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PLoS Med. 2009 Oct;6(10):e1000166. doi: 10.1371/journal.pmed.1000166. Epub 2009 Oct 20.

Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data.

Author information

1
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

BACKGROUND:

A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA.

METHODS AND FINDINGS:

In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell-mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model.

CONCLUSIONS:

Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches. Please see later in the article for the Editors' Summary.

PMID:
19841745
PMCID:
PMC2760136
DOI:
10.1371/journal.pmed.1000166
[Indexed for MEDLINE]
Free PMC Article

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