Role of the ABCA4 Gene Expression in the Clearance of Toxic Vitamin A Derivatives in Human Hair Follicle Stem Cells and Keratinocytes.

The ABCA4 gene encodes an ATP-binding cassette transporter that is expressed specifically in the disc of photoreceptor outer segments. Mutations in the ABCA4 gene are the main cause of retinal degenerations known as "ABCA4-retinopathies." Recent research has revealed that ABCA4 is expressed in other cells as well, such as hair follicles and keratinocytes, although no information on its significance has been evidenced so far. In this study, we investigated the role of the ABCA4 gene in human keratinocytes and hair follicle stem cells for the first time. We have shown that silencing the ABCA4 gene increases the deleterious effect of all-trans-retinal on human hair follicle stem cells.

Expression of Fucosyltransferase 4 (FUT4) mRNA Is Increased in Endometrium from Women with Endometriosis.

Endometriosis is a common gynecological disorder defined as the presence of endometrial-like tissue (glands and stroma) outside the uterus. The etiopathogenesis of endometriosis is still poorly recognized. It is speculated that stage-specific embryonic antigen 1 (SSEA-1)-positive stem-like glandular epithelial cells may contribute to the development of the disease. The synthesis of SSEA-1 is mediated by fucosyltransferase 4 encoded by the FUT4 gene. Therefore, this study aimed to evaluate the specific expression of FUT4 mRNA in biopsies of the endometrium from women with and without endometriosis. FUT4 mRNA levels were examined in 49 women with laparoscopically confirmed endometriosis and 28 controls by means of quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The expression of FUT4 mRNA was significantly increased in the endometrium of patients with endometriosis when compared to the controls (p < 0.0001). Expression of FUT4 mRNA in the endometrium was correlated with the severity of endometriosis (rs = 0.5579, p < 0.0001); however, there were no differences in endometrial FUT4 mRNA expression when comparing endometriotic lesions from various locations. The discriminatory ability of FUT4 mRNA expression was evaluated by receiver-operating characteristics (ROC), which showed high statistical significance (AUC = 0.90, p < 0.0001), thus indicating that an increased level of endometrial FUT4 mRNA may serve as a specific marker for endometriosis.

A Novel and Effective Method for Human Primary Skin Melanocytes and Metastatic Melanoma Cell Isolation.

The development of an effective method of melanocyte isolation and culture is necessary for basic and clinical studies concerning skin diseases, including skin pigmentation disorders and melanoma. In this paper, we describe a novel, non-enzymatic and effective method of skin melanocyte and metastatic melanoma cell isolation and culture (along with the spontaneous spheroid creation) from skin or lymph node explants. The method is based on the selective harvesting of melanocytes and melanoma cells emigrating from the cultured explants. Thereby, isolated cells retain their natural phenotypical features, such as expression of tyrosinase and Melan-A as well as melanin production and are not contaminated by keratinocytes and fibroblasts. Such melanocyte and melanoma cell cultures may be very useful for medical and cosmetology studies, including studies of antitumor therapies.

Endometriotic Peritoneal Fluid Stimulates Recruitment of CD4+CD25highFOXP3+ Treg Cells.

Endometriosis is a common gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus. The disease is associated with disturbed local and systemic immunity. It has been reported that the proportion of CD4+CD25highFOXP3+ Treg cells may be significantly increased in the peritoneal fluid of patients with endometriosis. Therefore, the aim of our study was to investigate whether the proportions of Treg cells in the peritoneal cavity of patients with endometriosis are related to the chemotactic and stimulatory activity of the local peritoneal milieu. The peritoneal fluid was collected from 13 women with ovarian endometriosis and 12 control women without the disease. T cell populations were analyzed by flow cytometry, cytokines and chemokines were evaluated using the cytometric bead kit, and cell chemotaxis was studied by cell migration assay. We confirmed that the proportions of Treg cells are increased in the peritoneal fluid of women with endometriosis as compared to the control women. Endometriosis was also associated with elevated concentrations of IL-6, IL-10, and TGF-ß1/2 as well as CCL20, CXCL8, CXCL9, and CXCL10. We did not reveal any changes in the proportion of peritoneal Th17 cells and concentrations of IL-17A. Peritoneal Treg cells positively correlated with concentrations of TGF-ß, IL-10, and CCL20. Endometriotic peritoneal fluid stimulated chemotaxis of both CD4+ and Treg cells. This chemotactic activity positively correlated with concentrations of CCL20. CCL20 stimulated the migration of Treg cells, and the chemotactic activity of the endometriotic peritoneal fluid was inhibited by neutralizing anti-CCL20 antibodies. These results imply that increased proportions of the peritoneal Treg cells in women with endometriosis may result from attraction and activation by local chemokines and cytokines, especially CCL20 and TGF-ß. Since Treg cells contribute to the immunopathogenesis of endometriosis, their chemotaxis and activation may be considered as a target for therapeutic intervention.

Peritoneal Fluid from Patients with Ovarian Endometriosis Displays Immunosuppressive Potential and Stimulates Th2 Response.

Endometriosis is a common gynaecological disorder characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is associated with chronic pelvic inflammation and autoimmune reactivity manifesting by autoantibody production and abrogated cellular immune responses. Endometriotic peritoneal fluid contains various infiltrating leucocyte populations and a bulk of proinflammatory and immunoregulatory cytokines. However, the nature and significance of the peritoneal milieu in women with endometriosis still remains obscure. Therefore, the aim of the present study was to investigate the immunoregulatory activity of the peritoneal fluid (PF) from women with endometriosis. The peritoneal fluid samples were collected during laparoscopic surgery from 30 women with and without endometriosis. Immunoregulatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF) and chemokines (CCL2, CCL5, CXCL8 and CXCL9) were evaluated in PF and culture supernatants generated by unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells cultured in the presence of PF. The effect of PF on the generation of Treg and Th17 cells in CD4+ T cell cultures, as well as the natural cytotoxic activity of peripheral blood mononuclear cells, was also investigated. Concentrations of IL-6, IL-10, CCL2, CXCL8 and CXCL9 were significantly upregulated in the PF from women with endometriosis when compared to control women, whereas concentrations of other cytokines and chemokines were unaffected. The culturing of unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells in the presence of endometriotic PF resulted in the downregulation of their IL-2, IFN-γ, IL-17A and TNF production as compared to culture medium alone. On the other side, endometriotic PF significantly stimulated the production of IL-4 and IL-10. Endometriotic PF also stimulated the release of CCL2 and CXCL8, whereas the production of CCL5 and CXCL9 was downregulated. Endometriotic PF stimulated the generation of Treg cells and had an inhibitory effect on the generation of Th17 cells in cultures of CD4+ T cells. It also inhibited the NK cell cytotoxic activity of the peripheral blood lymphocytes. These results strongly imply that the PF from patients with endometriosis has immunoregulatory/immunosuppressive activity and shifts the Th1/Th2 cytokine balance toward the Th2 response, which may account for deviation of local and systemic immune responses. However, a similar trend, albeit not a statistically significant one, was also observed in case of PF from women without endometriosis, thus suggesting that peritoneal milieu may in general display some immunoregulatory/immunosuppressive properties. It should be stressed, however, that our present observations were made on a relatively small number of PF samples and further studies are needed to reveal possible mechanism(s) responsible for this phenomenon.

Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes.

Endometriosis is an inflammatory condition manifested by the presence of endometrial-like tissue outside of the uterine cavity. The most common clinical presentations of endometriosis are dysmenorrhea, infertility, and severe pelvic pain. Few hypotheses attempt to explain the pathogenesis of endometriosis; however, none of the theories have been fully confirmed or considered universal. We examined somatic mutations in eutopic endometrium samples, deep endometriotic nodules and peripheral blood from 13 women with deep endometriosis of the rectovaginal space. Somatic variants were identified in laser microdissected samples using next-generation sequencing. A custom panel of 1296 cancer-related genes was employed, and selected genes representing cancer drivers and non-drivers for endometrial and ovarian cancer were thoroughly investigated. All 59 detected somatic variants were of low mutated allele frequency (<10%). In deep ectopic lesions, detected variants were significantly more often located in cancer driver genes, whereas in eutopic endometrium, there was no such distribution. Our results converge with other reports, where cancer-related mutations were found in endometriosis without cancer, particularly recurrent KRAS mutations. Genetic alterations located in ectopic endometriotic nodules could contribute to their formation; nevertheless, to better understand the pathogenesis of this disease, more research in this area must be performed.

Endometriosis Is Associated with Functional Polymorphism in the Promoter of Heme Oxygenase 1 (HMOX1) Gene.

Endometriosis is a common gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity. Etiopathogenesis of endometriosis is poorly understood; it is plausible, however, that the disease may be associated with oxidative stress related to local heme and iron metabolism. Therefore, the aim of the study was to reveal a possible association of endometriosis with a stress-inducible heme oxygenase 1 (HMOX1). For this purpose, 228 patients with clinically confirmed endometriosis and 415 control parous women from general Polish population were examined for functional -413A>T (rs2071746) single-nucleotide polymorphism (SNP) and (GT)n dinucleotide repeat length polymorphism in the promoter of HMOX1 gene. In addition, -413A>T SNP was assessed by the specific TaqMan® SNP Genotyping Assay, and (GT)n polymorphism was determined by PCR product size analysis. We found that endometriosis is associated with an increased frequency of -413A(GT)31,32 haplotype (OR (95%CI) = 1.27 (1.01-1.60), p = 0.0381) and -413A(GT)31,32 homozygous genotype [OR (95%CI) = 1.51 (1.06-2.17), p = 0.0238]. These data suggest that endometriosis is associated with functional polymorphism of HMOX1 gene, and this gene may play a part in the pathogenesis of this disorder.

Influence of Hypothermic Storage Fluids on Mesenchymal Stem Cell Stability: A Comprehensive Review and Personal Experience.

Mesenchymal stem cells have generated a great deal of interest due to their potential use in regenerative medicine and tissue engineering. Examples illustrating their therapeutic value across various in vivo models are demonstrated in the literature. However, some clinical trials have not proved their therapeutic efficacy, showing that translation into clinical practice is considerably more difficult and discrepancies in clinical protocols can be a source of failure. Among the critical factors which play an important role in MSCs' therapeutic efficiency are the method of preservation of the stem cell viability and various characteristics during their storage and transportation from the GMP production facility to the patient's bedside. The cell storage medium should be considered a key factor stabilizing the environment and greatly influencing cell viability and potency and therefore the effectiveness of advanced therapy medicinal product (ATMP) based on MSCs. In this review, we summarize data from 826 publications concerning the effect of the most frequently used cell preservation solutions on MSC potential as cell-based therapeutic medicinal products.

High expression of Matrix Gla Protein in Schnyder corneal dystrophy patients points to an active role of vitamin K in corneal health.

PURPOSE: Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disorder characterized by corneal lipid accumulation and caused by UBIAD1 pathogenic variants. UBIAD1 encodes a vitamin K (VK) biosynthetic enzyme. To assess the corneal and vascular VK status in SCD patients, we focused on matrix Gla protein (MGP), a VK-dependent protein. METHODS: Conformation-specific immunostainings of different MGP maturation forms were performed on corneal sections and primary keratocytes from corneal buttons of two SCD patients with UBIAD1 p.Asp112Asn and p.Asn102Ser pathogenic variants and unrelated donors. Native or UBIAD1-transfected keratocytes were used for gene expression analysis. Plasma samples from SCD patients (n = 12) and control individuals (n = 117) were subjected for inactive desphospho-uncarboxylated MGP level measurements with an ELISA assay. RESULTS: Substantial amounts of MGP were identified in human cornea and most of it in its fully matured and active form. The level of mature MGP did not differ between SCD and control corneas. In primary keratocytes from SCD patients, a highly increased MGP expression and presence of immature MGP forms were detected. Significantly elevated plasma concentration of inactive MGP was found in SCD patients. CONCLUSION: High amount of MGP and the predominance of mature MGP forms in human cornea indicate that VK metabolism is active in the visual system. Availability of MGP seems of vital importance for a healthy cornea and may be related to protection against corneal calcification. Systemic MGP findings reveal a poor vascular VK status in SCD patients and indicate that SCD may lead to cardiovascular consequences.

Effect of donor non-muscle myosin heavy chain (MYH9) gene polymorphisms on clinically relevant kidney allograft dysfunction.

BACKGROUND: Despite its established association with chronic kidney disease (CKD) the role of myosin-9 (MYH9) gene variation on transplanted kidney function remains unknown. This study aimed at evaluating the effect of donor MYH9 nephrogenic variants on renal allograft function within the first post transplantation year. METHODS: In the longitudinal kidney transplant study 207 deceased donors were genotyped for previously known risk MYH9 single nucleotide polymorphisms (SNPs). The predictor was MYH9 high-risk variants status. The primary outcome was mean eGFR found in low vs. high risk MYH9 genotypes between third and twelfth post-transplant month, the secondary outcome was the risk of proteinuria. RESULTS: Distribution of genotypes remained in Hardy-Weinberg equilibrium. The T allele of rs3752462 (dominant model, TT or TC vs. CC) was associated with higher filtration rate (P = 0.05) in a multivariate analysis after adjusting for delayed graft function and donor sex. Two G alleles of rs136211 (recessive model, GG vs. GA or AA) resulted in doubling the risk of proteinuria (OR = 2.22; 95% CI = 1.18-4.37, P = 0.017) after adjusting for donor and recipient sex. CONCLUSION: Deceased donor kidneys of European descent harboring MYH9 SNPs rs3752462 T allele show significantly superior estimated filtration rate while those of rs136211 GG genotype excessive risk of proteinuria. These findings, if replicated, may further inform and improve individualization of allocation and treatment policies.

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles.

ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

Does Caesarean Section or Preterm Delivery Influence TGF-ß2 Concentrations in Human Colostrum?

Human colostrum (HC) is a rich source of immune mediators that play a role in immune defences of a newly born infant. The mediators include transforming growth factor ß (TGF-ß) which exists in three isoforms that regulate cellular homeostasis and inflammation, can induce or suppress immune responses, limit T helper 1 cells (Th1) reactions and stimulate secretory immunoglobulin A (IgA) production. Human milk TGF-ß also decreases apoptosis of intestinal cells and suppresses macrophage cytokine expression. The aim of the study was to determine the concentration of TGF-ß2 in HC obtained from the mothers who delivered vaginally (VD) or by caesarean section (CS), and to compare the concentrations in HC from mothers who delivered at term (TB) or preterm (PB). In this study, 56% of preterm pregnancies were delivered via CS. The concentrations of TGF-ß2 were measured in HC from 299 women who delivered in the 1st Department of Obstetrics and Gynaecology, Medical University of Warsaw: 192 (VD), 107 (CS), 251 (TB), and 48 (PB). The colostrum samples were collected within 5 days post-partum. TGF-ß2 levels in HC were measured by the enzyme-linked immunosorbent assay (ELISA) test with the Quantikine ELISA Kit-Human TGF-ß2 (cat.no. SB250). Statistical significance between groups was calculated by the Student t-test using StatSoft Statistica 13 software. The mean TGF-ß2 concentration in patients who delivered at term or preterm were comparable. The levels of TGF-ß2 in HC were higher after preterm than term being 4648 vs. 3899 ng/mL (p = 0.1244). The delivery via CS was associated with higher HC concentrations of TGF-ß2. The levels of TGF-ß2 were significantly higher in HC after CS than VD (7429 vs. 5240 ng/mL; p = 0.0017). The data from this study suggest: caesarean section was associated with increased levels of TGF-ß2 in HC. The increased levels of TGF-ß2 in HC of women who delivered prematurely require further research. Early and exclusive breast-feeding by mothers after caesarean section and premature births with colostrum containing high TGF-ß2 levels may prevent the negative impact of pathogens which often colonize the gastrointestinal tract and may reduce the risk of chronic diseases in this group of patients.

Immunology of alopecia areata.

Alopecia areata is a condition that affects hair follicles and leads to hair loss ranging from small well-defined patches to complete loss of all body hair. Despite its high incidence, the pathobiology is not fully understood, and no single concept could be universally accepted. Alopecia areata is mostly considered to be an autoimmune disease, in which the collapse of hair follicle immune privilege plays a key role. Higher incidence rate in the female population and increased overall risk of other autoimmune disorders militate in favor of autoimmune hypothesis. Antibodies against multiple components of hair follicles almost exclusively attack in anagen phase, where melanogenesis takes place. It suggests involvement of melanogenesis-associated autoantigens as a target epitope. Some investigators believed that alopecia areata is not a truly autoimmune disease but is only 'consistent with' autoimmune mechanisms. High frequency of a positive family history up to 42% may reflects the contribution of heredity factors. In addition, no specific target autoantigen has been identified so far, and autoantibodies to hair follicle-associated antigens are detectable in normal individuals.

NK Cells as Potential Targets for Immunotherapy in Endometriosis.

Endometriosis is a common gynecological disease defined by the presence of endometrial-like tissue outside the uterus, most frequently on the pelvic viscera and ovaries, which is associated with pelvic pains and infertility. It is an inflammatory disorder with some features of autoimmunity. It is accepted that ectopic endometriotic tissue originates from endometrial cells exfoliated during menstruation and disseminating into the peritoneum by retrograde menstrual blood flow. It is assumed that the survival of endometriotic cells in the peritoneal cavity may be partially due to their abrogated elimination by natural killer (NK) cells. The decrease of NK cell cytotoxic activity in endometriosis is associated with an increased expression of some inhibitory NK cell receptors. It may be also related to the expression of human leukocyte antigen G (HLA-G), a ligand for inhibitory leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) receptors. The downregulated cytotoxic activity of NK cells may be due to inhibitory cytokines present in the peritoneal milieu of patients with endometriosis. The role of NK cell receptors and their ligands in endometriosis is also confirmed by genetic association studies. Thus, endometriosis may be a subject of immunotherapy by blocking NK cell negative control checkpoints including inhibitory NK cell receptors. Immunotherapies with genetically modified NK cells also cannot be excluded.

Isolation and culture of human primary keratinocytes-a methods review.

Keratinocyte culture is a necessary and widely used tool in a variety of experimental dermatological and biomedical studies. Literature search has revealed a variety of different protocols of human primary keratinocyte isolation and culture. Therefore, the aim of this paper was to review and summarize current trends in human primary keratinocyte culture techniques. We present data on the most popular and effective methods of human keratinocyte isolation and cultivation obtained from screening of 945 papers published during the last 10 years.

Recurrent miscarriage is associated with increased ghrelin mRNA expression in the endometrium- a case-control study.

Ghrelin has been found to be expressed in the human endometrium. Emerging evidence links ghrelin and its receptor with the reproductive system. Certain associations between ghrelin and angiogenesis have also been established. The aim of this small case-control study was to quantify and compare the expression of mRNA encoding ghrelin, ghrelin receptor (GHS-R), vascular endothelial growth factor A (VEGF A) and its receptors (VEGFR1-3) in the endometrium of women with recurrent miscarriage compared to parous controls. Correlations between the expression of particular genes were also investigated. Endometrial samples were obtained during the secretory phase of the menstrual cycle from 15 women with a history of recurrent miscarriage (first trimester pregnancy loss without a known cause) and 10 healthy parous controls. Ghrelin, GHS-R, VEGF A and VEGFR1-3 mRNA expression was analyzed by quantitative RT-PCR. The expression of mRNA for ghrelin and VEGF A was significantly higher in the study group than the control group. In the control group, the expression of ghrelin mRNA was positively correlated with the expression of VEGF A and VEGFR1 mRNA. In the study group, no such associations were observed. These results show that the expression of mRNA for ghrelin and VEGF A may be increased in the endometrium of women with recurrent miscarriage thus suggesting that ghrelin may play a role in the pathogenesis of recurrent miscarriage.

A Role of NKR-P1A (CD161) and Lectin-like Transcript 1 in Natural Cytotoxicity against Human Articular Chondrocytes.

Normal cartilage cells are susceptible to lysis by NK cells. This phenomenon may play a role in immune cartilage destruction; however, the mechanisms of chondrocyte recognition by NK cells remain poorly understood. Therefore, the aim of this study was to reveal a possible role of NKR-P1A/lectin-like transcript 1 (LLT1) interaction in NK cell-mediated cytotoxicity against normal human articular chondrocytes. Chondrocytes were isolated from articular cartilage obtained during talonavicular joint surgery. PBMC or polyclonal NK cells isolated from normal donors served as effector cells. Cell-mediated cytotoxicity against chondrocytes was evaluated by means of 18-h 51Cr-release assay. Specific mRNA expression was evaluated by classical and quantitative RT-PCR, and proteins were detected by Western blot analysis. We found that lysis of articular chondrocytes by PBMC or polyclonal NK cells was potentiated by stimulation with IL-2. Stimulation of effector cells with IL-2 downregulated mRNA expression of inhibitory NKR-P1A NK cell receptor, and blocking of NKR-P1A with specific mAbs resulted in increased chondrocyte killing. Chondrocytes constitutively expressed LLT1, a ligand of NKR-P1A. LLT1 expression by chondrocytes could be upregulated by IL-1α and TNF. Chondrocyte treatment with IL-1α resulted in their increased resistance to killing by natural cytotoxic cells. This could be reversed by blocking of NKR-P1A. These results show that susceptibility of normal articular chondrocytes to lysis by NK cells is modulated by NKR-P1A/LLT1 interactions. Thus, NKR-P1A/LLT1 interaction might provide some novel target for therapeutic interventions in the course of pathological cartilage injury.

The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis.

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.

Biological and Clinical Significance of Human NKRP1A/LLT1 Receptor/Ligand Interactions.

Killer cell lectin-like receptors (KLRs) are C-type lectin-like glycoproteins encoded by genes clustered in the natural killer gene complex (NKC) located on the short arm of human chromosome 12. In addition to the NKG2 subfamily, the NKC includes a less characterized group of genes coding for NKRP1 receptors and their ligands of the C-type lectin (CLEC) subfamily. Among this group, the best recognized is the NKRP1A/LLT1 pair encoded respectively by the KLRB1 and CLEC2D genes. Both molecules are type II transmembrane-signaling glycoproteins with an extracellular C-type lectin domain. NKRP1A is predominantly expressed on NK cells, where it acts as an inhibitory receptor. However, it stimulates T cells, which results in release of IL-17 and inflammatory cytokines. Triggering LLT1 on NK cells stimulates IFN-γ production. Similarly, it stimulates activation of B cells. LLT1 is also expressed by osteoblasts and chondrocytes and inhibits bone degradation. Expression of LLT1 by tumor cells may facilitate their escape from NK cell surveillance. On the other hand, NKRP1A may be involved in activation of T and B lymphocytes in the course of inflammatory reactions and pathogenesis of autoimmune disorders. Thus, the NKRP1A/LLT1 receptor/ligand system appears to be a new therapeutic target that may be useful in the treatment of cancer as well as some autoinflammatory disorders.