Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells.
نویسندگان
چکیده
Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors.
منابع مشابه
HLA-KIR Interactions and Immunity to Viral Infections
Host genetic factors play a central role in determining the clinical phenotype of human diseases. Association between two polymorphic loci in human genome, human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIRs), and genetically complex infectious disease, particularly those of viral etiology, have been historically elusive. Hence, defining the influence of genetic di...
متن کاملKiller Cell Immunoglobulin-Like Receptors Influence the Innate and Adaptive Immune Responses
Natural killer (NK) cells are a subset of lymphocytes which play a crucial role in early innate immune response against infection and tumor transformation. Furthermore, they secrete interferon-γ (IFN-γ) and tumor necrosis factor (TNF) prompting adaptive immu-nity. NK cells distinguish the unhealthy cells from the healthy ones through an array of cell-surface receptors. Human NK cells use inhibi...
متن کاملارتباط برهمکنشهای KIR-HLA با بیماریها
The killer cell immunoglobulin-like receptors (KIR) are a recently discovered family of activating and inhibitory receptors which control natural killer (NK) cell function. KIR exist as a diverse family of receptors that have evolved rapidly by both gene duplication and recombination events. These findings were unexpected for a family of genes involved primarily in the innate immune response. H...
متن کاملKIR-HLA combinations and susceptibility to tuberculosis
Introduction: Tuberculosis (TB), caused by Mycobacterium Tuberculosis (Mtb), with more than nine million new cases and almost two million deaths in each year is a worldwide important public health problem. Generally, human immune responses prevent Mtb spread, and the infection remains in a latent state. Both, innate and adaptive immune responses are involved against TB. However, the role of the...
متن کاملAssociation of KIR3DS1+HLA-B Bw4Ile80 Combination with Susceptibility to Tuberculosis in Lur Population of Iran
Background: Natural killer (NK) cells are the effector cells of innate immunity that respond to infection and tumor. Interactions between killer cell immunoglobulin like receptors (KIR) and human leukocyte antigen (HLA) class I molecules regulate NK cells responses to eliminate infected and transformed cells. Objective: To investigate the impact of KIR genes, HLA ligand genes, and KIR-HLA combi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer research
دوره 76 2 شماره
صفحات -
تاریخ انتشار 2016