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The Soluble Leukocyte-Associated Ig-Like Receptor (LAIR)-2 Antagonizes the Collagen/LAIR-1 Inhibitory Immune Interaction¹

Robert Jan Lebbink^*, Maaike C. W. van den Berg^*, Talitha de Ruiter^*, Nicolas Raynal, Joel A. G. van Roon, Peter J. Lenting, Boquan Jin^¶ and Linde Meyaard^2,*

^* Department of Immunology, University Medical Center, Utrecht, The Netherlands; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands; Thrombosis and Haemostasis Laboratory, University Medical Center, Utrecht, The Netherlands; and ^¶ Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi Province, China

Leukocyte-associated Ig-like receptor (LAIR)-1 is a collagen-receptor that inhibits immune cell function upon collagen binding. Next to LAIR-1, the human genome encodes LAIR-2, a putative soluble homolog. In this study we show, for the first time, that the LAIR-2 gene is broadly transcribed in human PBMC, mirroring the expression profile of LAIR-1. LAIR-2 protein is expressed as a soluble receptor exhibiting high affinity for various collagen molecules to which it binds in a hydroxyproline-dependent manner. In vitro stimulation of PBMC induces secretion of LAIR-2. We detect high amounts of LAIR-2 in urine of pregnant women, indicating that the soluble receptor is indeed produced in vivo and can be cleared from the body via urine. Furthermore, LAIR-2 levels are increased in synovial fluid of patients with rheumatoid arthritis as compared with osteoarthritis patients. We hypothesize that soluble LAIR-2 may function as a natural competitor for LAIR-1, thereby regulating its inhibitory potential. Indeed, LAIR-2 prevents binding of human LAIR-1 to collagens and LAIR-1 cross-linking in vitro, suggesting that the protein has an immunoregulatory function in vivo. Hence, we reveal a novel mechanism of immune regulation by a soluble LAIR receptor regulating the inhibitory potential of the membrane-bound LAIR-1 via competition for ligands.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 016.026.008 from the Netherlands Organization for Scientific Research.

² Address correspondence and reprint requests to Dr. Linde Meyaard, Department of Immunology, University Medical Center Utrecht, Room KC02.085.2, Lundlaan 6, 3584 EA Utrecht, The Netherlands. E-mail address: l.meyaard{at}umcutrecht.nl

³ Abbreviations used in this paper: LAIR, leukocyte-associated Ig-like receptor; hLAIR, human LAIR; SF, synovial fluid; RA, rheumatoid arthritis; OA, osteoarthritis; s, soluble; LILR, leukocyte Ig-like receptor; KIR, killer cell Ig-like receptor.

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