LAIR1 (leukocyte-associated Ig-like receptor-1, designated CD305) is an approximately 40 kDa type I transmembrane inhibitory glycoprotein belonging to the Ig superfamily (1-4). LAIR1 is a collagen-binding protein that is expressed in a differentiation- and activation-dependent manner on most immune cells, including T, B, NK and dendritic cells (DC), monocytes, CD34+ hematopoietic progenitors, most thymocytes, and selected granulocyte populations (2-7). Mature human LAIR1 is a 266 amino acid (aa) type I transmembrane protein that includes a 144 aa extracellular domain (ECD) with one collagen-binding C2-type Ig-like domain, and a 101 aa cytoplasmic domain with two ITIM motifs (2, 3, 8, 9). Of four potential human LAIR1 splice variants, LAIR1b has a 17 aa deletion within the ECD, but outside the Ig domain. LAIR1c differs from LAIR1b by one aa. LAIR1d has a 78 aa cytoplasmic truncation and lacks ITIM motifs. Human LAIR1 ECD shares <45% aa sequence identity with mouse, rat, bovine or canine LAIR1 ECD, but all are functional orthologs. Humans, but not rodents, also express the 152 aa secreted protein LAIR2, which shares 83% aa sequence identity with the LAIR1 ECD up to aa 140 and can block LAIR1 collagen binding (1, 2). A soluble form of LAIR1 found in plasma and urine also binds collagen (10). Adhesion of LAIR1 to collagens in the extracellular matrix, transmembrane collagens expressed by tumor cells, or antibody-mediated crosslinking of LAIR1, inhibits signals relayed by ITAM-bearing receptors and some cytokine-mediated signals (6-8, 13). Processes that are inhibited include B and T cell receptor-mediated activation, NK and T cell‑mediated cytotoxicity, and basophil degranulation (1-4, 8). LAIR1 is reduced or absent on chronic lymphocytic leukemia (CLL) B cells, and some B and DC cells in systemic lupus erythematosus (SLE). Its under‑expression potentially enhances CLL proliferation and SLE immune responses (7, 11, 12).