Linked Life Data

19342640

Source:http://linkedlifedata.com/resource/pubmed/id/19342640

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2009-4-3
pubmed:abstractText
Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4(+) T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4(+)CD25(-) T cells produce IL-21. We generated IL-21R-deficient (IL-21R(-/-)) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4(+) T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1(+) memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-kappaB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R(-/-) K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4(+) cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1550-6606
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
182
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4649-56
pubmed:meshHeading
pubmed-meshheading:19342640-Animals, pubmed-meshheading:19342640-Antibody Formation, pubmed-meshheading:19342640-Arthritis, pubmed-meshheading:19342640-Autoantigens, pubmed-meshheading:19342640-Autoimmune Diseases, pubmed-meshheading:19342640-CD4-Positive T-Lymphocytes, pubmed-meshheading:19342640-Cell Proliferation, pubmed-meshheading:19342640-Disease Models, Animal, pubmed-meshheading:19342640-Disease Progression, pubmed-meshheading:19342640-Gene Expression Regulation, pubmed-meshheading:19342640-Homeostasis, pubmed-meshheading:19342640-Immunoglobulin G, pubmed-meshheading:19342640-Interleukin-17, pubmed-meshheading:19342640-Interleukin-2 Receptor alpha Subunit, pubmed-meshheading:19342640-Interleukins, pubmed-meshheading:19342640-Mice, pubmed-meshheading:19342640-Mice, Knockout, pubmed-meshheading:19342640-Receptors, Interleukin-21, pubmed-meshheading:19342640-Signal Transduction
pubmed:year
2009
pubmed:articleTitle
A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice.
pubmed:affiliation
Department of Biomedical Sciences and Institute of Biomedical Sciences, College of Medicine, Hanyang University, Seoul, Korea.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't