title: Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis.
abstract: The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Song
authors.forename: Inyong
authors.initials: I
authors.lastname: Hwang
authors.forename: Kyung H
authors.initials: KH
authors.lastname: Cho
authors.forename: Michael A
authors.initials: MA
authors.lastname: Garcia
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Kim
authors.forename: Tiffany H
authors.initials: TH
authors.lastname: Wang
authors.forename: Tamsin M
authors.initials: TM
authors.lastname: Lindstrom
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Michael
authors.initials: M
authors.lastname: Nesheim
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Leung
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001777:Blood Coagulation / Q000502:physiology; D043424:Carboxypeptidase B / Q000097:blood* / Q000235:genetics; D015936:Complement C5a / Q000378:metabolism; D015536:Down-Regulation; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007527:Isoenzymes / Q000097:blood / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D013582:Synovial Fluid / Q000201:enzymology; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology
chemical_list: D007527:Isoenzymes; D043782:Receptor, Bradykinin B2; C506896:Spp1 protein, mouse; D053495:Osteopontin; D015936:Complement C5a; D043424:Carboxypeptidase B