Killer cell immunoglobulin-like receptors on NK cells: the how, where and why

Natural killer (NK) cells have killer cell immunoglobulin-like receptors (KIR) that recognize and interact with HLA class I antigen. The KIRs are a multigene family and its members are often highly polymorphic. Evidence is emerging from disease-association studies that KIR receptors can play beneficial roles in viral infections, such as HIV, HCV, but may also predispose to certain autoimmune diseases. Knowledge regarding expression and function of KIR on human NK cells is lagging behind the rapid expansion of sequencing and genetic data already generated. This review focuses on recent discoveries that have been made, which help bridge this gap. We now appreciate the importance of phenotypic diversity of KIR receptor expression in NK cells and are starting to unravel some of the mysteries surrounding control of their complex expression patterns. In particular, the role that HLA ligand contributes to KIR receptor expression will be discussed. It is also becoming increasingly clear that genetic factors, such as promoters and epi-genetic mechanisms such as methylation, are hugely important in controlling NK cell receptor expression and function. The relevance of phenotypic diversity of NK cell receptors will be discussed in light of these recent findings.     

Killer cell immunoglobulin-like receptors in Thai patients with leukemia and diffuse large B-cell lymphoma

Natural killer (NK) cells are key components of the innate immune system that have been implicated in the immune response against tumor cells. Killer cell immunoglobulin-like receptors (KIR) regulate NK cell activity by interaction with specific human leukocyte antigen (HLA) class I. In this study, KIR gene polymorphisms and their HLA ligands were investigated in Thai patients with chronic myelogenous leukemia (CML) (n = 60), acute myelogenous leukemia (AML) (n = 60), acute lymphoblastic leukemia (ALL) (n = 55), and diffuse large B-cell lymphoma (DLBCL) (n = 60) compared with 150 healthy controls. The frequency of KIR3DL1 with HLA-Bw4 was significantly lower in DLBCL patients than in controls (P = 0.0006, Pc = 0.02), whereas no significant differences were seen in KIR gene frequencies and their ligands between leukemia patients and controls. This study suggest a role of inhibitory KIR with its ligand in the protection against DLBCL.     

Genetic profiles of killer-cell immunoglobulin-like receptors and HLA ligands in Thai blood donors

Killer-cell immunoglobulin-like receptors (KIRs) play an important role in natural killer (NK) cell regulation. Interaction of KIRs with human leukocyte antigen (HLA) class I molecules can transmit signals to regulate the function of NK cells. In this study, the diversities of KIR genes and their ligands in 500 Thai blood donors were investigated. The coexistence of inhibitory KIRs (iKIR), activating KIRs (aKIR) and their ligands in the same individuals were also analyzed. Overall, 36 KIR genotypes were identified. The most common genotype was genotype AA1 (40.8%). All individuals carried at least one iKIR-HLA pair whereas 18% of the individuals lacked aKIR-HLA pair. The most common compound KIR-HLA profile was the presence of 3 iKIR-HLA pairs with 1 aKIR-HLA pair (21.4%). The most common compound gene profile of KIR-HLA pairs was the combined presence of KIR2DL3-C1, 3DL1-Bw4, 3DL2-A3/A11 and the full length KIR2DS4-its ligands (8%). This study provided a comprehensive analysis of the KIR-HLA profiles in Thai blood donors in regards to KIR genotypes, HLA ligands, KIR-HLA ligand pairs and compound gene profiles of both iKIRs and aKIRs and their ligands. These findings will be useful as baseline information for further studies in the associations of KIR genes and various diseases.     

TNFA-TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population

The contribution of single nucleotide polymorphisms in tumor necrosis factors (TNF) alpha and beta to autoimmune diseases, and to type 1 diabetes mellitus (T1DM) in particular, is not well established, and may be confounded by linkage disequilibrium to class II HLA genes. At least two polymorphisms seem to have functional relevance in the respective genes: TNFA-307 and TNFB+252. We have typed these two polymporphisms in samples of Moroccan T1DM patients and controls for which class II HLA genes had already been typed. Tumor necrosis factors and compound TNF-class II HLA haplotypes were inferred; it was the first time that such a design had been implemented. Independent of linkage disequilibrium with class II HLA, TNF haplotype TNFA-307*2 - TNFB+252*2 showed a significant protective effect (OR = 0.031), partly exacerbated by partial linkage to protective class II haplotypes. Such effect could be detected because Morocco shows the highest frequency of the TNFA-307*2 allele yet reported. This highlights the possible population differences in alleles contributing to autoimmune diseases.     

Killer cell immunoglobulin-like receptors and response to antiviral treatment in Thai patients with chronic hepatitis C virus genotype 3a

Genetic factors of the host have been shown to influence the outcome of treatment for hepatitis C virus (HCV) infection. Killer cell immunoglobulin‐like receptors (KIR) regulate natural killer (NK) cell activity by interaction with specific human leukocyte antigen (HLA) class I. In this study, KIR gene polymorphisms and their HLA ligands were investigated in 110 Thai patients with chronic HCV genotype 3a. Seventy‐six patients were sustained virological responders and 34 patients were virological non‐responders. KIR typing and HLA‐C typing were performed using PCR‐SSP (polymerase chain reaction with sequence specific primer). The frequency of HLA‐C1C2 was significantly higher in sustained responders than in non‐responders (P = 0.04). However, the frequencies of KIR2DL2/2DL3 genotype and KIR2DL2/2DL3‐HLA‐C1C1 genotype were significantly higher in non‐responders than in sustained responders (P = 0.02, 0.004, respectively). In summary, this study showed the association of KIR genes and ligands with the outcome of antiviral treatment in chronic hepatic C virus genotype 3a infection. J. Med. Virol. 83:1733–1737, 2011. © 2011 Wiley‐Liss, Inc.     

警报素既是免疫警报又是疾病警报

警报素(Alarmins)是机体处于组织损伤和炎症反应状态或生理应激时,由白细胞和上皮细胞等释放到胞外的内源性生物介质,也称为危险相关分子模式(Danger-associated molecular patterns,DAMPs)。通过趋化和激活抗原递呈细胞(Antigen presenting cells,APC)等免疫细胞从而增强固有免疫和适应性免疫应答。它与疾病的产生发展及转归密切相关,对于临床诊疗具有重要的指导意义。     

Increased level of serum HLA class I antigens in HIV infection correlation with disease progression

Analysis of (sHLA-I) antigens in a large number of HIV-positive subjects found a significant increase of their level, but did not detect any change in their molecular profile. Monitoring at yearly intervals for four years of the sHLA-I antigen level in 14 HIV-positive subjects with a normal sHLA-I antigen level at study entry showed a significant correlation between progressive increase of sHLA-I antigen level and disease progression. Furthermore, a Kaplan-Meier plot of the frequency of development of AIDS in 34 patients whose cases were followed for 7 years showed that sHLA-I antigen level is a strong predictor of progression to AIDS. Its predictive value is comparable to that of serum β₂-μ level, greater than that of serum neopterin, and lower than that of CD4 + T-cell percentage. The predictive value of sHLA-I antigen level in combination with serum β₂-μ level, neopterin level, or CD4 + T-cell percentage is greater than that of each individual variable. These results suggest that measurement of the sHLA-I antigen level may provide useful prognostic information in HIV-positive subjects. Human Immunology 40, 259–266 (1994)     

Posttraumatic growth and HIV disease progression

The relationship between posttraumatic growth (PTG; perceiving positive changes since diagnosis) and disease status, determined by changes in viral load and CD4 count over time, was examined among 412 people living with HIV. In controlled multiple regression models, PTG was not associated with disease status over time for the entire sample. However, there were significant associations for certain subgroups. PTG was positively associated with CD4 counts for Hispanic participants (vs. non-Hispanic) and those with low (vs. high) levels of optimism. PTG was inversely associated with viral load among those low (vs. high) in pessimism. Although PTG was inversely associated with depressive symptoms, alcohol, and illicit drug use, these factors did not account for the findings.     

Alcohol consumption and HIV disease progression

OBJECTIVE: To assess the relation between alcohol consumption and laboratory markers of HIV disease progression. METHODS: We prospectively assessed CD4 cell counts, HIV RNA levels, and alcohol consumption for up to 7 years in 595 HIV-infected persons with alcohol problems recruited between 1997 and 2003. We investigated the relation of these markers of HIV disease progression to alcohol consumption using longitudinal regression models controlling for known prognostic factors, including adherence and depressive symptoms, and stratified by antiretroviral therapy (ART) use. RESULTS: Among subjects who were not on ART, heavy alcohol consumption was associated with a lower CD4 cell count (adjusted mean decrease of 48.6 cells/microL compared with abstinence; P = 0.03) but not with higher log(10) HIV RNA. Among subjects who were on ART, heavy alcohol consumption was not associated with a lower CD4 cell count or higher log(10) HIV RNA. CONCLUSIONS: Heavy alcohol consumption has a negative impact on the CD4 cell count in HIV-infected persons not receiving ART. In addition to the known deleterious effects of alcohol on ART adherence, these findings suggest that avoiding heavy alcohol consumption in patients not on ART may have a beneficial effect on HIV disease progression.     

Natural killer cell crossmatch: functional analysis of inhibitory killer immunoglobulin-like receptors and their HLA ligands

Attempts to predict outcome of bone marrow transplantation based on killer immunoglobulin-like receptor (KIR) and HLA genotyping have yielded discordant results. To better understand the factors involved, we investigated natural killer (NK) cell function and correlated it with genetics and expression of inhibitory KIR and HLA ligands in 20 normal allogeneic pairs. KIR expression was analyzed by flow cytometry to estimate the percentage of NK cells that could be inhibited by the HLA ligands in each pair combination. NK cytotoxicity against ConA blasts demonstrated a positive correlation between the number of KIR/HLA matches and the predicted number of NK cells that could be inhibited. When 50% or more of the NK cells could be inhibited, cytotoxicity was lower (8%) than when 25% or less of the NK cells expressed KIR with matched HLA (49%) (p < 0.0001). Our data suggest that the interaction between inhibitory KIR and HLA ligands can be correlated to some extent with NK cell function, but measurement of NK activity may provide the best information for analysis of clinical situations.     

Killer immunoglobulin-like receptors (KIR) and their HLA-ligands in Italian paroxysmal nocturnal haemoglobinuria (PNH) patients

Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoietic disorder characterized by expansion of phosphatidylinositol glycan-A-defective progenitor(s). Immune-dependent mechanisms, likely involving a deranged T cell-dependent autoimmune response, have been consistently associated with the selection/dominance of PNH precursors. Natural killer (NK) lymphocytes might participate in PNH pathogenesis, but their role is still controversial. NK activity is dependent on the balance between activating and inhibiting signals. Key component in such regulatory network is represented by killer immunoglobulin-like receptors (KIR). KIR are also involved in the regulation of adaptive cytotoxic T cell response and associated with autoimmunity. This study investigated on the frequency of KIR genes and their known human leukocyte antigen (HLA) ligands in 53 PNH Italian patients. We observed increased frequency of genotypes characterized by ≤2 activating KIR as well as by the presence of an inhibitory/activating gene ratio ≥3.5. In addition, an increased matching between KIR-3DL1 and its ligand HLA-Bw4 was found. These genotypes might be associated with lower NK-dependent recognition of stress-related self molecules; this is conceivable with the hypothesis that an increased availability of specific T cell targets, not cleared by NK cells, could be involved in PNH pathogenesis. These data may provide new insights into autoimmune PNH pathogenesis.     

HLA genes associated with autoimmunity and progression to disease in type 1 diabetes

Insulin dependent diabetes mellitus (type I DM) is caused by an autoimmune process which culminates in destruction of pancreatic beta cells with resultant loss of insulin production. Preceding the clinical diagnosis of type I DM is a preclinical stage characterized by autoantibodies to insulin, glutamic acid decarboxylase (GAD) and a tyrosine phosphatase-like molecule (IA-2). We have studied both HLA class I and class 2 allele distributions in diabetic probands and autoantibody positive individuals in members of 452 families recruited for the Australian type I diabetes DNA repository. The results demonstrate that progression to autoimmunity as measured by the appearance of autoantibodies is strongly associated with the class 2 alleles DRB1*03 and DRB*04 and with DRB1*03/04 heterozygosity. In contrast, the progression to clinical disease appears associated with class I alleles A24, A30 and B18 while A1, A28, B14 and B56 appear negatively associated. The class 2 alleles appear to have a minimal role in the progression from autoantibody positivity to clinical disease. These results are consistent with the view that CD4+ T cells responding to peptides in the context of class 2 molecules are responsible for initiating autoantibody production, while the destruction of islet cells leading to clinical expression of the disease is the function of CD8+ T cells recognizing relevant peptides in the context of class I molecules.     

Expression of activating and inhibitory leukocyte immunoglobulin-like receptors in rheumatoid synovium: correlations to disease activity

Rheumatoid arthritis (RA) is a heterogeneous chronic inflammatory joint disease characterized by excessive activation of inflammatory cells of which the underlying mechanisms are not fully elucidated. Perturbed expression and function of immune regulatory molecules called leukocyte immunoglobulin-like receptors (LILRs) may contribute to uncontrolled inflammation. LILRs primarily expressed on the surface of leukocytes are emerging as critical regulators of the threshold and amplitude of leukocyte activation. Inhibitory LILRs (LILRBs) contain cytoplasmic tails with immunoreceptor tyrosine-based inhibitory motifs that provide negative signals. Activating LILRs (LILRAs) have short cytoplasmic domains lacking signaling motifs but transmit activating signals by linking to immunoreceptor tyrosine-based activation motifs of the FcR γ-chain. Here we show that activating LILRA2, A5 and inhibitory LILRB2, B3 were abundantly expressed in synovial tissue of > 75% RA patients. Expression of LILRA2, A5, and B3 significantly correlated to disease activity. In contrast, LILRA1 and B4 were expressed in a subset of patients and no B1 or B5 expression was detected. LILRA2 and A5 were mainly expressed by synovial macrophages and endothelial cells but not lymphocytes, whereas B2 and B3 were expressed by macrophages and lymphocytes. Increase in the number of macrophages expressing activating LILRs and macrophages and lymphocytes expressing inhibitory LILRs suggest a crosstalk between these cells that may regulate the levels of cellular activation and disease severity, while differences in expression pattern may contribute to disease heterogeneity.     

中国人群HLA-B等位基因与HIV-1感染者疾病进程相关性研究

目的：通过对中国人群HIV-1感染典型进展者（Typical progressors，TP）和长期不进展者（Long-term nonpmgressors，LTNP）HLA-B等位基因的分布频率的研究，探讨中国人群HLA-B等位基因与HIV-1感染者疾病进程的关系。方法：采用整群随机抽样方法从河南、吉林、辽宁、新疆、云南五省收集356例未经抗病毒治疗的HIV-1感染者血样，其中289例典型进展者和67例长期不进展者。应用聚合酶链反应-序列特异性引物技术（PCR-SSP）对其HLA-B等位基因特异性进行检测，并分析了他们的等位基因纯合子情况及Bw4／Bw6血清型，比较二组差异。结果：发现4个HLA-B等位基因位点在中国HIV-1感染人群中的表达频率较高，分别是HLA-B^＊13（TP：11．8％；LTNP：15．7％）、HLA-B^＊15（TP：17．3％；LTNP：8．2％）、HLA-B^＊40（TP：12．5％；LTNP：17．9％）、HIA-B^＊51（TP：9％；LTNP：10．4％）。其中长期不进展组HLA-B^＊67的等位基因频率为4．5％，典型进展组HLA-B^＊67的等位基因频率为1．2％，前者明显高于后者，具有显著性差异（P=0．022，OR=0．26，95％CI=0．08-0．89）。典型进展组的B^＊15的等位基因频率（17．3％）显著高于长期不进展组（8．2％）（P=0．009，OR=2．34，95％CI=1．18～4．76）。结论：HLA-B^＊67等位基因可能与延缓中国HIV-1感染者疾病进程相关，HLA-B^＊15等位基因可能与加速中国HIV-1感染者疾病进程相关。     

Weight loss and disease progression in HIV infection

Weight loss and malnutrition continue to be important issues that clinicians face when treating patients with HIV infection. In addition to specific clinical consequences, weight loss in these patients is linked to a greater risk of death and opportunistic complications. A loss of as little as 5% to 1-% of baseline body weight can be associated with a risk of death that is 2.5 times that seen in patients with HIV infection who do not lose weight. Furthermore, weight loss in patients with HIV infection can increase the risk of individual opportunistic infections by as much as 61% to 176%. Future studies may help define the prognostic implications of lipodystrophy and changes in body cell mass in patients with HIV who are taking antiretroviral therapy.     

Killer cell immunoglobulin-like receptor three domains long cytoplasmic tail 1 gene *007 may modulate disease progression of human immunodeficiency virus-1 infection in the Japanese population

One of the KIR allele, KIR3DL1*007, was associated with the progression to acquired immunodeficiency syndrome and not with the susceptibility to HIV-1 infection in the Japanese and Indian populations, implying that KIR3DL1*007-positive NK cells might eliminate HIV-infected cells less effectively than NK cells bearing the other KIR3DL1 alleles or KIR3DS1 alleles.