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

Takeshi Azuma, Gefeng Zhu, Haiying Xu, A. Cecilia Rietz, Charles G. Drake, Eric L. Matteson, Lieping Chen

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish (US)
Article numbere1000166
JournalPLoS Medicine
Volume6
Issue number10
DOIs
StatePublished - Oct 2009

ASJC Scopus subject areas

  • Medicine(all)

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