The Genomic Organization of the LILR Region Remained Largely Conserved Throughout Primate Evolution: Implications for Health And Disease

Abstract

The genes of the leukocyte immunoglobulin-like receptor (LILR) family map to the leukocyte receptor complex (LRC) on chromosome 19, and consist of both activating and inhibiting entities. These receptors are often involved in regulating immune responses, and are considered to play a role in health and disease. The human LILR region and evolutionary equivalents in some rodent and bird species have been thoroughly characterized. In non-human primates, the LILR region is annotated, but a thorough comparison between humans and non-human primates has not yet been documented. Therefore, it was decided to undertake a comprehensive comparison of the human and non-human primate LILR region at the genomic level. During primate evolution the organization of the LILR region remained largely conserved. One major exception, however, is provided by the common marmoset, a New World monkey species, which seems to feature a substantial contraction of the number of LILR genes in both the centromeric and the telomeric region. Furthermore, genomic analysis revealed that the killer-cell immunoglobulin-like receptor gene KIR3DX1, which maps in the LILR region, features one copy in humans and great ape species. A second copy, which might have been introduced by a duplication event, was observed in the lesser apes, and in Old and New World monkey species. The highly conserved gene organization allowed us to standardize the LILR gene nomenclature for non-human primate species, and implies that most of the receptors encoded by these genes likely fulfill highly preserved functions.

Comparative genomics of the Leukocyte Receptor Complex in carnivores

“…Previously published studies characterizing the LRC and the LILRs for multiple species within a family are limited. Those which can serve for comparison to the Felidae are the Hominidae, represented by humans, chimpanzees, bonobos, gorillas, and orangutans ( 18 ); the Bovidae, represented by cattle ( Bos taurus ) ( 22 , 57 ) and goats ( Capra hircus ) ( 21 ); and the Camelidae, represented by the Bactrian camel ( Camelus bactrianus ), the dromedary ( Camelus dromedarius ), and the wild camel ( Camelus ferus ) ( 56 ).…”

“…Less is known about the LILRs, which have mainly been studied in primates ( 18 ) and mice (as PIRs, the murine orthologues of LILRs) ( 19 ), as well as in several species of Cetartiodactyla, including pigs ( 20 ), goats ( 21 ), and cattle ( 22 ). Like other immunoreceptor gene families, the LILRs comprise both activating and inhibitory receptors ( 23 ).…”

“…Inhibitory LILRBs have long cytoplasmic tails containing 2 to 4 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) ( 24 ). In addition, several LILRAB genes with characteristics typical of both activating and inhibitory LILRs have been described in primates ( 18 ), and one human LILR without transmembrane and signaling domains is known to be expressed as a secreted protein ( 25 ). Both LILRA and LILRB gene products comprise 2 to 6 extracellular Ig domains, depending on the species: either 2 or 4 Ig domains are typical for human LILRs ( 24 ), while 6 Ig domains are typical for murine PIRs ( 26 ) and can also be found in some bovine LILRs ( 22 ).…”

“…LILRs are expressed in a variety of immune cells, including monocytes, macrophages, B and T lymphocytes, granulocytes, NK cells, mast cells, and dendritic cells ( 18 ). Although they have been shown to bind a variety of ligands, their interaction with MHC-I is the best described ( 27 ).…”

“…However, at this time the function of various LILRs is poorly characterized, especially in non-human species. In humans and to a lesser extent in mice, LILRs (and their PIR orthologues) have been shown to play roles in autoimmune and inflammatory diseases, viral responses, neurodegenerative disorders, infectious diseases, and cancer ( 18 , 29 ). Therefore, they are considered potentially useful as diagnostic markers and as a target for immunotherapies ( 30 – 33 ).…”