Abstract:
Rheumatoid arthritis (RA), a chronic autoimmune
form of inflammatory joint disease, progressively af-
fects multiple joints with pathological changes in the
synovia, cartilage, and bone. Numerous studies have
suggested a critical role for glucocorticoid-induced
tumor necrosis factor receptor family-related protein
(GITR) in the pathogenesis of autoimmune arthritis
by modulating both innate and adaptive immune re-
actions, but the underlying mechanisms by which
GITR activation promotes arthritic progression re-
main largely unclear. In this study, we found that
collagen-induced arthritis mice treated with the li-
gand of GITR (GITRL) displayed an earlier onset of
arthritis with a markedly increased severity of ar-
thritic symptoms and joint damage, in which signifi-
cantly increased Th17 cells in both spleen and drain-
ing lymph nodes were observed. Notably, results
showed that a marked expansion of Th17 cells with
increased ROR␥t mRNA expression was induced from
naïve CD4ⴙ T cells when cultured with GITRL. Consis-
tently, normal mice that were treated with GITRL
were found to display a substantial expansion of
splenic Th17 cells. Furthermore, we detected elevated
serum levels of GITRL in patients with RA, which were
positively correlated with an increase in interleu-kin-17 production. Taken together, the results from
this study have revealed a new function of GITRL in
exacerbating autoimmune arthritis via the enhance-
ment of the expansion of Th17 cells.
