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


RESULTS
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.
Azuma
Takeshi
T
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Zhu
Gefeng
G
Xu
Haiying
H
Rietz
A Cecilia
AC
Drake
Charles G
CG
Matteson
Eric L
EL
Chen
Lieping
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D018122:B7-1 Antigen / Q000378:metabolism*; D003430:Cross-Sectional Studies; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D023421:Models, Animal; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human