Role of glucocorticoid‐induced TNF receptor family gene (GITR) in collagen‐induced arthritis

Abstract

In rheumatoid arthritis (RA), a widespread autoimmune/inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid-induced TNFR family-related gene), a costimulatory molecule for T lymphocytes, increases CD4+CD25- effector T cell activation while inhibiting suppressor activity of CD4+CD25+ T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) -induced arthritis (CIA) using GITR-/- and GITR+/+ mice. Results indicate significantly less CIA induction in GITR-/- mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFNgamma, IL-6, TNFalpha, MIP-1alpha, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR-/- mice. Although CD4+CD25+ Treg cells from GITR+/+ and GITR-/- CII-challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.

Cytokine profiling of prostatic fluid from cancerous prostate glands identifies cytokines associated with extent of tumor and inflammation

“…GITR also correlates with neutrophilic infiltration. In GITR-/-mice, neutrophil infiltration into arthritic areas was significantly less than in GITR +/+ mice [31]. Whereas GITR-expressing Treg help limit collateral tissue damage caused by vigorous antimicrobial immune response in normal tissues [32], Treg cells are increased in human solid tumors and an increased number of Treg cells correlates with poor prognosis [33].…”

Effector T cells in rheumatoid arthritis: Lessons from animal models

“…However, while T reg cells from healthy mice or mice that have responded to treatment are effective in suppressing effector T cell responses, those from diseased animals are not [111]. Additionally, several studies in knockout mice or in mice treated with effective disease-ameliorating therapies associate disease resistance or improvement with an increase in T reg numbers in the DLN and joints of arthritic mice or an enhancement in T reg suppressor activity [111,[113][114][115][116]. On the other hand, disease-exacerbating genetic deletions or therapies result in decreased T reg numbers or activity [108,117].…”

A Microbial Polysaccharide Reduces the Severity of Rheumatoid Arthritis by Influencing Th17 Differentiation and Proinflammatory Cytokines Production

“…CIA was induced in 6-to 8-wk-old male DBA/1 mice by intradermal tail base injection of 100 g of chicken type II collagen (CII) (Sigma-Aldrich) as described elsewhere (28). Disease onset was considered to occur on the day that swelling or erythema was observed in a paw.…”