Expression of Killer Cell Immunoglobulin-like Receptors (KIR) in Sex-associated Malignancies

@#Introduction: Sex shapes immune response with possible consequence on tumor immune escape. Acute lymphoblastic leukemia (ALL) predominates in males while ovarian cancer (OC) occurs in females. NK cells essential for tumor killing may have male preponderance. Association of sex, NK cell activity and malignancies is unclear. We hypothesize that sex differentially affects KIR expressions in sex-biased cancers. Method: Expression of inhibitory (KIR2DL1-5 and KIR3DL1-3) and activating (KIR2DS1-2 and 4-5 and KIR3DS1) genes in B-, T-cell ALL, OC and normal controls were determined by reverse-transcription polymerase-chain-reaction. Result: All normal males (but not females) expressed the framework genes and generally maintained haplotype A, except KIR3DL1. Normal females expressed more activating KIRs. Frequencies of KIR2DL1, 2DL4 and 2DS2 were significantly reduced among ovarian cancer patients. Sex difference in frequencies of KIR expression was not detected in ALL as majority were undetectable except framework gene KIR3DL2, was more frequent among T-ALL. Conclusion: Cancers may be associated with reduced KIR expression and influence of sex requires investigation.

Immune reconstruct regularity profile of KIR2DL1 and KIR3DL1 in unrelated-donor allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

Objective@#To investigate the immune reconstruct regularity profile of KIR2DL1 and KIR3DL1 in unrelated-donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) with KIR-AA genotype.@*Method@#75 donor-recipient pairs were performed by KIR genotying using PCR-SSP, and all donors were identified with KIR-AA genotype. Dynamic detections (including unrelated-donor on the day of transplantation and the recipient each month post allo-HSCT) of the expression of KIR2DL1/3DL1 on NK cell and mRNA level were performed in 291 cases using flow cytometry (FCM) and real-time fluorescent quantitation PCR (RT-qPCR) .@*Result@#①The median expression of KIR2DL1 in unrelated-donor on transplant’s day was 21.60%, the median expression of KIR2DL1 in recipient 1M, 2M, 3M and 3-6M after transplantation were 7.40%, 12.00%, 16.92%, 17.64% respectively. The median expression of KIR2DL1 in unrelated-donor on transplant’s day was 265.14 copies/10 000abl copies, the median expression of KIR2DL1 in recipient 1M, 2M, 3M, 3-6M, 6-9M, 9-12M after transplantation were 332.17, 438.31, 723.25, 414.17, 180.76 and 234.67 copies/10 000abl copies respectively. The median expression of KIR2DL1 on NK cells and mRNA level gradually increased at all time points after transplantation, and reached the highest expression at 3 months after transplantation. But mRNA expression levels increased earlier than NK cell membrane proteins. ②The median expression of KIR3DL1 in unrelated-donors on transplant’s day was 18.56%, the median expression of KIR3DL1 in recipient 1M, 2M, 3M, 3-6M after transplantation were 23.83%, 22.57%, 23.02%, 21.60% respectively. The median expression of KIR3DL1 in unrelated-donor on transplant’s day was 572.29 copies/10 000abl copies, the median expression of KIR3DL1 in recipient 1M, 2M, 3M, 3-6M, 6-9M, 9-12M after transplantation were 1 233.74, 1 140.42, 876.73, 1 057.07, 739.02 and 514.43 copies/10 000abl copies respectively. The median expression of KIR3DL1 on NK cells and mRNA level were higher than donors at 1 month after transplantation, and stable expression at all time points after transplantation, so mRNA and NK cell membrane proteins expression increased at the same time.@*Conclusion@#The immune reconstruct regularity of KIR2DL1 and KIR3DL1 gene were different, which provided an experimental basis for selecting the best time to detect the expressions of KIR2DL1 and 3DL1 after transplantation.

Distribution of donor-specific aKIR after unrelated allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

Objective@#To analyze the distribution and proportion of donor-specific activated killer cell immunoglobulin like receptor (aKIR) genes and their clinical application values in unrelated allogeneic hematopoietic stem cell transplantation (allo-HSCT) .@*Methods@#Retrospective analyses of KIR genotyping using polymerase chain reaction with sequence specific primers (PCR-SSP) were performed in 216 pairs of donors and recipients.@*Results@#The frequency of donor-specific KIR genes was 53.7% (116/216) in 216 patients receiving unrelated allo-HSCT, with the frequency of 78.3% (112/143) in the KIR genes mismatched group and 5.5% (4/73) in matched group. Of the 116 patients with detectable donor-specific KIR genes, 99.1% (115/116) patients had various donor-specific aKIR genes. Among 55 pairs of donors’ KIR-Bx genotype and patients’ KIR-AA genotype group, the most commonly observed genotypes were Bx1, Bx2, Bx3, Bx4, in which the donor-specific KIR genes were respectively KIR 3DS1, 2DL5A, 2DS5, 2DS1; KIR 3DS1, 2DL5A, 2DS3, 2DS1; KIR 2DS2, 2DL2; KIR 2DS2, 2DL2, 3DS1, 2DL5A, 2DS5, 2DS1. Of 44 pairs of donors’ KIR-AA genotype and patients’ KIR-Bx (AB) genotype group, 36.4% (16/44) recipients had donor-specific KIR2DS4 (FUL) gene. In 143 pairs of KIR mismatched group, the frequencies of donor-specific KIR genes were KIR2DS1 (35.7%) , KIR3DS1 (32.9%) , KIR2DS5 (29.4%) , KIR2DS4 (FUL) (25.9%) , KIR2DL2 (25.2%) , KIR2DS2 (24.5%) , KIR2DS3 (21.7%) and KIR3DL1 (8.4%) , respectively.@*Conclusion@#The donor-specific aKIR genes mainly existed in KIR mismatched group after unrelated allo-HSCT, and the different pairs of donors’ and patients’ KIR genotypes led to the diverse donor-specific aKIR. But there were higher specific aKIR genes in higher frequency of KIR AA, Bx1, Bx2, Bx3, Bx4 genotypes. All these can provide the experimental basis for studying the role of the donor-specific aKIR genes on the prognosis of HSCT.

The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis

OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions. .

Importância das disparidades genéticas nos genes HLA e KIR na resposta de pacientes submetidos ao transplante alogênico de células progenitoras hematopoiéticas para o tratamento de doenças onco-hematologicas / Importance of genetic differences in HLA and KIR genes in the response of patients undergoing allogeneic hematopoietic stem cell transplantation for treatment of onco-hematological diseases

No organismo humano, as moléculas HLA (Human Leukocyte Antigens) são proteínas expressas na superfície da maioria das células nucleadas e são codificadas por genes localizados no braço curto do cromossomo 6 na região do Complexo Principal de Histocompatibilidade (CPH). Essas proteínas são caracterizadas pelo alto grau de polimorfismo, e também faz a ligação com receptores KIR (Immunoglobulin-like Receptors), expressos nas células Natural Killer. Os receptores KIR, que reconhecem moléculas do complexo HLA de classe I, estão entre os principais receptores inibidores dos linfócitos NK. Células infectadas por vírus e células tumorais perdem ou têm diminuída a expressão de moléculas HLA de classe I e, por isso, são eliminadas pela ausência de ligação entre moléculas HLA e receptores KIR inibitórios. Atualmente, muitos estudos têm destacado a importância dos genes KIR e HLA no Transplante de Células Progenitoras Hematopoiéticas (TCPH). O TCPH é o tratamento de escolha para muitas doenças hematológicas e dependem de vários fatores incluindo o estágio da doença, o regime de condicionamento, a fonte de células, o grau de identidade HLA entre doador e receptor e o desenvolvimento da doença do enxerto contra o hospedeiro (DECH). Estudos recentes indicam que a presença de células NK alorreativas no enxerto representa um fator favorável à recuperação de pacientes, uma vez que essas células têm a capacidade de eliminar células tumorais residuais pela ausência ou diminuição da expressão de moléculas HLA e sem a indução da DECH. Também outros fatores podem estar envolvidos na resposta pós-transplante, como a presença e ausência de determinados alelos HLA e genes KIR, os quais podem estar ligados à melhor ou pior resposta pós-transplante.

In the human organism, the HLA (human leukocyte antigens) are proteins expressed on the surface of most nucleated cells and are encoded by genes located on the short arm of chromosome 6 in the region of the Major Histocompatibility Complex (MHC). These proteins are characterized by a high degree of polymorphism, and also make the connection with KIR (Immunoglobulin-like Receptors), expressed in Natural Killer cells. KIR receptors that recognize HLA molecules of class I are among the major inhibitory receptors of NK-cells. Virus infected cells and tumor cells have lost or diminished expression of HLA class I molecules and therefore are eliminated by the absence of binding between HLA molecules and inhibitory KIR receptors. Currently, many studies have highlighted the importance of KIR and HLA genes in Hematopoietic Stem Cell Transplantation (HSCT). HPCT is the treatment of choice for many hematological malignancies and depends on various factors including stage of disease, the conditioning regimen, the source of cells, the degree of identity between donor and recipient HLA and development of chronic graft-versus-host (GVHD). Recent studies indicate that the presence of alloreactive NK cells in the graft is a factor aiding the recovery of patients, since these cells have the ability to eliminate residual tumor cells by the absence or diminution of expression of HLA molecules and without inducing GVHD.

Frequency of Killer Cell Immunoglobulin-like Receptors (KIRs) in Korean Patients with Chronic HCV Infection

Natural killer (NK) cells play an important role in innate immunity, especially in the response to viral infections, such as hepatitis C virus (HCV). Killer cell immunoglobulin-like receptors (KIRs) are the primary receptors of NK cells that mediate innate immunity. KIRs are also involved in acquired immunity, because some KIRs are expressed on the surface of certain subsets of T cells. In this study, the frequency of KIR genes, HLA-C allotypes, and combinations of KIR genes with their HLA-C ligands were evaluated in two different groups of the Korean population: controls and patients with chronic HCV infection. The study population consisted of 147 Korean patients with chronic HCV infection. The frequency of KIR2DS2 in patients with chronic HCV infection was 9.5% which was significantly lower than 19.5% of the control (P < 0.01). However, there were no significant differences in the frequency of other KIR genes, HLA-C allotypes or different combinations of KIR genes with their HLA-C ligands. This study can contribute to the further prospective study with a larger scale, suggesting the assumption that KIR2DS2 might aid in HCV clearance by enhancing both the innate and acquired immune responses of people in Korea.

Correlation between killer cell immunoglobulin-like receptors genes and pre-eclampsia / 中华妇产科杂志

objective To analyze the killer cell immunoglobulin-like receptors(KIR)gene polymorphism of pre-eclampsia patients and approach the correlation between KIR genes and pre-eclampsia.Methods The KIR gene polymorphisms of 71 pre-eclampsia patients and 100 healthy pregnant women were detected by PCR-SSP.The KIR2DL4 mRNA level in placentas from pre-eclampsia and gestational normal pregnancies were quantified by real time RT-PCR.Forty pre-eclampsia patients and 38 healthy pregnant women were detected for single nucleotide polymorphisms(SNP)in the gene coding and joint areas between introns and extrons by directly sequencing techniques of KIR2DL4 genomic DNA.Finally,all alleles and genotypes of KIR2DL4 gene were case-control studied.Result Distributions of some relatively activating KIR genotypes shewed a significant association with pre-eclampsia.Real-time RT-PCR showed that KIR2DL4 mRNA can be measured both in placenta of women with pre-eclampsia being of pre-eclampsia waft significantly lower than that of normal pregnancy.only as much as 0.276 times that of controls.We identified 18 polymorphisms,of which,7 were first reported.But no significant differences in genotype distributions or allele frequencies were observed in these SNPs between cases and controls.Conclusion The distributions of some relatively activating KIR genotypes showed a significant association with pre-eclampsia,which indicates that the polymorphism of KIR genes may be associated with the genetic predisposition to pre-eclampsia.And because the expression of KIR2DL4 mRNA in the placentas of cases wag significantly lower than control group,it is speculated that the decrease of KIR2DL4 expression in placenta may participate in the pathogenesis of pre-eclampsia.