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Temporal cytokine expression and the target organ attributes unravel novel aspects of autoimmune arthritis.

Astry B, Venkatesha SH, Moudgil KD - Indian J. Med. Res. (2013)

Bottom Line: Further, various inhibitors of angiogenesis are effective in suppressing arthritis.Taken together, the differential cytokine responses and unique attributes of the target organ have revealed novel aspects of disease susceptibility and joint damage in AA.The translation of this basic research in animal models to RA patients would not only advance our understanding of the disease process, but also offer novel avenues for immunomodulation of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.

ABSTRACT
Susceptibility to autoimmunity is determined by multiple factors. Defining the contribution of the quantitative versus qualitative aspects of antigen-directed immune responses as well as the factors influencing target organ susceptibility is vital to advancing the understanding of the pathogenesis of autoimmunity. In a series of studies, we have addressed these issues using the adjuvant-induced arthritis (AA) model of human rheumatoid arthritis (RA). Lewis rats are susceptible to AA following immunization with heat-killed Mycobacterium tuberculosis H37Ra, whereas Wistar-Kyoto (WKY) rats of the same MHC (major histocompatibility complex) haplotype are resistant. Comparative studies on these and other susceptible/resistant rodent strains have offered interesting insights into differential cytokine responses in the face of comparable T cell proliferative response to the disease relevant antigens. Study of the cytokine kinetics have also permitted validation of the disease-protective versus disease-aggravating effects of specific cytokines by treatment of rats/mice with those cytokines at different phases of the disease. In regard to the target organ attributes, the migration of arthritogenic leukocytes into the joints; the expression of mediators of inflammation, angiogenesis, and tissue damage; the role of vascular permeability; and the characteristics of vascular endothelial cells have been examined. Further, various inhibitors of angiogenesis are effective in suppressing arthritis. Taken together, the differential cytokine responses and unique attributes of the target organ have revealed novel aspects of disease susceptibility and joint damage in AA. The translation of this basic research in animal models to RA patients would not only advance our understanding of the disease process, but also offer novel avenues for immunomodulation of this disease.

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CD4+ T cell differentiation and cellular phenotype. Naïve CD4+ T cells can differentiate into several different types of T helper (Th) or regulatory T (Treg or Tr) cells depending on the cytokine environment in which these are activated. The regulating transcription factors of these subsets and their characteristic effector cytokines are shown. (CD, cluster of differentiation; GATA3, GATA binding protein 3; T-bet, T-box expressed in T cells; RORγt, retinoic acid receptor-related orphan receptor gamma; Foxp3, Forkhead box p3; IL, interleukin; IFN, interferon; TGF, transforming growth factor.
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Figure 1: CD4+ T cell differentiation and cellular phenotype. Naïve CD4+ T cells can differentiate into several different types of T helper (Th) or regulatory T (Treg or Tr) cells depending on the cytokine environment in which these are activated. The regulating transcription factors of these subsets and their characteristic effector cytokines are shown. (CD, cluster of differentiation; GATA3, GATA binding protein 3; T-bet, T-box expressed in T cells; RORγt, retinoic acid receptor-related orphan receptor gamma; Foxp3, Forkhead box p3; IL, interleukin; IFN, interferon; TGF, transforming growth factor.

Mentions: T helper cells: The majority of animal models of RA are T cell-mediated diseases29 similar to the human disease31. The CD4+ helper T cells play an important role in the initiation and progression of acute inflammation in situations involving immune response to self (autoimmunity) or foreign (e.g. infectious disease) antigens. The cytokines produced by these cells help to facilitate the activation and chemotactic migration of other cell types to the site of inflammation during the immune response. The most widely studied helper CD4+ T cell types are the T helper 1 (Th1), Th2, and Th17. The cytokines produced by dendritic cells (DC) during an immune response are among the important factors that dictate the differentiation of T helper progenitor cells into specific subsets32 (Fig. 1). For example, when activated DCs and macrophages produce interleukin (IL)-12, it activates the ‘signal transducer and activator of transcription’ (STAT) 4 pathway leading to the upregulation of the transcription factor ‘T-box expressed in T cells’ (T-bet). T-bet induces Th1 cell differentiation resulting in upregulation of interferon (IFN)γ and downregulation of ‘GATA binding protein 3’ (GATA3) and IL-43233. The Th1 cell produces IFNγ and promotes cellular immune response. In contrast, IL-4 signaling through STAT6 leads to a Th2 differentiation, upregulation of GATA3, and downregulation of IFNγ34.


Temporal cytokine expression and the target organ attributes unravel novel aspects of autoimmune arthritis.

Astry B, Venkatesha SH, Moudgil KD - Indian J. Med. Res. (2013)

CD4+ T cell differentiation and cellular phenotype. Naïve CD4+ T cells can differentiate into several different types of T helper (Th) or regulatory T (Treg or Tr) cells depending on the cytokine environment in which these are activated. The regulating transcription factors of these subsets and their characteristic effector cytokines are shown. (CD, cluster of differentiation; GATA3, GATA binding protein 3; T-bet, T-box expressed in T cells; RORγt, retinoic acid receptor-related orphan receptor gamma; Foxp3, Forkhead box p3; IL, interleukin; IFN, interferon; TGF, transforming growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928702&req=5

Figure 1: CD4+ T cell differentiation and cellular phenotype. Naïve CD4+ T cells can differentiate into several different types of T helper (Th) or regulatory T (Treg or Tr) cells depending on the cytokine environment in which these are activated. The regulating transcription factors of these subsets and their characteristic effector cytokines are shown. (CD, cluster of differentiation; GATA3, GATA binding protein 3; T-bet, T-box expressed in T cells; RORγt, retinoic acid receptor-related orphan receptor gamma; Foxp3, Forkhead box p3; IL, interleukin; IFN, interferon; TGF, transforming growth factor.
Mentions: T helper cells: The majority of animal models of RA are T cell-mediated diseases29 similar to the human disease31. The CD4+ helper T cells play an important role in the initiation and progression of acute inflammation in situations involving immune response to self (autoimmunity) or foreign (e.g. infectious disease) antigens. The cytokines produced by these cells help to facilitate the activation and chemotactic migration of other cell types to the site of inflammation during the immune response. The most widely studied helper CD4+ T cell types are the T helper 1 (Th1), Th2, and Th17. The cytokines produced by dendritic cells (DC) during an immune response are among the important factors that dictate the differentiation of T helper progenitor cells into specific subsets32 (Fig. 1). For example, when activated DCs and macrophages produce interleukin (IL)-12, it activates the ‘signal transducer and activator of transcription’ (STAT) 4 pathway leading to the upregulation of the transcription factor ‘T-box expressed in T cells’ (T-bet). T-bet induces Th1 cell differentiation resulting in upregulation of interferon (IFN)γ and downregulation of ‘GATA binding protein 3’ (GATA3) and IL-43233. The Th1 cell produces IFNγ and promotes cellular immune response. In contrast, IL-4 signaling through STAT6 leads to a Th2 differentiation, upregulation of GATA3, and downregulation of IFNγ34.

Bottom Line: Further, various inhibitors of angiogenesis are effective in suppressing arthritis.Taken together, the differential cytokine responses and unique attributes of the target organ have revealed novel aspects of disease susceptibility and joint damage in AA.The translation of this basic research in animal models to RA patients would not only advance our understanding of the disease process, but also offer novel avenues for immunomodulation of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.

ABSTRACT
Susceptibility to autoimmunity is determined by multiple factors. Defining the contribution of the quantitative versus qualitative aspects of antigen-directed immune responses as well as the factors influencing target organ susceptibility is vital to advancing the understanding of the pathogenesis of autoimmunity. In a series of studies, we have addressed these issues using the adjuvant-induced arthritis (AA) model of human rheumatoid arthritis (RA). Lewis rats are susceptible to AA following immunization with heat-killed Mycobacterium tuberculosis H37Ra, whereas Wistar-Kyoto (WKY) rats of the same MHC (major histocompatibility complex) haplotype are resistant. Comparative studies on these and other susceptible/resistant rodent strains have offered interesting insights into differential cytokine responses in the face of comparable T cell proliferative response to the disease relevant antigens. Study of the cytokine kinetics have also permitted validation of the disease-protective versus disease-aggravating effects of specific cytokines by treatment of rats/mice with those cytokines at different phases of the disease. In regard to the target organ attributes, the migration of arthritogenic leukocytes into the joints; the expression of mediators of inflammation, angiogenesis, and tissue damage; the role of vascular permeability; and the characteristics of vascular endothelial cells have been examined. Further, various inhibitors of angiogenesis are effective in suppressing arthritis. Taken together, the differential cytokine responses and unique attributes of the target organ have revealed novel aspects of disease susceptibility and joint damage in AA. The translation of this basic research in animal models to RA patients would not only advance our understanding of the disease process, but also offer novel avenues for immunomodulation of this disease.

Show MeSH
Related in: MedlinePlus