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The role and clinical implications of G6PI in experimental models of rheumatoid arthritis.

Kamradt T, Schubert D - Arthritis Res. Ther. (2004)

Bottom Line: The antigens that trigger the pathogenic immune response in rheumatoid arthritis (RA) remain unknown.The autoreactive transgenic T cells recognize G6PI and provide help for the production of arthritogenic IgG antibodies against G6PI.Here we review the pathomechanisms that lead from systemic autoreactivity to arthritis in these models, consider the relevance of anti-G6PI immune reactivity for RA, and discuss the insights into the pathogenesis of RA and possibly other autoimmune conditions that can be gained from these models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut für Immunologie, Klinikum der Friedrich-Schiller Universität Jena, Jena, Germany. Immunologie@med.uni-jena.de

ABSTRACT
The antigens that trigger the pathogenic immune response in rheumatoid arthritis (RA) remain unknown. Until recently it was assumed that either viral or microbial antigens, or joint-specific antigens were the target of arthritogenic T and B lymphocytes in RA. Consequently, murine models of arthritis are induced by immunization with either joint-specific antigens such as type II collagen or microbial products such as streptococcal cell wall. In the K/BxN T-cell receptor transgenic mouse model arthritis is caused by a systemic autoimmune response to the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI). The autoreactive transgenic T cells recognize G6PI and provide help for the production of arthritogenic IgG antibodies against G6PI. More recently it was shown that G6PI immunization induces severe symmetrical peripheral polyarthritis in genetically unaltered DBA/I mice. In that model CD4+ T cells are necessary not only for the induction but also for the effector phase of arthritis. Here we review the pathomechanisms that lead from systemic autoreactivity to arthritis in these models, consider the relevance of anti-G6PI immune reactivity for RA, and discuss the insights into the pathogenesis of RA and possibly other autoimmune conditions that can be gained from these models.

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Arthritis scores of (■) DBA/1 wild-type, (●) DBA/1 FcγR common γ-chain deficient, and (▲) DBA/1 FcγRIIB deficient mice. Data are presented as mean clinical scores ± standard error of the mean only for those mice that developed arthritis. Arthritis incidence was 10/11 in DBA/1 wild-type, 8/24 in DBA/1 FcγR common γ-chain deficient, and 16/16 in DBA/1 FcγRIIB deficient mice. From [93], © 2004. The American Association of Immunologists, Inc. Reprinted with permission.
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Figure 2: Arthritis scores of (■) DBA/1 wild-type, (●) DBA/1 FcγR common γ-chain deficient, and (▲) DBA/1 FcγRIIB deficient mice. Data are presented as mean clinical scores ± standard error of the mean only for those mice that developed arthritis. Arthritis incidence was 10/11 in DBA/1 wild-type, 8/24 in DBA/1 FcγR common γ-chain deficient, and 16/16 in DBA/1 FcγRIIB deficient mice. From [93], © 2004. The American Association of Immunologists, Inc. Reprinted with permission.

Mentions: DBA/1 mice that lack the FcγR common γ chain and thus cannot signal through the activating FcγRI and FcγRIII are protected from G6PI-induced arthritis. In addition, mice that lack the inhibitory FcγRIIB develop severe and prolonged G6PI-induced arthritis (Fig. 2) [93]. Therefore, IgG antibodies and FcγR+effector cells are necessary for the development of G6PI-induced arthritis. Nevertheless, arthritis cannot be induced in naïve recipients by transfer of serum or antibodies from arthritic DBA/1 mice [93]. It is currently unclear why G6PI-induced arthritis cannot be transferred with serum from arthritic animals; it is possible that the antibodies present in the serum some 14 days after immunization lack the necessary affinity for G6PI. Thus, unlike the CIA and K/B×N models, both CD4+ T cells and antibodies are necessary for the development of G6PI-induced arthritis, and neither transfer of T cells nor transfer of antibodies alone can induce arthritis in recipient mice. TNF-α is indispensable for the development of G6PI-induced arthritis in normal mice; treatment of mice with the soluble p75 TNF receptor (etanercept) completely prevents the development of arthritis [93].


The role and clinical implications of G6PI in experimental models of rheumatoid arthritis.

Kamradt T, Schubert D - Arthritis Res. Ther. (2004)

Arthritis scores of (■) DBA/1 wild-type, (●) DBA/1 FcγR common γ-chain deficient, and (▲) DBA/1 FcγRIIB deficient mice. Data are presented as mean clinical scores ± standard error of the mean only for those mice that developed arthritis. Arthritis incidence was 10/11 in DBA/1 wild-type, 8/24 in DBA/1 FcγR common γ-chain deficient, and 16/16 in DBA/1 FcγRIIB deficient mice. From [93], © 2004. The American Association of Immunologists, Inc. Reprinted with permission.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064898&req=5

Figure 2: Arthritis scores of (■) DBA/1 wild-type, (●) DBA/1 FcγR common γ-chain deficient, and (▲) DBA/1 FcγRIIB deficient mice. Data are presented as mean clinical scores ± standard error of the mean only for those mice that developed arthritis. Arthritis incidence was 10/11 in DBA/1 wild-type, 8/24 in DBA/1 FcγR common γ-chain deficient, and 16/16 in DBA/1 FcγRIIB deficient mice. From [93], © 2004. The American Association of Immunologists, Inc. Reprinted with permission.
Mentions: DBA/1 mice that lack the FcγR common γ chain and thus cannot signal through the activating FcγRI and FcγRIII are protected from G6PI-induced arthritis. In addition, mice that lack the inhibitory FcγRIIB develop severe and prolonged G6PI-induced arthritis (Fig. 2) [93]. Therefore, IgG antibodies and FcγR+effector cells are necessary for the development of G6PI-induced arthritis. Nevertheless, arthritis cannot be induced in naïve recipients by transfer of serum or antibodies from arthritic DBA/1 mice [93]. It is currently unclear why G6PI-induced arthritis cannot be transferred with serum from arthritic animals; it is possible that the antibodies present in the serum some 14 days after immunization lack the necessary affinity for G6PI. Thus, unlike the CIA and K/B×N models, both CD4+ T cells and antibodies are necessary for the development of G6PI-induced arthritis, and neither transfer of T cells nor transfer of antibodies alone can induce arthritis in recipient mice. TNF-α is indispensable for the development of G6PI-induced arthritis in normal mice; treatment of mice with the soluble p75 TNF receptor (etanercept) completely prevents the development of arthritis [93].

Bottom Line: The antigens that trigger the pathogenic immune response in rheumatoid arthritis (RA) remain unknown.The autoreactive transgenic T cells recognize G6PI and provide help for the production of arthritogenic IgG antibodies against G6PI.Here we review the pathomechanisms that lead from systemic autoreactivity to arthritis in these models, consider the relevance of anti-G6PI immune reactivity for RA, and discuss the insights into the pathogenesis of RA and possibly other autoimmune conditions that can be gained from these models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut für Immunologie, Klinikum der Friedrich-Schiller Universität Jena, Jena, Germany. Immunologie@med.uni-jena.de

ABSTRACT
The antigens that trigger the pathogenic immune response in rheumatoid arthritis (RA) remain unknown. Until recently it was assumed that either viral or microbial antigens, or joint-specific antigens were the target of arthritogenic T and B lymphocytes in RA. Consequently, murine models of arthritis are induced by immunization with either joint-specific antigens such as type II collagen or microbial products such as streptococcal cell wall. In the K/BxN T-cell receptor transgenic mouse model arthritis is caused by a systemic autoimmune response to the ubiquitously expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI). The autoreactive transgenic T cells recognize G6PI and provide help for the production of arthritogenic IgG antibodies against G6PI. More recently it was shown that G6PI immunization induces severe symmetrical peripheral polyarthritis in genetically unaltered DBA/I mice. In that model CD4+ T cells are necessary not only for the induction but also for the effector phase of arthritis. Here we review the pathomechanisms that lead from systemic autoreactivity to arthritis in these models, consider the relevance of anti-G6PI immune reactivity for RA, and discuss the insights into the pathogenesis of RA and possibly other autoimmune conditions that can be gained from these models.

Show MeSH
Related in: MedlinePlus