Enhanced secretion of leukocyte-associated immunoglobulin-like receptor 2 (LAIR-2) and soluble LAIR-1 in rheumatoid arthritis: LAIR-2 is a more efficient antagonist of the LAIR-1-collagen inhibitory interaction than is soluble LAIR-1

Abstract

Objective. Human leukocyte-associated immunoglobulin-like receptor 1 (hLAIR-1) is an immune inhibitory receptor for collagen that is expressed on most immune cells. We previously showed that the LAIR-1-collagen interaction could be antagonized by the secreted homolog hLAIR-2, which can be detected in the synovial fluid of rheumatoid arthritis (RA) patients. In addition, the extracellular part of hLAIR-1 is a putative antagonist upon shedding from the cell membrane. The purpose of this study was to determine the relative roles of hLAIR-2 and soluble hLAIR-1 (shLAIR-1) in the regulation of the LAIR-1-collagen interaction.Methods. The ability of recombinant LAIR proteins to abrogate LAIR-1-collagen binding was tested by flow cytometry and adhesion assays. Collagen binding capacity was analyzed by surface plasmon resonance. Plasma, urine, and synovial fluid were screened for the presence of sLAIR-1 and LAIR-2 by enzyme-linked immunosorbent assay.Results. Recombinant LAIR-2 proteins abrogated the binding of collagen to LAIR-1 more efficiently than did recombinant sLAIR-1. Consistent with these findings, surface plasmon resonance analysis showed that LAIR-2 had a higher affinity for collagen than did LAIR-1. Activated CD4؉ T cells were the main producers of LAIR-2, whereas the source of sLAIR-1 remains elusive. Both soluble LAIR-1 and LAIR-2 could be detected in the plasma and urine of healthy control subjects and patients with RA. Urinary levels of both proteins were significantly increased in RA patients, and LAIR-2 levels in urine were significantly correlated with markers of inflammation. Conclusion. Our data suggest that LAIR-2 is a more potent antagonist of LAIR-1 function in vivo, while both sLAIR-1 and LAIR-2 are potential biomarkers that may be used to monitor urine samples for evidence of systemic inflammation.Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory immune receptor for collagens and is expressed on most immune cells (1-3). Upon triggering, LAIR-1 inhibits various cellular functions (2,4-8). Since receptor and ligand are widely expressed, the regulation of the interaction must be tightly controlled to allow for appropriate cellular activation. We and other investigators have previously shown that upon maturation or activation, LAIR-1 expression on neutrophils, T cells, and B cells decreases, providing a regulatory mechanism at the level of receptor expression (8-11).

C1q limits dendritic cell differentiation and activation by engaging LAIR-1

“…Although α2β1 integrins bind collagens and may function as C1q receptors, they lack an intracellular ITIM domain (1,25). LAIR-2, which has been shown to be increased in certain autoimmune settings (17), also bound C1q and blocked C1q effects on cell differentiation and activation. Thus, LAIR-2 may be a key physiological regulator of C1q and LAIR-1 interactions.…”

“…Evidence that disrupted LAIR-1-mediated immune silencing leads to a loss of self-tolerance in disease settings includes deficient LAIR-1 expression on pDCs and B cells in SLE, correlating with increased IFN-α production and defective regulation of B-cell antibody secretion, respectively, and increased levels of LAIR-2 (a soluble LAIR-1 inhibitor) in rheumatoid arthritis (14,16,17). Based on the increasingly evident contribution of LAIR-1 and C1q to immune homeostasis, the extent of shared activities of LAIR-1 and C1q, and the presence of numerous potential LAIR binding sites on the CLR of C1q, we hypothesized that LAIR-1 binds C1q to suppress immune cell activity.…”

Dynamic Gene Expression Profile Changes in Synovial Fluid following Meniscal Injury; Osteoarthritis (OA) Markers Found

“…(Supplementary Figure 1) Included in the top 5% expressed genes were several genes with previously reported association to inflammation and/ or Rheumatic or Osteoarthritis; such as LAIR 1, TMSB4X, CCR6, IL18 and IL10 [2,[14][15][16][17].…”

“…These reported genes include LAIR1, TMSB4X, CCR6, IL18, IL10 [2,[14][15][16][17]. LAIRI is the highest expressed gene among all the samples.…”

Inhibition of the Classical and Lectin Pathway of the Complement System by Recombinant LAIR-2

“…Ligation of LAIR-1 generates a threshold for activation of various cellular functions [6]. Collagens serve as ligands for LAIR-1 [7,8], and we recently found that in particular dimeric recombinant LAIR proteins have a high affinity for collagen [9]. Recently, Son et al [10] reported C1q as ligand for LAIR-1 on dendritic cells.…”