Reproductive failure in humans is a very important social and economic problem, because nowadays women decide to conceive later in life and delay motherhood. Unfortunately, with increasing age they have less chance for natural fertilization and maintenance of pregnancy. Many of them need assisted reproductive technology. Approximately 10% of women after in vitro fertilization-embryo transfers experience recurrent implantation failure (RIF). Multiple factors may contribute to RIF, including oocyte and sperm quality, parental chromosomal anomalies, genetic or metabolic abnormalities of the embryo, poor uterine receptivity, immunological disturbances in the implantation site, and some gynecologic pathologies such as endometriosis, uterine fibroids, hydrosalpinx and endometrial polyps. Moreover, the procedure of in vitro fertilization itself could adversely influence the implantation. Nowadays, many studies are focused on the role of natural killer (NK) cells in normal and pathologic pregnancy because NK cells constitute the dominant cell population in the endometrium and they come in close contact with the allogeneic extravillous trophoblast cells in early pregnancy decidua. The majority of these cells are of CD56^bright phenotype. These cells can express killer immunoglobulin-like receptors (KIRs), which, upon recognition of HLA class I molecules (HLA-C and HLA-G) on trophoblasts, may either stimulate or inhibit NK cells to produce soluble factors, and display low cytotoxicity necessary for maintenance of the allogeneic embryo and fetus in the next steps of pregnancy. Moreover, some members of the leukocyte immunoglobulin-like receptor (LILR) family, also named ILT (immunoglobulin-like transcript), are present in the human placenta. LILRB1 (ILT2) was described mainly on stromal cells, while LILRB2 (ILT4), in addition to stromal cells, was also found around vessels in the smooth muscle layer. In this review we focus on the possible role of polymorphism of KIR, LILRB and their ligands (HLA-C, HLA-G) in susceptibility to recurrent implantation failure, which could serve as diagnostic biomarkers of this disease.

KIR2DS5 gene encodes an activating natural killer cell receptor whose ligand is not known. It was recently reported to affect the outcome of hematopoietic stem cell transplantation. In our studies on KIR2DS5 gene associations with human diseases, we compared the frequencies of this gene in patients and relevant controls. Typing for KIR2DS5 gene was performed by either individual or multiplex polymerase chain reactions which, when compared in the same samples, gave concordant results. We noted an apparently protective effect of KIR2DS5 gene presence in several clinical conditions, but not in others. Namely, this effect was observed in ankylosing spondylitis (p = 0.003, odds ratio [OR] = 0.47, confidence interval [CI] = 0.28–0.79), endometriosis (p = 0.03, OR = 0.25, CI = 0.07–0.82) and acute rejection of kidney graft (p = 0.0056, OR = 0.44, CI = 0.24–0.80), but not in non-small-cell lung carcinoma, rheumatoid arthritis, spontaneous abortion, or leukemia (all p>0.05). In addition, the simultaneous presence of KIR2DS5 gene and HLA-C C1 allotype exhibited an even stronger protective effect on ankylosing spondylitis (p = 0.0003, OR = 0.35, CI = 0.19–0.65), whereas a lack of KIR2DS5 and the presence of the HLA-C C2 allotype was associated with ankylosing spondylitis (p = 0.0017, OR = 1.92, CI = 1.28–2.89), whereas a lack of KIR2DS5 and presence of C1 allotype was associated with rheumatoid arthritis (p = 0.005, OR = 1.47, CI = 1.13–1.92). The presence of both KIR2DS5 and C1 seemed to protect from acute kidney graft rejection (p = 0.017, OR = 0.47, CI = 0.25–0.89), whereas lack of KIR2DS5 and presence of C2 seemed to favor rejection (p = 0.0015, OR = 2.13, CI = 1.34–3.37). Our results suggest that KIR2DS5 may protect from endometriosis, ankylosing spondylitis, and acute rejection of kidney graft.

Killer cell immunoglobulin-like receptors (KIRs) are a family of cell surface inhibitory or activating receptors expressed on natural killer cells and some subpopulations of T lymphocytes. KIR genes are clustered in the 19q13.4 region and are characterized by both allelic (high numbers of variants) and haplotypic (different numbers of genes for inhibitory and activating receptors on individual chromosomes) polymorphism. This contributes to diverse susceptibility to diseases and other clinical situations. Associations of KIR genes, as well as of genes for their ligands, with selected diseases such as psoriasis vulgaris and atopic dermatitis, rheumatoid arthritis, recurrent spontaneous abortion, and non-small cell lung cancer are discussed in the context of NK and T cell functions.

Endometriosis is a disease in which endometriotic tissue occurs outside the uterus. Its pathogenesis is still unknown. The most widespread hypothesis claims that ectopic endometrium appears as a result of retrograde menstruation and its insufficient elimination by immunocytes. Some reports have shown expression of non-classical HLA-G molecules on ectopic endometrium. HLA-G is recognized by KIR2DL4, LILRB1 and LILRB2 receptors on natural killer (NK) and other cells. These receptors are polymorphic, which may affect their activity. In this study we investigated whether HLA-G, KIR2DL4, LILRB1 and LILRB2 polymorphisms may influence susceptibility to endometriosis and disease progression. We used polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and allelic discrimination methods with TaqMan SNP Genotyping Assays for typing of 276 patients with endometriosis and 314 healthy fertile women. The HLA-G rs1632947:GG genotype was associated with protection against the disease and its severe stages; HLA-G rs1233334:CT protected against progression; LILRB1 rs41308748:AA and LILRB2 rs383369:AG predisposed to the disease and its progression. No effect of KIR2DL4 polymorphism was observed. These results support the role of polymorphisms of HLA-G and its receptors LILRB1 and LILRB2 in susceptibility to endometriosis and its progression.

Smoking is a major risk factor for lung cancer, therefore lung cancer epidemiological trends reflect the past trends of cigarette smoking to a great extent. The geographic patterns in mortality closely follow those in incidence. Although lung cancer is strongly associated with cigarette smoking, only about 15% of smokers get lung cancer, and also some never-smokers develop this malignancy. Although less frequent, lung cancer in never smokers is the seventh leading cause of cancer deaths in both sexes worldwide. Lung cancer in smokers and never-smokers differs in many aspects: in histological types, environmental factors representing a risk, and in genes associated with this disease. In this review, we will focus on the genetic differences between lung cancer in smokers versus never-smokers: gene expression, germ-line polymorphisms, gene mutations, as well as ethnic and gender differences. Finally, treatment options for smokers and never-smokers will be briefly reviewed.