific for the galactosylated CII peptide and constitutes a powerful tool for analysis of the importance of these cells and their effector functions throughout the different phases of arthritis.
doi:10.1186/ar3108
PMCID: PMC2945055  PMID: 20682070
11.  Inhibition of macropinocytosis blocks antigen presentation of type II collagen in vitro and in vivo in HLA-DR1 transgenic mice 
Professional antigen-presenting cells, such as dendritic cells, macrophages and B cells have been implicated in the pathogenesis of rheumatoid arthritis, constituting a possible target for antigen-specific immunotherapy. We addressed the possibility of blocking antigen presentation of the type II collagen (CII)-derived immunodominant arthritogenic epitope CII259–273 to specific CD4 T cells by inhibition of antigen uptake in HLA-DR1-transgenic mice in vitro and in vivo. Electron microscopy, confocal microscopy, subcellular fractionation and antigen presentation assays were used to establish the mechanisms of uptake, intracellular localization and antigen presentation of CII by dendritic cells and macrophages. We show that CII accumulated in membrane fractions of intermediate density corresponding to late endosomes. Treatment of dendritic cells and macrophages with cytochalasin D or amiloride prevented the intracellular appearance of CII and blocked antigen presentation of CII259–273 to HLA-DR1-restricted T cell hybridomas. The data suggest that CII was taken up by dendritic cells and macrophages predominantly via macropinocytosis. Administration of amiloride in vivo prevented activation of CII-specific polyclonal T cells in the draining popliteal lymph nodes. This study suggests that selective targeting of CII internalization in professional antigen-presenting cells prevents activation of autoimmune T cells, constituting a novel therapeutic strategy for the immunotherapy of rheumatoid arthritis.
doi:10.1186/ar1964
PMCID: PMC1779380  PMID: 16704744
12.  Expression of a transgenic T cell receptor beta chain enhances collagen- induced arthritis 
SWR/J transgenic (tg) mice were generated expressing the TCR beta chain derived from an anticollagen type II (CII) arthritogenic T cell clone. The SWR/J strain was selected because it is resistant to collagen- induced arthritis (CIA) and lacks the V beta gene segment used by the T cell clone. Expression of the tg beta chain on all thymocytes and peripheral lymph node T cells led to a more efficient anti-CII immune response, but did not confer CIA susceptibility to SWR/J mice. Nevertheless, this tg beta chain enhanced predisposition to CIA as (DBA/1 x SWR) F1 beta tg mice were more susceptible than normal F1 littermates. Our results demonstrate that the expression of the tg beta chain contributes to CIA susceptibility, but by itself it is not sufficient to overcome CIA resistance in the SWR/J strain.
PMCID: PMC2119315  PMID: 1386871
13.  Deletion of Fcγ Receptor IIB Renders H-2b Mice Susceptible to Collagen-induced Arthritis  
Autoimmune diseases, like rheumatoid arthritis, result from a dysregulation of the immune response culminating in hyperactivation of effector cells leading to immune-mediated injury. To maintain an appropriate immune response and prevent the emergence of autoimmune disease, activation signals must be regulated by inhibitory pathways. Biochemical and genetic studies indicate that the type IIB low-affinity receptor for immunoglobulin (Ig)G (FcγRIIB) inhibits cellular activation triggered through antibody or immune complexes and may be an important component in preventing the emergence of autoimmunity. To investigate the role of FcγRIIB in the development of type II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans, we have examined its contribution in determining the susceptibility to CIA in the nonpermissive H-2b haplotype. H-2b mice immunized with bovine CII do not develop appreciable disease. In contrast, immunization of the FcγRIIB-deficient, H-2b mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the FcγRIIB-deficient mice developing CIA (6.9 ± 3.6) was comparable to that of DBA/1 mice (8.6 ± 1.9), an H-2q strain susceptible for CIA induction. IgG1, IgG2a, and IgG2b antibody responses against CII were elevated in the FcγRIIB-deficient animals, especially in those mice showing arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthritic paws from FcγRIIB-deficient mice revealed that cartilage was destroyed and bone was focally eroded in association with marked lymphocyte and monocyte/macrophage infiltration, very similar to the pathologic findings observed in DBA/1 mice. These results indicate that a nonpermissive H-2b haplotype can be rendered permissive to CIA induction through deletion of FcγRIIB, suggesting that FcγRIIB plays a critical role in suppressing the induction of CIA.
PMCID: PMC1887699  PMID: 9874575
collagen-induced arthritis; autoimmunity; Fc receptor; gene targeting; macrophage
14.  Induction of IL-10-producing CD4+CD25+ T cells in animal model of collagen-induced arthritis by oral administration of type II collagen 
Arthritis Research & Therapy  2004;6(3):R213-R219.
Induction of oral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases, including rheumatoid arthritis (RA). Oral administration of type II collagen (CII) has been proven to improve signs and symptoms in RA patients without troublesome toxicity. To investigate the mechanism of immune suppression mediated by orally administered antigen, we examined changes in serum IgG subtypes and T-cell proliferative responses to CII, and generation of IL-10-producing CD4+CD25+ T-cell subsets in an animal model of collagen-induced arthritis (CIA). We found that joint inflammation in CIA mice peaked at 5 weeks after primary immunization with CII, which was significantly less in mice tolerized by repeated oral feeding of CII before CIA induction. Mice that had been fed with CII also exhibited increased serum IgG1 and decreased serum IgG2a as compared with nontolerized CIA animals. The T-cell proliferative response to CII was suppressed in lymph nodes of tolerized mice also. Production of IL-10 and of transforming growth factor-β from mononuclear lymphocytes was increased in the tolerized animals, and CD4+ T cells isolated from tolerized mice did not respond with induction of IFN-γ when stimulated in vitro with CII. We also observed greater induction of IL-10-producing CD4+CD25+ subsets among CII-stimulated splenic T cells from tolerized mice. These data suggest that when these IL-10-producing CD4+CD25+ T cells encounter CII antigen in affected joints they become activated to exert an anti-inflammatory effect.
doi:10.1186/ar1169
PMCID: PMC416445  PMID: 15142267
collagen-induced arthritis; IL-10; oral tolerance; type II collagen
15.  Obesity aggravates the joint inflammation in a collagen-induced arthritis model through deviation to Th17 differentiation 
Experimental & Molecular Medicine  2012;44(7):424-431.
White fat cells secrete adipokines that induce inflammation and obesity has been reported to be characterized by high serum levels of inflammatory cytokines such as IL-6 and TNF-α. Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis, but the relationship between RA and obesity is controversial. We made an obese inflammatory arthritis model: obese collagen-induced arthritis (CIA). C57BL/6 mice were fed a 60-kcal high fat diet (HFD) from the age of 4 weeks and they were immunized twice with type II collagen (CII). After immunization, the obese CIA mice showed higher arthritis index scores and histology scores and a more increased incidence of developing arthritis than did the lean CIA mice. After treatment with CII, mixed lymphocyte reaction also showed CII-specific response more intensely in the obese CIA mice than lean CIA. The anti-CII IgG and anti-CII IgG2a levels in the sera of the obese CIA mice were higher than those of the lean CIA mice. The number of Th17 cells was higher and the IL-17 mRNA expression of the splenocytes in the obese CIA mice was higher than that of the lean CIA mice. Obese CIA mice also showed high IL-17 expression on synovium in immunohistochemistry. Although obesity may not play a pathogenic role in initiating arthritis, it could play an important role in amplifying the inflammation of arthritis through the Th1/Th17 response. The obese CIA murine model will be an important tool when we investigate the effect of several therapeutic target molecules to treat RA.
doi:10.3858/emm.2012.44.7.047
PMCID: PMC3406287  PMID: 22513335
arthritis, experimental; inflammation; mice; obesity; Th17 cells
16.  An HLA-DR1 Transgene Confers Susceptibility to Collagen-induced Arthritis Elicited with Human Type II Collagen 
The Journal of Experimental Medicine  1997;185(6):1113-1122.
Rheumatoid arthritis (RA) is an autoimmune disease that is strongly associated with the expression of several HLA-DR haplotypes, including DR1 (DRB1*0101). Although the antigen that initiates RA remains elusive, it has been shown that many patients have autoimmunity directed to type II collagen (CII). To test the hypothesis that HLA-DR1 is capable of mediating an immune response to CII, we have generated transgenic mice expressing chimeric (human/ mouse) HLA-DR1. When the DR1 transgenic mice were immunized with human CII (hCII), they developed a severe autoimmune arthritis, evidenced by severe swelling and erythema of the limbs and marked inflammation and erosion of articular joints. The development of the autoimmune arthritis was accompanied by strong DR1-restricted T and B cell responses to hCII. The T cell response was focused on a dominant determinant contained within CII(259–273) from which an eight amino acid core was defined. The B cell response was characterized by high titers of antibody specific for hCII, and a high degree of cross-reactivity with murine type II collagen. These data demonstrate that HLA-DR1 is capable of presenting peptides derived from hCII, and suggest that this DR1 transgenic model will be useful in the development of DR1-specific therapies for RA.
PMCID: PMC2196244  PMID: 9091584
17.  Staphylococcal enterotoxin B increases the severity of type II collagen induced arthritis in mice. 
Annals of the Rheumatic Diseases  1995;54(4):298-304.
OBJECTIVE--To observe the influence of T cell subset changes on the development of experimental arthritis, by using the bacterial superantigen staphylococcal enterotoxin B (SEB) to modulate the T cell repertoire during the arthritogenic response to type II collagen (CII) in vivo. METHODS--DBA/1 mice were injected with SEB before immunisation with CII, and assessed for the development of collagen induced arthritis (CIA) and an immune response to CII. Mice with established arthritis were also treated therapeutically with SEB. Flow cytometry was used to evaluate the effect of the therapy on T cell subsets and T cell receptor (TCR) V beta expression. RESULTS--Mice injected with SEB developed arthritis significantly faster than saline treated control animals, and developed more severe clinical features. Mice treated with SEB after the onset of CIA were also observed to progress more rapidly to a severe arthritis than mice treated with saline alone. The level of anti-CII antibody was not affected by SEB injection. Flow cytometric analysis of TCR expression in mice 21 days after injection of CII showed decreased expression of V beta 6 and V beta 8 cells in SEB treated mice, compared with collagen immunised control mice. Injection of SEB alone caused a decrease in V beta 8, but not V beta 6 T cells compared with the values in normal DBA/1 mice. No significant variations in the T cell repertoire were detected 70 days after CII immunisation. CONCLUSIONS--Treatment with the bacterial enterotoxin SEB before the induction of arthritis did not suppress the immunological or arthritogenic response to CII in DBA/1 mice, despite the modulation of the V beta 8 T cell subset. Treatment of mice with established arthritis using SEB provoked a more severe disease course.
PMCID: PMC1005577  PMID: 7763108
18.  Modulation of collagen-induced arthritis by adenovirus-mediated intra-articular expression of modified collagen type II 
Arthritis Research & Therapy  2010;12(4):R136.
Introduction
Rheumatoid arthritis (RA) is a systemic disease manifested by chronic inflammation in multiple articular joints, including the knees and small joints of the hands and feet. We have developed a unique modification to a clinically accepted method for delivering therapies directly to the synovium. Our therapy is based on our previous discovery of an analog peptide (A9) with amino acid substitutions made at positions 260 (I to A), 261 (A to B), and 263 (F to N) that could profoundly suppress immunity to type II collagen (CII) and arthritis in the collagen-induced arthritis model (CIA).
Methods
We engineered an adenoviral vector to contain the CB11 portion of recombinant type II collagen and used PCR to introduce point mutations at three sites within (CII124-402, 260A, 261B, 263D), (rCB11-A9) so that the resulting molecule contained the A9 sequence at the exact site of the wild-type sequence.
Results
We used this construct to target intra-articular tissues of mice and utilized the collagen-induced arthritis model to show that this treatment strategy provided a sustained, local therapy for individual arthritic joints, effective whether given to prevent arthritis or as a treatment. We also developed a novel system for in vivo bioimaging, using the firefly luciferase reporter gene to allow serial bioluminescence imaging to show that luciferase can be detected as late as 18 days post injection into the joint.
Conclusions
Our therapy is unique in that we target synovial cells to ultimately shut down T cell-mediated inflammation. Its effectiveness is based on its ability to transform potential inflammatory T cells and/or bystander T cells into therapeutic (regulatory-like) T cells which secrete interleukin (IL)-4. We believe this approach has potential to effectively suppress RA with minimal side effects.
doi:10.1186/ar3074
PMCID: PMC2945026  PMID: 20615221
19.  Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-γ 
Arthritis Research & Therapy  2005;7(2):R402-R415.
Mice with a deficiency in IFN-γ or IFN-γ receptor (IFN-γR) are more susceptible to collagen-induced arthritis (CIA), an experimental autoimmune disease that relies on the use of complete Freund's adjuvant (CFA). Here we report that the heightened susceptibility of IFN-γR knock-out (KO) mice is associated with a functional impairment of CD4+CD25+ Treg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II (CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role of Treg cells in the effector phase of CIA. IFN-γR deficiency did not affect the number of CD4+CD25+ T cells in the central and peripheral lymphoid tissues. In addition, CD4+CD25+ T cells isolated from naive IFN-γR KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4+CD25+ T cells became significantly more impaired in IFN-γR-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly specific marker for Treg cells, was lower. We further demonstrated that the effect of endogenous IFN-γ, which accounts for more suppressive activity in wild-type mice, concerns both Treg cells and accessory cells. Our results demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-γ.
doi:10.1186/ar1500
PMCID: PMC1065335  PMID: 15743488
arthritis; autoimmunity; interferon-γ; regulatory T cells
20.  Antigen-specific T cell–mediated gene therapy in collagen-induced arthritis 
Journal of Clinical Investigation  2001;107(10):1293-1301.
Autoantigen-specific T cells have tissue-specific homing properties, suggesting that these cells may be ideal vehicles for the local delivery of immunoregulatory molecules. We tested this hypothesis by using type II collagen–specific (CII-specific) CD4+ T hybridomas or primary CD4+ T cells after gene transfer, as vehicles to deliver an immunoregulatory protein for the treatment of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). CII-specific T cells or hybridomas were transduced using retroviral vectors to constitutively express the IL-12 antagonist, IL-12 p40. Transfer of engineered CD4+ T cells after immunization significantly inhibited the development of CIA, while cells transduced with vector control had no effect. The beneficial effect on CIA of IL-12 p40-transduced T cells required TCR specificity against CII, since transfer of T cells specific for another antigen producing equivalent amounts of IL-12 p40 had no effect. In vivo cell detection using bioluminescent labels and RT-PCR showed that transferred CII-reactive T-cell hybridomas accumulated in inflamed joints in mice with CIA. These results indicate that the local delivery of IL-12 p40 by T cells inhibited CIA by suppressing autoimmune responses at the site of inflammation. Modifying antigen-specific T cells by retroviral transduction for local expression of immunoregulatory proteins thus offers a promising strategy for treating RA.
PMCID: PMC209299  PMID: 11375419
21.  Multifunctional T cell reactivity to native and glycosylated type-II collagen in rheumatoid arthritis 
Arthritis and rheumatism  2012;64(8):2482-2488.
Objective
Type II collagen (CII) is a cartilage-specific protein to which a loss of immune tolerance may trigger autoimmune reactions and cause arthritis. The major T cell epitope on CII, aa259-273, can be presented by several HLA-DRB1*04 alleles in its native or posttranslational-glycosylated form. Here, we aimed to functionally explore and compare CII-autoreactive T cells from blood and synovial fluid of patients with rheumatoid arthritis (RA).
Methods
Peripheral blood were obtained from HLA-DRB1*04 RA and control subjects (n=10 each), then stimulated in vitro with several variants of the CII259-273 epitope: (a) unmodified, or glycosylated on (b) lysine-264, (c) lysine-270, or (d) both lysine-264 and 270. Upregulation of CD154 was used to identify responding T cells. These cells were further characterized by intracellular staining for IL-17, IFNγ and IL-2 by flow cytometry. For RA patients, synovial T cells were investigated in parallel.
Results
Multifunctional T cell responses towards all examined variants of the CII259-273 peptide could be detected in RA patients and to a lesser extent also in healthy HLA-matched individuals (p<0.001). In RA, a comparison between blood and joint-derived T cell function revealed a significant increase of the proinflammatory cytokine IFNγ (p=0.027) in synovial T cells. Studies of longitudinal samples show that T cell responses were sustained over the course of disease, and even included epitope spreading.
Conclusions
The identification of inflammatory T cell responses to both glycosylated and non-glycosylated variants of the major CII epitope in RA patients suggests that CII autoreactivity may be more common than previously appreciated.
doi:10.1002/art.34459
PMCID: PMC3387353  PMID: 22392632
22.  Characterization of T cell phenotype and function in a double transgenic (collagen-specific TCR/HLA-DR1) humanized model of arthritis 
Introduction
T cells orchestrate joint inflammation in rheumatoid arthritis (RA), yet they are difficult to study due to the small numbers of antigen-specific cells. The goal of this study was to characterize a new humanized model of autoimmune arthritis and to describe the phenotypic and functional changes that occur in autoimmune T cells following the induction of pathological events.
Methods
We developed a double transgenic mouse containing both the HLA-DR1 transgene and an HLA-DR1-restricted collagen-specific TCR in order to obtain large numbers of antigen-specific T cells that can be used for immunologic studies.
Results
In vitro, CII-specific T cells from this mouse proliferated vigorously in response to the CII immunodominant peptide A2 and the cells altered their phenotype to become predominately CD62Llow and CD44high “activated” T cells. The response was accompanied by the production of Th1, Th2, and Th17-type cytokines. Following immunization with bovine CII/CFA, these mice develop an accelerated arthritis compared to single transgenic HLA-DR1 mice. On the other hand, when the mice were treated orally with the analog peptide A12, (a suppressive analog of collagen we have previously described), arthritis was significantly suppressed, despite the fact that >90% of the CD4+ T cells express the TCR Tg. In GALT tissues taken from the A12-treated mice, IL-2, IFN-γ, and IL-17 production to the autoimmune collagen determinant dropped while high levels of IL-10 and IL-4 were produced.
Conclusions
We have developed a humanized model of autoimmune arthritis that will be useful for the study of T cell directed therapies as well as T cell mediated mechanisms of autoimmune diseases.
doi:10.1186/ar4433
PMCID: PMC3978884  PMID: 24405551
23.  Effects of collagen-induced rheumatoid arthritis on amyloidosis and microvascular pathology in APP/PS1 mice 
BMC Neuroscience  2011;12:106.
Background
Evidence suggests that rheumatoid arthritis (RA) may enhance or reduce the progression of Alzheimer's disease (AD). The present study was performed to directly explore the effects of collagen-induced rheumatoid arthritis (CIA) on amyloid plaque formation, microglial activation, and microvascular pathology in the cortex and hippocampus of the double transgenic APP/PS1 mouse model for AD. Wild-type or APP/PS1 mice that received type II collagen (CII) in complete Freund's adjuvant (CFA) at 2 months of age revealed characteristics of RA, such as joint swelling, synovitis, and cartilage and bone degradation 4 months later. Joint pathology was accompanied by sustained induction of IL-1β and TNF-α in plasma over 4 weeks after administration of CII in CFA.
Results
CIA reduced levels of soluble and insoluble amyloid beta (Aβ) peptides and amyloid plaque formation in the cortex and hippocampus of APP/PS1 mice, which correlated with increased blood brain barrier disruption, Iba-1-positive microglia, and CD45-positive microglia/macrophages. In contrast, CIA reduced vessel density and length with features of microvascular pathology, including vascular segments, thinner vessels, and atrophic string vessels.
Conclusions
The present findings suggest that RA may exert beneficial effects against Aβ burden and harmful effects on microvascular pathology in AD.
doi:10.1186/1471-2202-12-106
PMCID: PMC3217907  PMID: 22029666
24.  Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen 
Arthritis Research & Therapy  2005;7(5):R1148-R1157.
Antibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/c×B10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/c×B10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.
doi:10.1186/ar1800
PMCID: PMC1257444  PMID: 16207332
25.  To B or not to B: Role of B cells in pathogenesis of arthritis in HLA transgenic mice 
Journal of autoimmunity  2011;37(2):95-103.
Population studies have shown that amongst all the genetic factors linked with autoimmune disease development, MHC class II genes are the most significant. Experimental autoimmune arthritis resembling human rheumatoid arthritis (RA) can be induced in susceptible strains of mice following immunization with type II collagen (CIA). We generated transgenic mice lacking endogenous class II molecules and expressing various HLA genes including RA-associated, HLA-DRB1*0401 and HLA-DQ8, and RA-resistant, DRB1*0402, genes. The HLA molecules in these mice are expressed on the cell surface and can positively select CD4+ T cells expressing various Vβ T cell receptors. Endogenous class II invariant chain is required for proper functioning of the class II transgene. Arthritis development in transgenic mice is CD4+ and B cells dependent. Studies in humanized mice showed that B cells are required as antigen presenting cells in addition to antibody producing cells for the development of CIA. The transgenic mice expressing *0401 and *0401/DQ8 genes developed sex-biased arthritis with predominantly females being affected, similar to that of human RA. Further, the transgenic mice produced autoantibodies like rheumatoid factor and anti-cyclic antibodies. Antigen presentation by B cells leads to a sex specific immune response in DRB1*0401 mice suggesting a role of B cells and HLA-DR in rendering susceptibility to develop arthritis in females.
doi:10.1016/j.jaut.2011.05.002
PMCID: PMC3173520  PMID: 21665435
MHC polymorphism; HLA transgenic mice; Rheumatoid arthritis; B cells; antigen presentation

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