A meta-analysis of the relationship between brain dopamine receptors and obesity: a matter of changes in behavior rather than food addiction?

Addiction to a wide range of substances of abuse has been suggested to reflect a 'Reward Deficiency Syndrome'. That is, drugs are said to stimulate the reward mechanisms so intensely that, to compensate, the population of dopamine D2 receptors (DD2R) declines. The result is that an increased intake is necessary to experience the same degree of reward. Without an additional intake, cravings and withdrawal symptoms result. A suggestion is that food addiction, in a similar manner to drugs of abuse, decrease DD2R. The role of DD2R in obesity was therefore examined by examining the association between body mass index (BMI) and the Taq1A polymorphism, as the A1 allele is associated with a 30-40% lower number of DD2R, and is a risk factor for drug addiction. If a lower density of DD2R is indicative of physical addiction, it was argued that if food addiction occurs, those with the A1 allele should have a higher BMI. A systematic review found 33 studies that compared the BMI of those who did and did not have the A1 allele. A meta-analysis of the studies compared those with (A1/A1 and A1/A2) or without (A2/A2) the A1 allele; no difference in BMI was found (standardized mean difference 0.004 (s.e. 0.021), variance 0.000, Z=0.196, P<0.845). It was concluded that there was no support for a reward deficiency theory of food addiction. In contrast, there are several reports that those with the A1 allele are less able to benefit from an intervention that aimed to reduce weight, possibly a reflection of increased impulsivity.

The successful use of cardiopulmonary support for a transected bronchus.

A 20-year-old male was involved in a motor vehicle accident and computed tomography revealed a completely transected right mainstem bronchus. An Emergency Department (ED) right anterior thoracotomy was necessary soon after arrival at our institution secondary to acute desaturation that was unresponsive to ventilator and chest tube management. This allowed direct intubation and ventilation of the right middle and lower lobes directly through the thoracotomy incision, which stabilized the patient for transport to the operating room. Once there, percutaneous cardiopulmonary support (CPS) was initiated to allow primary surgical repair of the transected bronchus. Post surgery, the patient was transported to the surgical intensive care unit on CPS which he required for an additional two days. The patient eventually did well and was discharged home. To our knowledge this is the first successful reported case of using the Avalon Elite dual lumen veno-venous cannula for CPS in a patient with complete right main-stem bronchus transection and bilateral pulmonary contusions.

The impact of glycaemic load on cognitive performance: A meta-analysis and guiding principles for future research.

The effect of breakfast glycaemic load (GL) on cognition was systematically examined. Randomised and non-randomised controlled trials were identified using PubMed, Scopus, and Cochrane Library (up to May 2022). 15 studies involving adults (aged 20 - 80 years) were included. Studies had a low risk, or some concerns, of bias. A random-effects meta-analysis model revealed no effect of GL on cognition up to 119 min post-consumption. However, after 120 min, immediate episodic memory scores were better following a low-GL compared to a high-GL (SMD = 0.16, 95% confidence interval [CI] = -0.00 to 0.32, p = 0.05, I2 = 5%). Subgroup analyses indicated that the benefit was greater in younger adults (<35 years) and those with better GT. A qualitative synthesis of 16 studies involving children and adolescents (aged 5 - 17 years) suggested that a low-GL breakfast may also benefit episodic memory and attention after 120 min. Methodological practises were identified which could explain a failure to detect benefits in some studies. Consequently, guiding principles were developed to optimise future study design.

A model of human cytokine regulation based on transfection of gamma interferon gene fragments directly into isolated peripheral blood T lymphocytes.

An approach has been optimized permitting measurement of human cytokine reporter gene expression after transient transfection directly into purified human peripheral blood T lymphocytes. Comparing the expression of interleukin 2 (IL-2) CAT with a series of specially engineered gamma interferon (IFN-gamma) constructs, a fundamental difference in the molecular mechanisms regulating these two cytokines has been suggested. A potent, tissue-specific, constitutive-acting positive regulatory element was located between sequences -215 and -53 in the human IFN-gamma gene. Deletion analyses suggested that sequences slightly upstream, between positions -251 to -215, exerted a powerful dominant suppressive influence over that positive element. Negative elements appear to play a major role in controlling the regulation of human IFN-gamma gene expression. We thus propose a model of cytokine gene regulation in which selective derepression may be an important fundamental mechanism of induction and/or positive modulation.

Interleukin 2-induced proliferation of murine natural killer cells in vivo.

The growth factor, IL-2, was administered to mice to evaluate the in vivo responsiveness of NK cells to this factor. The immediate effects of this factor on NK cells were determined by examining cytotoxic activity at 18-24 h after a single treatment with rIL-2. Although moderate doses of rIL-2 (3 x 10(4) U) could be shown to activate existing cytotoxic cells on a per cell basis, higher doses (10(6) U) were required to elicit blast size killer cells. The elicited killer cells were characterized as NK cells by the following criteria: (a) they were readily induced in athymic mice; (b) they mediated killing of NK-sensitive YAC-1 target cells but not NK-resistant P815 target cells; and (c) they expressed the NK cell determinants asialo ganglio-n-tetraosylceramide and NK1.1, but not the T cell determinants CD3, L3T4, or Lyt-2. High-dose IL-2 treatment induced not only the appearance of blast size NK cells, but also the expansion of this population. After treatments, the number of large granular lymphocytes and the number of NK1.1+ cells were increased at least twofold. Analysis of DNA content within the NK1.1+ cell subset demonstrated that IL-2 preferentially drove NK1.1+ cells into S and G2/M phases of the cell cycle. The in vivo elicited blast lymphocytes were examined by Northern blot analysis and in situ hybridization for expression of the IL-2-R p55 alpha chain gene. As previous work from this laboratory has demonstrated that NK cells proliferate in response to IFNs and IFN inducers in vivo, blast lymphocytes were also prepared after IFN treatments. The NK cells were not induced to express detectable levels of the alpha chain gene under any of the conditions examined. Blast T lymphocytes, isolated at times during viral infections when IL-2 production can be demonstrated in vitro, were induced to transcribe the alpha chain gene. Treatments of euthymic mice with high-dose IL-2 also induced transcription of the alpha chain gene in 41% of the non-B blast lymphocytes, but only background percentages of the NK1.1+ cells expressed the alpha chain gene. Transcription of the alpha chain gene was not induced in the NK cell-abundant athymic mice after IL-2 treatment. All of the in vivo elicited blast lymphocytes were induced to express IFN-gamma. Taken together, these data definitively demonstrate that IL-2 can induce NK cell proliferation and expansion in vivo. They also show that exposure to IL-2 in vivo, either by administration or endogenous production of the factor, induces transcription of the IL-2-R alpha chain gene in populations of cells containing T cell subsets. The results suggest, however, that murine NK cells are not induced to express high levels of the alpha chain gene in response to IL-2 in vivo.

Two essential regulatory elements in the human interferon gamma promoter confer activation specific expression in T cells.

Like interleukin 2 (IL-2), interferon gamma (IFN-gamma) is an early response gene in T cells and both are prototypical T helper cell type 1 (Th-1) lymphokines. Yet IL-2 and IFN-gamma production are independently regulated, as demonstrated by their differential expression in certain T cell subsets, suggesting that the regulatory elements in these two genes must differ. To explore this possibility, the 5' flank of the human IFN-gamma gene was analyzed. Expression of IFN-gamma promoter-driven beta-galactosidase reporter constructs containing 538 bp of 5' flank was similar to that by constructs driven by the IL-2 promoter in activated Jurkat T cells; expression nearly as great was observed with the construct containing only 108 bp of IFN-gamma 5' flank. These IFN-gamma promoter constructs faithfully mirrored expression of the endogenous gene, in that expression required activation both with ionomycin and PMA, was inhibited by cyclosporin A, and was not observed in U937 or THP-1 cells. The region between -108 and -40 bp in the IFN-gamma promoter was required for promoter function and contained two elements that are conserved across species. Deletion of 10 bp within either element reduced promoter function by 70%, whereas deletions in nonconserved portions of this region had little effect on promoter function. The distal conserved element (-96 to -80 bp) contained a consensus GATA motif and a potential regulatory motif found in the promoter regions of the GM-CSF and macrophage inflammatory protein (MIP) genes. Factors binding to this element, including GATA-3, were found in Jurkat nuclear extracts by electromobility shift assays and two of the three complexes observed were altered in response to activation. One or both of these motifs are present in the 5' flank of multiple, other lymphokine genes, including IL-3, IL-4, IL-5, and GM-CSF, but neither is present in the promoter of the IL-2 gene. The proximal conserved element (-73 to -48 bp) shares homology with the NFIL-2A element in the IL-2 promoter; these elements compete for binding of factors in Jurkat nuclear extracts, although the NFIL-2A element but not the IFN-gamma element binds Oct-1. Factors binding to this element in the IFN-gamma gene were present in extracts from resting and activated Jurkat T cells. However, by in vivo footprinting of intact cells, this element was protected from methylation only with activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of gene rearrangement and mRNA expression of the beta chain of the T cell receptor in spontaneous rat large granular lymphocyte leukemia lines.

Using the murine cDNA clone for the beta chain of the T cell antigen receptor, we have examined four highly cytotoxic rat large granular lymphocyte (LGL) leukemia lines for the expression of unique rearrangements and mRNA transcription of the genes coding for the T cell antigen receptor. In contrast to normal rat T cells and nine rat T cell lines, the LGL leukemia lines exhibited no detectable gene rearrangements in the beta chain locus after digestion of LGL DNA by four restriction enzymes. Northern blots containing RNA from these LGL tumor lines demonstrated a low level of aberrant or nonrearranged beta chain transcription (less than 10 copies per cell) but virtually no translatable 1.3 kilobase message. These results demonstrate that LGL leukemia lines which mediate both natural killer (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC) activities do not express the beta chain of the T cell receptor. The nature of the NK cell receptor for antigen remains elusive.

Cloning and functional characteristics of murine large granular lymphocyte-1: a member of the Ly-49 gene family (Ly-49G2)

Large granular lymphocyte (LGL) 1 is a cell surface glycoprotein expressed on a subset (50%) of C57BL/6 natural killer (NK) cells. Immunoprecipitation experiments reveal that the LGL-1 protein exists as a disulfide-linked 40-kD homodimer. Functional studies of LGL-1+ cells indicate that selected H-2d target cells are not lysed efficiently by these interleukin (IL)-2-cultured NK cells. These findings suggested that LGL-1 may be a member of the Ly-49 gene family. Here we report the molecular cloning of the LGL-1 cDNA from a severe combined immunodeficient-adherent lymphokine-activated killer cell library transfected into Cos-7 cells and find LGL-1 to be homologous to the Ly-49 gene at both the nucleotide (85%) and amino acid levels (73%). Sequencing of our LGL-1 cDNA has revealed it to be nearly identical to the Ly-49G2 cDNA recently isolated by cross-hybridization with an Ly-49 probe. LGL-1 represents a type II transmembrane protein of 267 amino acids with its carboxyl end exposed extracellularly. The LGL-1 protein contains 11 highly conserved cysteine residues and a 25-amino acid transmembrane region. Southern blot analysis demonstrates that there are a number of homologous genes in mouse DNA that hybridize strongly to LGL-1. Northern analyses using poly A+ RNA from LGL-1+ NK cells indicate that LGL-1 is expressed as a 1.4 kb mRNA. Two-color flow cytometry analysis (FCA) of C57BL/6 splenic NK cells demonstrates that LGL-1 and Ly-49 label overlapping subsets of cells. FCA identifies four subsets of NK cells as defined by LGL-1 versus Ly-49 staining. We have sorted these individual subsets, expanded them in IL-2, and performed cytotoxicity experiments to determine their target cell profiles in relation to class I expression. Results of these studies are complex, but indicate that Ly-49 may not be the only molecule that recognizes class I as an inhibitory signal for cytotoxicity. LGL-1+ cells also fail to lyse several H-2d-expressing tumor targets and concanavalin A lymphoblasts from BALB/c but not C57BL/6 mice. This inhibition of lysis by LGL-1+ NK cells is negated by addition of monoclonal antibody (mAb) 4D11 that recognizes the LGL-1 protein. When mAbs to the class I molecules H-2Dd and H-2Ld (alpha 1 alpha 2 domains only) are added to cytotoxicity assays, LGL-1+ cells lyse H-2d targets very effectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin 2 induction of pore-forming protein gene expression in human peripheral blood CD8+ T cells.

Our studies have analyzed pore-forming protein (PFP) mRNA expression in resting and stimulated human peripheral blood CD3- large granular lymphocytes (LGL), CD3+ T cells, and their CD4+ or CD8+ subsets. Signals that stimulate T cells to develop cytotoxic activity (i.e., IL-2 or OKT-3 mAb) led to the induction of PFP mRNA in T cells. The data indicated that IL-2 directly increased PFP mRNA in the CD8+ subset of T cells, in the absence of new DNA or protein synthesis. Abrogation of IL-2-induced PFP mRNA expression and cytotoxic potential of T cells by the anti-p75 IL-2 receptor mAb suggested that low numbers of p75 IL-2 receptors on CD8+ T cells were capable of transducing signals responsible for these IL-2-induced effects. The induction of T cell PFP mRNA via CD3, using OKT-3 mAb, was less rapid but greater than that caused by IL-2; however, a combination of PMA and ionomycin, which bypasses crosslinking of the TCR/CD3 complex, could not mimic this increase in PFP mRNA levels in T cells. The role of second messenger systems in regulating PFP mRNA expression remains to be determined. In contrast, high constitutive PFP mRNA expression was observed in CD3- LGL and these mRNA levels could not be enhanced by stimulation with IL-2. The cytotoxic potential of peripheral blood T cells and LGL induced in response to IL-2 correlated with IL-2-induced PFP mRNA levels in these cells and was consistent with PFP being one of several important molecules involved in the effector function of cytotoxic lymphocytes.

Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers.

We previously reported that natural killer cell stimulatory factor (NKSF), a heterodimeric lymphokine purified from the conditioned medium of human B lymphoblastoid cell lines, induces interferon gamma (IFN-gamma) production from resting peripheral blood lymphocytes (PBL) and synergizes with interleukin 2 in this activity. In this study, we show that human NKSF induces IFN-gamma production from both resting and activated human PBL and from freshly isolated murine splenocytes. Human T and NK cells produce IFN-gamma in response to NKSF, but resting PBL require the presence of nonadherent human histocompatibility leukocyte antigens DR+ (HLA-DR+) accessory cells to respond to NKSF. The mechanism(s) by which NKSF induces IFN-gamma production results in accumulation of IFN-gamma mRNA, is insensitive to cyclosporin A, and synergizes with those mediated by phytohemagglutinin, phorbol diesters, anti-CD3 antibodies, and allogeneic antigens, but not by Ca2+ ionophores. The ability of NKSF to directly induce IFN-gamma production and to synergize with other physiological IFN-gamma inducers, joined with the previously described ability to enhance lymphocyte cytotoxicity and proliferation, indicates that this lymphokine is a powerful immunopotentiating agent.

Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1.

Interleukin-1 (IL-1) is a major regulator of inflammation and immunity. IL-1 induces T lymphocyte growth by acting as a second signal (together with antigen) in enhancing the production of interleukin-2 (IL-2). An IL-1-responsive element in the promoter region of the human IL-2 gene was similar to the binding site for the transcription factor AP-1. IL-1 enhanced expression of c-jun messenger RNA, whereas the antigenic signal enhanced messenger RNA expression of c-fos. Thus, the two components of the AP-1 factor are independently regulated and the AP-1 factor may serve as a nuclear mediator for the many actions of IL-1 on cells.

IFN-gamma: recent advances in understanding regulation of expression, biological functions, and clinical applications.

Interferon-gamma (IFN-gamma) is a key immunoregulatory protein that plays a major role in the host innate and adaptive immune response. Also known as type II interferon, IFN-gamma is a single-copy gene whose expression is regulated at multiple levels by the host. Transcription control is regulated through epigenetic mechanisms as well as the accessibility of chromatin and the binding of activating and inhibitory proteins to promoter and enhancer elements. Post-transcriptional control is mediated through mRNA localization and mRNA stability while post-translational control occurs through the activation of protein kinase R by the 5' portion of the mRNA, protein folding within the endoplasmic reticulum and the possible interaction of the mRNA with microRNAs. The biological effects of IFN-gamma are widespread, as almost every cell type is altered upon interaction with this protein. Thus it has become very apparent that IFN-gamma is a multipotent cytokine whose regulation and effects are complex and essential to host survival.

Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization.

Atopic diseases such as allergy and asthma are characterized by increases in Th2 cells and serum IgE antibodies. The binding of allergens to IgE on mast cells triggers the release of several mediators, of which histamine is the most prevalent. Here we show that histamine, together with a maturation signal, acts directly upon immature dendritic cells (iDCs), profoundly altering their T cell polarizing capacity. We demonstrate that iDCs express two active histamine receptors, H1 and H2. Histamine did not significantly affect the LPS-driven maturation of iDCs with regard to phenotypic changes or capacity to prime naive T cells, but it dramatically altered the repertoire of cytokines and chemokines secreted by mature DCs. In particular, histamine, acting upon the H2 receptor for a short period of time, increased IL-10 production and reduced IL-12 secretion. As a result, histamine-matured DCs polarized naive CD4(+) T cells toward a Th2 phenotype, as compared with DCs that had matured in the absence of histamine. We propose that the Th2 cells favor IgE production, leading to increased histamine secretion by mast cells, thus creating a positive feedback loop that could contribute to the severity of atopic diseases.

Posttranscriptional control of human gamma interferon gene expression in transfected mouse fibroblasts.

Human gamma interferon genomic DNA was introduced into NIH 3T3 fibroblasts by calcium phosphate precipitation and was not expressed in these cells at the cytoplasmic mRNA or protein level. Treatment of the transfected cells with cycloheximide (1 microgram/ml) induced the accumulation of cytoplasmic gamma interferon mRNA and biologically active human gamma interferon. Analysis of the nuclear enriched RNA from untreated cells indicated that human gamma interferon mRNA was present, suggesting that cycloheximide may act by inhibiting a specific nuclease or may enhance the processing or transport of the RNA from the nucleus to the cytoplasm.

The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element.

Our group has previously reported that the nuclear factor Yin-Yang 1 (YY1), a ubiquitous DNA-binding protein, is able to interact with a silencer element (BE) in the gamma interferon (IFN-gamma) promoter region. In this study, we demonstrated that YY1 can directly inhibit the activity of the IFN-gamma promoter by interacting with multiple sites in the promoter. In cotransfection assays, a YY1 expression vector significantly inhibited IFN-gamma promoter activity. Mutation of the YY1 binding site in the native IFN-gamma promoter was associated with an increase in the IFN-gamma promoter activity. Analysis of the DNA sequences of the IFN-gamma promoter revealed a second functional YY1 binding site (BED) that overlaps with an AP1 binding site. In this element, AP1 enhancer activity was suppressed by YY1. Since the nuclear level of YY1 does not change upon cell activation, our data support a model that the nuclear factor YY1 acts to suppress basal IFN-gamma transcription by interacting with the promoter at multiple DNA binding sites. This repression can occur through two mechanisms: (i) cooperation with an as-yet-unidentified AP2-like repressor protein and (ii) competition for DNA binding with the transactivating factor AP1.

Detection of c-rel-related transcripts in mouse hematopoietic tissues, fractionated lymphocyte populations, and cell lines.

A portion of the human cellular homolog of v-rel, the transforming gene of the leukemogenic retrovirus reticuloendotheliosis virus, strain T, was used to survey RNAs from several mouse tissues, selected lymphocyte populations, and hematopoietic cell lines for c-rel expression. Relatively high levels of a high-molecular-weight transcript were observed in peripheral B and T cells, whereas lower levels were detectable in functionally immature thymocytes. These results suggested that, unlike c-myb and c-ets, the c-rel proto-oncogene plays a role in later stages of lymphocyte differentiation.

Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human c-Rel.

The cis-acting control elements of the interleukin-2 receptor alpha-chain (IL-2R alpha) gene contain a potent kappa B-like enhancer whose activity can be induced by various mitogenic stimuli. Recent cloning of the p50 and p65 subunits of the kappa B-binding protein NF-kappa B complex revealed a striking sequence homology of these proteins with the c-rel proto-oncogene product (c-Rel). On the basis of this homology, we examined the potential role of c-Rel in controlling IL-2R alpha transcription. We now demonstrate that the recombinant human c-Rel protein binds to the kappa B element in the IL-2R alpha promoter and results in alteration of the DNA structure in the adjacent downstream regulatory elements containing the CArG box and the GC box. We found that human c-Rel can activate transcription from the IL-2R alpha promoter, but not the kappa B-containing human immunodeficiency virus type 1 promoter, upon cotransfection into Jurkat T cells. Furthermore, truncation of the carboxyl terminus of c-Rel results in a c-Rel mutant (RelNA) that (i) localizes exclusively in the nucleus and (ii) acts in synergy with wild-type c-Rel in activating transcription from the kappa B site of the IL-2R alpha promoter. Finally, induction of surface IL-2R alpha expression coincides with the induced levels of endogenous c-Rel and induced c-Rel binding to the IL-2R alpha kappa B site. Our study identified c-Rel as one component of the Rel/NF-kappa B-family proteins involved in the kappa B-dependent activation of IL-2R alpha gene expression. Furthermore, our results suggest that a Re1NA-like cellular factor (e.g., NF-kappa B p50 or p49 subunit) acts in synergy with c-Re1 during T-cell activation.

Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production.

The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including interleukin-12, tumor necrosis factor alpha, and gamma interferon (IFN-gamma), following human retrovirus infection is well documented. One process by which such gene expression may be modulated is altered DNA methylation. In subsets of T-helper cells, the expression of IFN-gamma, a cytokine important to the immune response to viral infection, is regulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many possible genes whose methylation status could be affected by viral infection, we examined the IFN-gamma gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HIV-1) results in (i) increased DNA methyltransferase expression and activity, (ii) an overall increase in methylation of DNA in infected cells, and (iii) the de novo methylation of a CpG dinucleotide in the IFN-gamma gene promoter, resulting in the subsequent downregulation of expression of this cytokine. The introduction of an antisense methyltransferase construct into lymphoid cells resulted in markedly decreased methyltransferase expression, hypomethylation throughout the IFN-gamma gene, and increased IFN-gamma production, demonstrating a direct link between methyltransferase and IFN-gamma gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-gamma gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.

Immunomodulation of natural killer cell activity by flavone acetic acid: occurrence via induction of interferon alpha/beta.

The investigational drug flavone acetic acid (FAA) systemically augments natural killer (NK) cell activity in normal and tumor-bearing mice and in human cancer patients. The results from the present investigation demonstrate that in vivo administration of FAA induces in a dose-dependent manner high levels of serum interferon (IFN) within 4 hours in BALB/c, C57BL/6, and BALB/c nude mice. Antibody neutralization studies indicated that FAA induced IFN of the alpha/beta type, while molecular hybridization studies demonstrated that FAA rapidly stimulated the production of IFN alpha mRNA in splenic leukocytes. In vivo administration of anti-IFN alpha/beta antibodies to FAA-treated mice inhibited the FAA-induced augmentation of splenic NK cell activity at 4 hours. These results suggest that FAA mediates its anti-tumor effects indirectly by immunomodulation as well as directly by antiproliferative or cytotoxic activity.

Natural killer (NK) cell lytic dysfunction and putative NK cell receptor expression abnormality in members of a family with chromosome 3p-linked von Hippel-Lindau disease.

UNLABELLED: BACKGROUND. Using antibodies to a putative natural killer (NK) cell receptor (pNKR), we recently cloned a novel cDNA and localized this gene to the short arm of human chromosome 3, region 3p21-3p24. Individuals susceptible to or clinically manifesting von Hippel-Lindau disease (VHL) have a genetic defect telomeric to this region on chromosome 3. This defect, resulting in VHL, is manifested by a high incidence of certain tumors. PURPOSE: Based on the location of this gene, we sought to determine if VHL patients have a defect in gene expression of pNKR. METHODS: Because of the proximity of the VHL and pNKR genetic regions, the variable expression of VHL tumors, and the ability of NK cells to target tumor cells, we investigated NK cell activity and other aspects of the immunologic status in 40 members (four branches) of a family with a high incidence of VHL tumors. RESULTS: Individuals affected with VHL and lacking in normal surface expression of pNKR had virtually no NK cell lytic activity. Analysis of genotypes and phenotypes of all subjects revealed that the greatest difference in NK cell lytic activity (P = .0002) was seen when family members exhibited both VHL and pNKR surface expression defects, compared with normal relatives who had neither defect. Furthermore, the lack of NK cell activity strongly correlated (P = .0005) with abnormal pNKR protein surface expression. Of particular interest, individuals who lacked NK cell activity had normal numbers of NK cells. In addition, analysis of leukocyte subsets indicated normal numbers of T and B cells, monocytes, and NK cells in both affected and normal individuals. CONCLUSIONS: These data indicate that although all affected individuals have the cell population responsible for NK cell activity, many have cells low in expression of pNKR and lack functional NK cell activity. Overall, these results indicate that, in addition to a predisposition to the development of neoplasms, VHL patients have a defect in a specific mechanism of natural immunosurveillance that correlates with a defect in expression of a novel large granular lymphocyte pNKR protein.