KIR3DL1+HLA-B Bw4Ile80 and KIR2DS1+HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population

Contribution of killer cell immunoglobulin-like receptors (KIR) and their human leucocyte antigen (HLA) class I ligands in the pathogenesis of autoimmune diseases has been shown in several studies. In this study, the possible association of KIR genes, their known HLA ligands and compound KIR/HLA genotypes with ankylosing spondylitis (AS) was assessed. Combined KIR/HLA ligand genotyping was performed by a polymerase chain reaction-sequence-specific primers assay in 35 Iranian patients with AS, and genotypes were compared to those in 200 healthy individuals. The frequencies of telomeric cluster genes KIR2DL5A, KIR2DS1 and KIR3DS1 were significantly increased in AS patient group (P(c) = 0.0082, P(c) = 0.0195 and P(c) = 0.0328, respectively). Conversely, HLA-Bw4 ligand (the presence of one or more -B Bw4(Ile80) , -B Bw4(Thr80) and -A Bw4 epitopes) (P(c) = 0.0004) and HLA-B Bw4(Ile80) (P(c) = 0.053) were less frequent in these patients. Meanwhile, compound KIR/HLA genotype analyses revealed lower frequency of KIR3DL1+HLA-B Bw4(Ile80) (P(c) = 0.0343) and higher frequency of KIR2DS1+HLA-C2 (P(c) = 0.0308) combinations in patients with AS than in controls. In addition, the genotypes iKIR+HLA > aKIR+HLA (P(c) = .0308) and iKIR+HLA > aKIR (P(c) = 0.0258) were statistically less common, and genotypes iKIR+HLA = aKIR+HLA (P(c) = 0.0081) and iKIR+HLA < aKIR (P(c) = 0.077) were more common in patient group. Our findings suggest a role for excessive or inappropriate NK cell activation through 'KIR/HLA' system in AS disease.     

Possible KIR-driven genetic pressure on the genesis and maintenance of specific HLA-A,B haplotypes as functional genetic blocks

The HLA genomic structure underlines the permanence of fixed haplotypes transmitted in blocks as allelic combinations. One of the most discussed concerns is how and why such a strong linkage between HLA alleles has been maintained for so long. We hypothesized a possible KIR-driven pressure in the genesis of specific HLA-A,B haplotypes. Certain HLA-A and -B molecules are ligands for the same KIR receptors through the Bw4 binding motif spanning residues 77-83 in the α1 domain. We analyzed the HLA-A and -B genomic types of 9897 Caucasian people (3533 newborns and 6364 adults) subdividing them according to the presence/absence of the HLA-B Bw4 serological epitope. For each HLA-B Bw4- and Bw6-cross-reactive group, we evaluated the presence/absence of HLA-A ligands for KIR3DL1 (HLA-A*23, HLA-A*24, HLA-A*32) and KIR3DL2 (HLA-A*03, HLA-A*11). The frequency of HLA-A KIR ligands significantly increased moving from the HLA-B Bw4/Bw4 to the HLA-B Bw4/Bw6 and the HLA-B Bw6/Bw6 groups among both newborns and adults (P<0.0001). Here, we suggest that, when the HLA-B KIR-ligand motif is lacking, the HLA-A KIR-ligand might have a vicarious role in controlling the natural killer cell-mediated innate immune response. Basing upon this compensatory function in the engagement of KIR receptors, we hypothesize that specific HLA-A,B ancestral haplotypes were generated.     

Genetic profile of KIR and HLA in southern Chinese Han population

KIR and their HLA ligands are encoded by two of the most diverse gene families in the human genome. The function of KIR on the NK cell is highly dependent on the normal expression of class I HLA on the target cell. Previous population studies in southern Chinese have been focused on the KIR framework genes and genotypes but little is known about the compound profiles of KIR/HLA. The present study examined 503 unrelated individuals from southern Chinese Han population for the polymorphism of KIR and class I HLA genes. All 16 KIR genes were detected in the study population and the four framework genes KIR3DL2, 3DL3, 3DP1, and 2DL4 were present in all individuals. Thirty unique KIR gene profiles were found reflecting a rather limited number of KIR haplotypes in this population. KIRAA1 was the most common profile observed in 54.7% of the samples. Among the AA1 individuals, 15.6% were homozygous for the deleted KIR2DS4. Haplotype A (74.8%) was more common than haplotype B (25.2%). HLA-C1 was a much more common ligand for 2D KIRs than C2. Bw4-80I, Bw4-80T, and the Bw4-bearing HLA-A alleles were detected at similar frequencies. The matched KIR+HLA pairs 2DL2/3+C1 (98.1%), 3DL1+Bw4 (73.3%), 3DL2+A3/11 (60.0%) were the most common ones whereas 3DS1+Bw4-80I was the least common (9.4%). A total of 193 unique compound profiles of KIR–HLA were identified in 480 informative individuals, 130 of the profiles being detected only once. The study provided a comprehensive analysis of the KIR/HLA profiles in southern Chinese in regards of the presence/absence of KIR genes, HLA ligands, matched KIR+HLA pairs, and KIR/HLA compound profiles. The results could help to better understand the role played by KIR/HLA interaction in associated diseases and clinical transplantation in southern Chinese.     

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4(+) T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the 'B' haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4(+) T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.     

K562细胞转染HLA-B分子对NK细胞杀伤功能的影响

为了研究不同HLA B分子对NK细胞杀伤活性的影响 ,我们分别构建pcDNA3 HLA B 390 5 2、B 2 70 4、B 5 1 0 2 2基因真核表达载体 ;借助脂质体将各质粒转染入K5 6 2细胞 ,经G4 1 8筛选 ,分别获得阳性表达细胞株 ;并应用LDH法检测转染细胞对不同个体外周血NK细胞杀伤活性的抑制效应。结果显示 :与转染了空质粒的对照组相比 ,外周血NK细胞对K5 6 2 B39的杀伤率无明显影响 ,而对K5 6 2 B2 7,K5 6 2 B5 1的杀伤率降低。当使用针对NK细胞受体KIR3DL1的单抗DX9封闭NK细胞后 ,此抑制效应大部分消失。提示靶细胞表达HLA Bw4分子可明显抑制NK细胞的杀伤效应 ,而表达HLA Bw6分子对NK细胞杀伤功能无明显影响     

中国HIV-1感染者KIR基因多态性与疾病进展关系的研究

目的 通过对中国HIV-1感染缓慢进展者(TP)和典型进展者(TP)杀伤细胞免疫球蛋白样受体(KIR)基因频率的研究,探讨中国人群K/R基因多态性与HIV-1感染者疾病进程的关系.方法 采用聚合酶链反应-序列特异性引物(PCR-SSP)技术,分析43例HIV-1感染SP和38例TPKIR基因位点的多态性.结果 SP组和TP组的KIR2DS3等位基因频率分别为3.6%和14.2%,SP组显著低于TP组,两组的KIR2DS3等位基因频率差异具有统计学意义(P=0.018,OR=0.210,95%CI=0.053-0.833);SP组的活化性KIR基因数目低于TP组,但差异无统计学意义(P=0.208).结论 低表达KIR2D53基因可能是延缓中国HlV-1感染者疾病进程的保护因素之一.     

KIR及HLA-A、B基因多态性与急性淋巴细胞白血病的相关性

目的探讨急性淋巴细胞白血病患者的杀伤细胞免疫球蛋白样受体（killer cell immunoglobulin-like receptors,KIR）和人类白细胞抗原（human leukocyte antigen,HLA）HLA-A、B等位基因多态性。方法采用Luminex流式技术-序列特异性寡核苷酸探针反向杂交（flow cytometry-sequence specific oligonucleotide probe,FLOW-SSOP）方法对内蒙地区48例急性淋巴细胞白血病患者HLA-A、B等位基因多态性进行分析,PCR-SSP技术进行KIR抑制基因的低分辨率检测。以北方地区健康群体资料作为正常对照。结果 （1）在急性淋巴细胞白血病中HLA-A＊31XX,A＊6901等位基因频率高于对照组（1.955%,0.071%）,差异有统计学意义（P〈0.05）;A＊33XX等位基因频率低于对照组（5.825%）,差异有统计意义（P〈0.05）;（2）在HLA-B等位基因中,急性淋巴细胞白血病B＊07XX,＊27XX,＊38XX,＊41XX,＊49XX,＊59XX等位基因频率高于对照组（2.069%,0.968%,0.702%,0.091%,0.051%,0.061%）,差异有统计学意义（P〈0.05）;其中HLA-B＊59XX的相对危险度高（RR=35.156）,其它等位基因频率在两组之间无显著性差异。在急性白血病患者中,高频率KIR基因有KIR3DP1,2DP1,2DL1,2DL3,3DL1、2DL5,2DS4及3DS1。急性白血病组3DL1基因型频率比对照组的显著降低。结论 HLA-A＊31XX,A＊6901;B＊07XX,B＊27XX,B＊38XX,B＊41XX,B＊49XX,B＊59XX;等位基因与ALL相关联,有遗传易感作用。HLA-B＊59XX等位基因携带者,可能患ALL的危险度增高（RR=35.156）KIR3DL1和2DS4均与ALL呈关联。     

KIR‐HLA‐A and B alleles of the Bw4 epitope against HIV infection in discordant heterosexual couples in Chaco Argentina

Activating and inhibitory killer immunoglobulin‐like receptors (KIR) and their ligands HLA‐Bw4 (loci A and B) were studied by way of establishing whether they can contribute to protection against HIV‐1 infection in highly exposed and persistently seronegative (HESN) patients. Twenty‐three HIV‐1 serodiscordant heterosexual couples, 100 HIV‐1⁺ patients and 200 healthy individuals were included in this retrospective case–control study. HLA typing was performed by means of PCR followed by sequence‐specific oligonucleotide probe reverse hybridization. KIR3DL1 and KIR3DS1 were studied by PCR sequence‐specific primers. The frequency of KIR3DS1(3DS1/3DL1)‐Bw4 combination was significantly higher in HESN patients versus the discordant couples (P = 0·0003) and HIV‐1⁺ patients (P = 0·0001). Conversely, the KIR3DL1/KIR3DL1 homozygosity was significantly decreased in HESN patients versus the discordant couples (P = 0·00003), and HIV‐1⁺ patients (P = 0·00066). The frequency of HLA‐A*32 and HLA‐B*44 was higher in HESN versus their discordant couples (P = 0·009; P = 0·049), and HIV‐1⁺ patients (P = 0·00002; P = 0·0001). This had greater significance in combination with KIR3DS1 (3DS1/3DL1). KIR3DS1(3DS1/3DL1) could have a greater effect on protection against HIV‐1 infection in HESN patients when bound to a specific HLA allele, in this case HLA‐A*32 and HLA‐B*44, both Bw4 alleles. The differences probably arise both in the HLA alleles and in the subtypes of KIR receptors depending on the ethnic group studied.     

HLA-B*44 Is Associated with a Lower Viral Set Point and Slow CD4 Decline in a Cohort of Chinese Homosexual Men Acutely Infected with HIV-1

HLA class I alleles have been shown to have differential impacts on the viral load and the outcome of HIV-1 disease progression. In this study, HLA class I types from residents of China with acute HIV-1 infection, diagnosed between 2006 and 2011, were identified and the association between expression of individual HLA alleles and the level of the set point viral load was analyzed. A lower level of set point viral load was found to be associated with the Bw4 homozygote on HLA-B alleles. B*44 and B*57 alleles have also been found to be associated with lower set point viral load. The set point viral load of B*44-positive individuals homozygous for Bw4 was significantly lower than that of B*44-negative individuals homozygous for Bw4 (P = 0.030). The CD4 count declined to <350 in fewer B*44-positive individuals than B*44-negative individuals (X² = 7.295, P = 0.026). B*44-positive individuals had a lower magnitude of p24 pool-specific T cell responses than B*44-negative individuals homozygous for Bw4, though this was not statistically significant. The p24 pool-specific T cell responses were also inversely correlated with lower viral load (r_s = −0.88, P = 0.033). Six peptides within p24 were recognized to induce the specific-T cell response in B*44-positive individuals, and the peptide breadth of response was same as that in B*44-negative individuals homozygous for Bw4, but the median magnitude of specific-T cell responses to the recognized peptides in B*44-positive individuals was lower than that in B*44-negative individuals homozygous for Bw4 (P = 0.049). These findings imply that weak p24-specific CD8⁺ T cell responses might play an important role in the control of HIV viremia in B*44 allele-positive individuals. Such studies might contribute to the development of future therapeutic strategies that take into account the genetic background of the patients.     

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-B*2705

We have solved the crystal structures of three HLA-B*2705-peptide complexes with the immunodominant viral peptides: EBV EBNA3C 258-266 (RRIYDLIEL), influenza (flu) nucleoprotein NP383-391 (SRYWAIRTR), and HIV gag 264-273 (KRWIILGLNK). Long-term non-progression during HIV infection has been associated with presentation by HLA-B*2705, and T cell recognition, of the highly immunodominant KRWIILGLNK peptide. The tight hydrogen-bonding network observed between the HLA-B*2705 B-pocket and the peptide P2 arginine guanadinium anchor explains why mutation of this residue during HIV infection results in loss of peptide binding, immune escape and progression to AIDS. Prominent, solvent-exposed structures within these peptides may participate in generating T cell responses to these immunodominant epitopes. In the HLA-B*2705 complex with flu NP383-391, the amino acid side chains of residues 4, 7 and 8 are solvent-exposed whilst in the HIV decamer, the main-chain bulges into the solvent around P7. Thus, HLA-B*2705 presents viral peptides in a range of conformations. Tetrameric complexes of HLA-B*2705 with the HIV and flu but not EBV peptides bound strongly to the killer-Ig-like receptor (KIR)3DL1. Substitution of EBV P8 glutamate to threonine allowed recognition by KIR3DL1. In the HLA-B*2705-EBV structure the P8 glutamate side chain is solvent-exposed and may inhibit KIR3DL1 binding through electrostatic forces.     

Interaction of NK inhibitory receptor genes with HLA-C and MHC class II alleles in Hepatitis C virus infection outcome

Natural killer cells are important in innate defense against viral infections. The interplay between stimulatory and inhibitory natural killer cell receptors and their corresponding human leukocyte antigen ligands are known to influence the outcome of acute Hepatitis C virus infection. Frequencies of NK receptor genes (8 inhibitory, 6 activating and 2 pseudogenes) and HLA class II alleles (DRB1, DQB1) were analyzed in 160 Puerto-Rican American drug users with Hepatitis C virus infection; 121 had chronic viremia (CV) and 39 were spontaneous clearance (SC). We further ruled out genetic stratification using short tandem repeats. Interaction between KIR gene receptor 2DL3/2DL3 and its ligand, C1/C1 of HLA-Cw alleles and spontaneous clearance was confirmed (p=0.03, OR=3.05). We also found a new interaction between the KIR receptor gene 2DL3 with HLA-DRB1*1201 (p=0.0001, OR=22) associated with SC, and an association of HLA DQB1*0501 (p=0.05, OR=0.30) with CV. Our findings suggested a role for MHC class II alleles in Hepatitis C virus peptide presentation to T cells together with NK ligand interaction involving pathways that will be useful for the development of immunotherapeutic interventions.     

HLA-B polymorphism in Japanese HIV-1-infected long-term surviving hemophiliacs

Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency virus (HIV) in early 1980s through contaminated blood products. In 1995, a cohort of HIV-infected, asymptomatic patients with hemophilia was set up for follow-up study. Although the patients met the criteria for long-term non-progressor (LTNP) at the entry to the cohort, some of them later developed lymphopenia during five more years of observation. We collected blood samples from 80 long-term survivors; 42 of them did not require antiviral therapy, but the rest were under treatment. Analysis of HLA-B genotype revealed that carriers of known HIV-resistant alleles such as HLA-B*5701, B*5801, and alleles of B27 antigenic group were not increased in frequency, but that HLA-B*1507 was increased in the cohort (6.25% vs. 1.03%, OR = 6.40, p = 0.039). We also observed the decrease in carriers of HLA-B*5401 (3.75% vs. 14.95%, OR = 0.22, p = 0.016). HLAB* 5401 is a relatively common allele in East Asian populations and belongs to the same B22 antigenic group as B55 and B56 which were reported to associate with rapid progression. Our data indicated that HLA class I is one of the host factors involved in the retardation of HIV disease progression as also reported in the previous studies; however, the alleles associated with this resistance were not the same because of divergent host genetic background.     

Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1

KIR3DL1 is a natural killer (NK) cell receptor that recognizes the Bw4 epitope of human leukocyte antigen (HLA) class I molecules. Following hematopoietic stem cell transplantation for patients lacking Bw4, KIR3DL1‐expressing NK cells from Bw4‐positive donors can be alloreactive and eliminate tumor cells. However, KIR3DL1 alleles having T instead of C at nucleotide 320 (encoding leucine 86 instead of serine 86) are not expressed on the cell surface. Thus, not all individuals testing positive for KIR3DL1 are optimal donors for Bw4‐negative recipients. Therefore, we developed a method for genotyping codon 86, which was validated by its perfect correlation with NK cell phenotype for 100 donors of diverse KIR3DL1/S1 genotype. We typed 600 donors and found that ～12.2% had the KIR3DL1 gene, but did not express cell‐surface KIR3DL1. By contrast, high‐expressing allotypes were identified when haplotypes from four families with duplicated KIR3DL1/S1 genes were characterized at high resolution. Identifying donors who have KIR3DL1 but lack cell‐surface KIR3DL1 would refine donor selection. With this technique, the number of individuals identified who may not be optimal donors for Bw4‐negative patients increases by threefold, when compared with standard methods. Taken together, we propose that allele typing of killer cell Ig‐like receptor (KIR) polymorphisms should become a standard practice when selecting donors.     

HLA-A and DPB1 loci confer susceptibility to Graves' disease.

To investigate HLA-linked genetic factors involved in the pathogenesis of Graves' disease, 76 patients and 317 healthy controls in the Japanese population were examined for HLA-A, B, C, DR, and DQ specificities by serologic typing and for HLA-DPB1 alleles by DNA typing by using the PCR-SSOP method. The frequencies of HLA-A2, B46, Cw11, and DPB1*0501 were increased and those of HLA-A24, B7, Bw52, and DR1 were decreased in the patients. The increased frequencies of HLA-A2 and DPB1*0501 in the patients were statistically significant when the corrected p value (pc) was applied (pc < 0.02 and pc < 0.002, respectively). ORs for a risk to develop the disease were calculated among individuals positive for DPB1*0501 and/or HLA-A2, and the highest OR (10.5) was observed in individuals possessed both DPB1*0501 and HLA-A2. This observation suggests a synergic involvement of a HLA class II allele (DPB1*0501) and an HLA class I allele (HLA-A2) in the pathogenesis of Graves' disease.     

Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans

A small proportion of human immunodeficiency virus-1 (HIV-1) infected individuals, termed HIV-1 controllers, suppress viral replication to very low levels in the absence of therapy. Genetic investigations of this phenotype have strongly implicated variation in the class I major histocompatibility complex (MHC) region as key to HIV-1 control. We collected sequence-based classical class I HLA genotypes at 4-digit resolution in HIV-1-infected African American controllers and progressors (n = 1107), and tested them for association with host control using genome-wide single nucleotide polymorphism data to account for population structure. Several classical alleles at HLA-B were associated with host control, including B*57:03 [odds ratio (OR) = 5.1; P= 3.4 × 10(-18)] and B*81:01 (OR = 4.8; P= 1.3 × 10(-9)). Analysis of variable amino acid positions demonstrates that HLA-B position 97 is the most significant association with host control in African Americans (omnibus P = 1.2 × 10(-21)) and explains the signal of several HLA-B alleles, including B*57:03. Within HLA-B, we also identified independent effects at position 116 (omnibus P= 2.8 × 10(-15)) in the canonical F pocket, position 63 in the B pocket (P= 1.5 × 10(-3)) and the non-pocket position 245 (P= 8.8 × 10(-10)), which is thought to influence CD8-binding kinetics. Adjusting for these HLA-B effects, there is evidence for residual association in the MHC region. These results underscore the key role of HLA-B in affecting HIV-1 replication, likely through the molecular interaction between HLA-B and viral peptides presented by infected cells, and suggest that sites outside the peptide-binding pocket also influence HIV-1 control.     

Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA‐A3 and A11 in vivo

Although HLA‐A3 and A11 have been reported to be ligands for KIR3DL2, evidence for any in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, previously associated (lower risk) with activating KIR genes. KIR3DL2*001 was increased in patients (odds ratio (OR) = 2.04; p = 0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA‐A3 or A11 (OR = 3.76, p = 0.013), providing the first evidence that HLA‐A3 and A11 may interact with KIR3DL2 in vivo. The nonsynonymous single nucleotide polymorphism 1190T (rs3745902) was associated with protection (OR = 0.52, p = 0.018). This SNP results in a threonine‐to‐methionine substitution. Individuals who have methionine in this position exhibit a lower percentage of KIR3DL2‐positive natural killer (NK) cells and also lower intensity of KIR3DL2 on expressing natural killer cells; additionally, we show that the expression of KIR3DL2 is independent of other killer cell immunoglobulin‐like receptors. Pemphigus foliaceus is a very unique complex disease strongly associated with immune‐related genes. It is the only autoimmune disease known to be endemic, showing a strong correlation with environmental factors. Our data demonstrate that this relatively unknown autoimmune disease may facilitate understanding of the molecular mechanisms of KIR3DL2 ligand recognition.     

A weak association of HLA-B*2702 with Behçet's disease

This study aimed to analyse the association of HLA-B alleles other than -B51 with Beh?et's disease (BD). We also investigated the frequency of HLA-B alleles sharing the same natural killer cell immunoglobulin-like receptor (KIR) binding sequence with HLA-B51. Broad-genotyping of HLA-B locus by PCR-SSOP in 174 Turkish BD patients and 191 healthy controls confirmed the strong association of B*51 with BD (60.9% in BD patients, 24.6% in healthy controls, OR = 4.78). No other HLA-B allele was identified showing an association with BD after adjusting for multiple testing or by using relative predispositional effects (RPE) analysis after the deletion of B*51. HLA-B alleles reacting with the sequence specific oligonucleotide probe 23, which corresponds to the KIR binding site of B*51, were found to be positive in 127 BD patients (73%) and 90 controls (47%) (OR = 3.03, 95% CI 2-4.7). The repeated RPE analysis after separating HLA-B alleles carrying B51-KIR binding sequence as distinct alleles within a broad-type allele group revealed B*2702 allele as the only allele showing an association with BD after the deletion of B*51. Selective increase of B*2702, the only B*27 allele carrying the same KIR binding sequence with B*51, warrants investigation of the possibility of interaction of HLA molecules with KIRs on NK or other T cells in the pathogenesis of BD.     

Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris

Psoriasis vulgaris, particularly its juvenile form, is strongly associated with the HLA-Cw*06 allele encoding the HLA-Cw6 molecule. This molecule is recognized by the inhibitory receptor KIR2DL1 and the activatory receptor KIR2DS1, which are expressed on natural killer cells and subpopulations of T lymphocytes. Humans differ by the presence or absence of particular KIR genes. We hypothesized that either activatory KIR2DS1 or inhibitory KIR2DL1 gene frequencies might be different in psoriatic patients from a control population. Therefore, we compared the frequencies of KIR2D inhibitory (L) and activatory (S) genes in 116 psoriasis vulgaris patients and in 123 healthy controls. Fourteen novel gene combinations were found. KIR2DS1 was present in 85% of the patients, but only in 51% of the controls (corrected p [pc] < 0.0009). Similarly, HLA-Cw*06 was much more frequent in patients (77%) than in controls (17%; pc < 0.00002). Statistical analysis suggests that, although the contribution of these two factors to psoriasis is partially independent, they interact nevertheless. This result strongly speaks for a role of KIR2DS1 on recognition of HLA-Cw6 in susceptibility to psoriasis.