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The leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is a collagen-binding inhibitory receptor important for the regulation of immune responses, expressed on the majority of peripheral blood mononuclear cells (PBMC). LAIR-2 is a soluble homolog that antagonizes LAIR-1 inhibitory function by binding the same ligands. We sought to investigate whether LAIR1 and LAIR2 single nucleotide polymorphisms (SNP) are associated with differential mRNA expression levels. We analyzed 14 SNPs of LAIR1 (6) and LAIR2 (8) by mass spectrometry-based genotyping and extracted mRNA from PBMC of 177 healthy subjects, followed by quantitative assays. Four SNPs of LAIR1 and two SNPs of LAIR2 mark differential mRNA levels in healthy individuals. To verify the biological relevance of these findings, we analyzed additional 515 individuals (282 patients and 233 controls) to check if LAIR1 and LAIR2 differential mRNA expression could be related to susceptibility to pemphigus foliaceus (PF), an autoimmune blistering skin disease endemic in Brazil. Two LAIR1 variants (rs56802430 G, OR = 1.52, p = 0.0329; rs11084332 C, OR = 0.57, p = 0.0022) and one LAIR2 (rs2287828 T+, OR = 1.9, p = 0.0097) contribute to differential susceptibility to PF. Furthermore, we demonstrate interactions among four LAIR2 SNPs (rs2042287, rs2287828, rs2277974 and rs114834145). A haplotype harboring these SNPs is strongly associated with higher LAIR2 mRNA levels (4.5-fold, p = 0.0069) and with higher susceptibility to PF (OR = 4.02, p = 0.0008). We suggest that LAIR1 and LAIR2 genetic variants are associated with regulation of gene expression and variable PF susceptibility, and show indirect association of LAIR2 differential mRNA expression with PF pathogenesis. Our data demonstrate how this relatively unknown disease can add invaluable knowledge regarding the role of LAIR1 and LAIR2 in immune responses.

KIR (killer cell immunoglobulin-like receptors) and HLA (human leukocyte antigens) are two distinct gene families with remarkable importance for human immune responses. The recognition of HLA molecules by activating and inhibitory KIR promotes a balance of signals that regulates NK cell function and is especially important for the innate defense against pathogens and early placentation. There is no documented gametic association between these two gene families and no evidence of common regulation. However, due to the critical role of KIR recognition for immunity and reproduction, the possibility of KIR-HLA combinations being under selective pressure is not surprising. In this manuscript, we first summarize the HLA-KIR system, the HLA molecules that are the putative ligands for KIR, and then we review the evidences that suggest these two gene families are coevolving as an integrated system.