Chemokine-receptor polymorphisms: clarity or confusion for HIV-1 prognosis?
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Biomedical subjects
P Garred
Publications and source records attributed to P Garred.
MBP, anti-MBP and anti-PLP antibodies, and intrathecal complement activation in multiple sclerosis.
Intrathecal immunoglobulin synthesis and activation of the complement cascade occurs in patients with multiple sclerosis (MS). The present study aimed at further studying the relation between intrathecal immunoglobulin synthesis and complement activation. We compared total intrathecal synthesis of IgA, IgG, and IgM, the number of cells secreting anti-myelin basic protein (MBP) and anti-proteolipid protein (PLP) antibodies of the IgG isotype and intrathecal activation of the complement cascade in patients with possible onset symptoms of MS (n = 18) or clinically definite MS (n = 30). Early activation of the complement cascade correlated with intrathecal synthesis of IgM. Intrathecal IgG, IgA and IgM synthesis also correlated weakly with the presence of cells secreting anti-MBP or anti-PLP autoantibodies. Full activation of the complement cascade did not correlate with any measures of intrathecal antibody synthesis. These findings suggest a complex relation between different immunoglobulin isotypes and complement activation which may have similarly complex roles in the pathogenesis of MS.
Acute Disease↗
Mannan binding lectin in rheumatoid arthritis. A longitudinal study.
OBJECTIVE: Low serum levels of mannan binding lectin (MBL) are associated with increased risk of recurrent infections. We determined whether there was an association between serum MBL levels and the course and prognosis of rheumatoid arthritis (RA). METHODS: MBL was analyzed in sera from 99 patients with RA who were included in a longterm prospective study. RESULTS: Compared with controls, a high fraction of patients lacked detectable MBL in serum (11 vs 3%; p = 0.025). Comparing patients with MBL serum levels above and below the median revealed that those with levels below the median were younger at onset of RA (p = 0.043) and had higher erythrocyte sedimentation rate (p = 0.006), joint swelling score (p = 0.019), limitation of joint motion score (p = 0.027), and annual increase in radiographic destruction score (p = 0.053). CONCLUSION: MBL insufficiency may be a contributing pathogenetic factor in RA.
Adolescent↗
CC chemokine receptor 5 polymorphism in rheumatoid arthritis.
OBJECTIVE: Some chemokine receptors have been shown to be co-receptors for human immunodeficiency virus (HIV-1). A 32 base pair deletion allele in the CC chemokine receptor 5 gene (CCR5 delta32 allele) affects both transmission of HIV-1 and acquired immunodeficiency syndrome (AIDS)-free survival. Chemokines are suggested to be critical for establishment of inflammatory processes in autoimmune diseases such as rheumatoid arthritis (RA). We hypothesized that the defective allele may modulate the inflammatory process in RA. METHODS: Using polymerase chain reaction methods, we investigated the significance of the CCR5 delta32 allele in 163 Danish patients with RA and monitored clinical and paraclinical variables. RESULTS: The gene frequency of the CCR5 delta32 allele (0.10) did not deviate significantly from healthy controls and from that reported in healthy Caucasian populations, nor did the distribution deviate from the Hardy-Weinberg predictions (131 wild type, 30 heterozygous, 2 homozygous for the deletion allele; p = 0.85). However, a significantly increased proportion of those carrying the deletion allele were negative for IgM rheumatoid factor (RF) compared to those homozygous for the normal allele (29 vs 9%; p = 0.007). The proportion of CCR5 delta32 allele carriers with swollen joints was decreased compared to those homozygous for the normal allele (35 vs 58%, respectively; p = 0.03), as was the duration of morning stiffness (median 0 vs 60 min, respectively; p = 0.0002). CONCLUSION: The CCR5 delta32 allele seems to have some influence on RA variables including RF, which suggests that inhibition of chemokine receptors might be a potential target for disease modifying therapy in RA.
Adult↗
Modest salt restriction in older people.
Explore the source record for details and available documents.
Aged↗
HIV-infected individuals with the CCR delta32/CCR5 genotype have lower HIV RNA levels and higher CD4 cell counts in the early years of the infection than do patients with the wild type. Copenhagen AIDS Cohort Study Group.
The relations among serum HIV RNA levels, CD4 cell counts, presence of the mutant CCR5-allele in heterozygous form, and clinical outcome was analyzed in 96 patients from the Copenhagen AIDS Cohort. In the early years of the infection, patients with the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than did patients homozygous for the normal allele. The long-term clinical benefit of being heterozygous is small and cannot solely explain the large interpatient variation in progression rates. The beneficial effect of being heterozygous seems to be mediated by events in the early stages of the HIV infection.
CD4 Lymphocyte Count↗
Dual effect of CCR5 delta 32 gene deletion in HIV-1-infected patients. Copenhagen AIDS Study Group.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin.
BACKGROUND: Low serum concentrations of mannose-binding lectin (MBL) are associated with increased susceptibility to recurrent infection. Three variant alleles in the MBL gene (B, C, and D), cause low serum concentrations of the protein. We investigated whether variant alleles of MBL affect susceptibility to infection with HIV and progression of AIDS. METHODS: Between 1983 and 1986, all men who attended two clinics in Copenhagen for HIV screening were invited to take part in our study. We investigated the prevalence of variant alleles of MBL (detected by PCR) and assessed the prognostic value of these alleles and the corresponding serum MBL concentrations (measured by ELISA) in 96 homosexual men with HIV infection and in two control groups (123 healthy adults and 36 HIV-negative homosexual men at high risk of HIV infection because of their sexual behaviour). Follow-up was for up to 10 years. FINDINGS: Eight (8%) of the HIV-infected men were homozygous for the variant MBL alleles compared with one (0.8%) of the healthy controls (p = 0.005) and none of the high-risk homosexual controls (p = 0.05). We found no significant association between MBL genotype and time from first positive HIV test to progression of AIDS (p = 0.8). However, in the 61 HIV-infected men who developed AIDS, the median survival time was significantly shorter after the AIDS diagnosis for men who were carriers of the variant alleles (both homozygous and heterozygous) than for men homozygous for the normal MBL allele (11 [IQR 4-21] vs 18 months [9-44], p = 0.007). Among men who developed AIDS, there was a significant difference in survival time between those with serum MBL concentrations below the lower quartile, those within the IQR, and those above the upper quartile (p = 0.02). Multivariate analysis showed that men who developed AIDS and had low serum MBL concentrations had an increased rate of rapid death, independently of CD4 T-cell counts at AIDS diagnosis. INTERPRETATION: Our findings suggest that homozygous carriers of variant MBL alleles are at increased risk of HIV infection, either directly or indirectly because of increased susceptibility to coinfections. These alleles are also associated with a significantly shorter survival time after a diagnosis of AIDS.
Acquired Immunodeficiency Syndrome↗
Mannan-binding lectin in the sub-Saharan HIV and tuberculosis epidemics.
Inherited deficiency of mannan-binding lectin (MBL) has been shown to predispose to infections. Conversely, it has also been suggested that MBL might facilitate the uptake of certain intracellular microbes. The aim of this study was to investigate whether MBL plays a role in the HIV and tuberculosis epidemics in Africa. Thus, the authors determined the MBL serum concentration in 173 HIV infected patients (150 with concomitant tuberculosis), 94 patients with tuberculosis without being HIV infected, and 113 controls from Tanzania. The frequency of MBL deficiency was significantly increased in HIV infected patients compared with controls (12.1% and 3.5%, respectively). The frequency of patients deficient of MBL did not differ between controls and HIV negative patients with tuberculosis. However, HIV negative patients with tuberculosis had significantly higher MBL levels than both controls and HIV infected patients with or without tuberculosis. These results indicate that low levels of MBL are associated with increased risk of sexually transmitted HIV infection in Africans. By contrast, high levels of MBL may be involved in the pathogenesis of tuberculosis in immunocompetent individuals.
Adolescent↗
Heterozygosity for a deletion in the CKR-5 gene leads to prolonged AIDS-free survival and slower CD4 T-cell decline in a cohort of HIV-seropositive individuals.
OBJECTIVE: Recently, it has been shown that a homozygous 32 base-pair deletion in the gene encoding CKR-5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1. We have investigated whether HIV-seropositive individuals who were heterozygous for the CKR-5 deletion had a different course of the disease. DESIGN: Thirty-five high-risk HIV-seronegative and 99 HIV-seropositive Danish homosexual men followed form 1985 to 1996 and 37 blood donors were analysed for their CKR-5 genotype by polymerase chain reaction. RESULTS: Two (6%) of the 35 HIV-seropositive subjects at high-risk of infection were homozygous and seven (20%) were heterozygous for the CKR-5 deletion. This was not significantly different from the distribution in normal donors. Twenty-two (22%) of the 99 HIV-seropositive subjects were heterozygous and none was homozygous. Two subgroups of patients who had an opposite course of the HIV disease were identified. Of nine long-term non-progressors, six (66%) were heterozygous for the deletion. This frequency is significantly higher than in nine rapid progressors of whom non was heterozygous. The frequency of heterozygotes in long-term non-progressors was also significantly higher than in the cohort as a whole. A Kaplan-Meier plot of the HIV-seropositive subjects, of whom 57 developed AIDS, showed a significantly better prognosis within the first 7 years of follow-up for those who were heterozygous for the deletion. Heterozygous individuals also had a significantly slower decrease in CD4 T-cell count per year. CONCLUSION: Individuals who are heterozygous for the 32-base-pair deletion in the CKR-5 gene have a slower decrease in their CD4 T-cell count and a longer AIDS-free survival than individuals with the wild-type gene for up to 11 years of follow-up.
CD4 Lymphocyte Count↗
Population studies of the human V kappa A18 gene polymorphism in Caucasians, blacks and Eskimos. New functional alleles and evidence for evolutionary selection of a more restricted antibody repertoire.
Immunoglobulin gene polymorphisms are interesting because they reflect differences in the available antibody repertoire which may affect the susceptibility to specific infections. Until recently, the human V kappa gene, A18, was known as a nonfunctional gene only. In this study, we cloned and sequenced four apparently functional alleles and determined the gene frequencies in three well-defined populations: Danish Caucasians, eastern Greenland Eskimos and Mozambican blacks. The A18b allele that was recently described in Native American Navajos by Atkinson et al. was found in all three populations with gene frequencies of 8%, 45% and 23% in Caucasians, Eskimos and blacks, respectively. Conversely, the frequencies of the nonfunctional A18a allele were 92%, 55% and 57%. Further, three new A18 alleles, c, d, and e were found exclusively in blacks, among whom they had an total frequency of 19%. These data indicate that both the A18a and A18b alleles originated before the diversification of Africans and non-Africans 90,000 years ago, whereas the A18c, A18d and A18e alleles may have a more recent origin. The functionality of the A18b allele was documented by the demonstration of properly rearranged and somatically hypermutated A18b messenger RNA present in the blood lymphocytes of individuals carrying this allele. The expression clearly exceeded that of a known functional V gene, A2, indicating that functional A18 alleles contribute significantly to the available antibody repertoire. In this context, it is surprising that the functional A18b allele apparently has been negatively selected in the Caucasian population, among whom 85% completely lack a functional gene.
Alleles↗
Immobilized heparin inhibits the increase in leukocyte surface expression of adhesion molecules.
The effect of heparin coating of artificial materials on the surface expression of leukocyte surface molecules was assessed in blood from 9 donors in an experimental model of extracorporeal circulation. The leukocyte surface molecules CD11b, complement receptor type 3 (CR3), and CD45, leukocyte common antigen (LCA), on granulocytes and monocytes exposed to unmodified polyvinyl chloride tubes increased significantly compared with unmanipulated controls (p < 0.001) whereas a very modest and nonsignificant increase was observed in blood circulated in heparin-coated tubes. Accordingly, a highly significant reduction in expression of the 2 molecules was achieved by heparin coating (p < 0.001). The expression of CD11b and CD45 correlated with the degree of complement activation in plasma (rho = 0.6, p = 0.003). The expression of CD14 (endotoxin receptor) and CD16 (Fc gamma III receptor) was increased to the same extent in blood from unmodified and heparin-coated tubes (p < 0.02), and no correlation to complement activation was seen (rho = -0.275, p = 0.17 and rho = -0.004, p = 1, respectively). In conclusion, heparin coating of artificial surfaces has a substantial effect, reducing the expression of molecules involved in cellular adhesion and activation (CD11b and CD45), and the increase of these molecules by unmodified surfaces is complement dependent. In contrast, up-regulation of other surface molecules (CD14 and CD16) seems to be independent of heparin coating and complement activation and, thus, might be regulated by other mechanisms.
Anticoagulants↗
Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.
BACKGROUND: Acquired deficiencies of certain complement proteins and impaired opsonisation activity have been implicated in the pathogenesis of the increased susceptibility to infections of patients with alcoholic cirrhosis. METHODS: Serum concentrations of C3 and C4, plasma concentrations of C3bc, C9, and the terminal C5b-9 complement complex (TCC), and haemolytic complement activity (classic and alternative pathway) of serum, and serum opsonic activity were determined in 46 patients with compensated alcoholic cirrhosis, 31 who were decompensated, and in 15 healthy subjects. After 19 months (median) the investigated variables were analysed for their use in prognosis of recurrent infections and survival. RESULTS: C3 and C4 concentrations and the haemolytic complement activity of the alternative pathway were decreased in decompensated cirrhotic patients compared with controls (p < 0.01). Univariate analysis (log rank test) showed that low concentrations (< or = lower quartile) of C3 (p < 0.001) and C3bc (p < 0.05), haemolytic complement activity of the alternative pathway (p < 0.01) and classic pathway (p < 0.05), and decompensated cirrhosis (p < 0.001) were associated with an increased risk of infection and increased mortality. Multivariate (Cox) analysis showed that low C3 concentrations and decompensation of cirrhosis were significant predictors of infections and mortality (p < 0.02). CONCLUSIONS: Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.
Adult↗
[Plasma calprotectin. A new prognostic marker of survival in alcoholic liver cirrhosis].
The purpose of this study was to determine plasma concentrations of calprotectin in patients with different severity of alcoholic cirrhosis. Additionally, the prognostic value of calprotectin for recurrent infections and for survival was investigated after a median observation period of 19 months. No difference was found in calprotectin levels when comparing healthy controls (n = 16), compensated (n = 50) and decompensated cirrhotics (n = 34). However, high calprotectin concentrations (> median) was a significant prognostic marker of poor survival (p = 0.001, Log-rank test). Calprotectin levels (> median) showed an independent and much higher prognostic value than variables of liver disease (multivariate Cox model). During follow-up calprotectin levels (> median) were also a predictor of recurrent infection (p = 0.009, Log-rank test). Thus, in patients with alcoholic cirrhosis, plasma calprotectin appears to be a new prognostic marker of survival, which seems independent of severity of liver disease. Furthermore, high plasma calprotectin levels may characterize a group of cirrhotics with recurring bacterial infections.
Adult↗
Anti-interleukin-6 autoantibodies in plasma are associated with an increased frequency of infections and increased mortality of patients with alcoholic cirrhosis.
Altered cytokine metabolism has been implicated in the pathogenesis of alcoholic liver disease. Recently, autoantibodies to cytokines have been proposed to act as modifiers of cytokine functions. In this study plasma levels of anti-interleukin-1 alpha (IL-1 alpha autoantibodies and anti-IL-6 autoantibodies were determined by RIAs in 96 patients with alcoholic cirrhosis and in 16 healthy individuals. After 19 months (median) the prognostic significance of the cytokine autoantibodies was investigated using univariate analysis (Log-rank test) and multivariate regression analysis (Cox model). The seroprevalences of anti-IL-1 alpha autoantibodies and anti-IL-6 autoantibodies (42 and 18%, respectively) in the patients were not different from healthy individuals and did not relate to severity of liver disease. The presence of anti-IL-1 alpha autoantibodies was of no prognostic significance. Independent of severity of liver disease, patients with anti-IL-6 autoantibodies in plasma had a higher risk of acquiring infections and higher risk of death (P < 0.02) compared to patients without anti-IL-6 autoantibodies. The authors concluded that anti-IL-6 autoantibodies are associated with increased mortality when present in the plasma of patients with alcoholic cirrhosis, which is probably secondary to recurrent infections, but not to underlying severity of liver disease.
Adult↗
Serum clusterin and vitronectin in alcoholic cirrhosis.
Clusterin and vitronectin are multifunctional regulatory proteins which both serve as complement lysis inhibitors. Previous data have strongly suggested that serum vitronectin is mainly produced in the liver, whereas the biosynthetic origin for serum clusterin has not been determined. In the present study we aimed to determine the role of the liver in producing these proteins and to evaluate the proteins as possible markers of liver failure. We therefore quantified clusterin and vitronectin in serum from patients suffering from alcoholic liver cirrhosis (n = 83), and in serum-free culture supernatants from the hepatoma cell line HepG2. The median clusterin concentration was 0.20 g/l in cirrhosis and 0.37 g/l in the controls, whereas corresponding vitronectin values were 0.19 and 0.26 g/l, respectively. The concentration of both proteins showed significant correlation (p < 0.0001) with disease severity and with established plasma markers of hepatic synthetic function, such as albumin and prothrombin complex. The clusterin level, but not the vitronectin level, correlated with survival (p = 0.005). The rates of synthesis of clusterin, vitronectin and C3 from HepG2 cells were 0.02, 0.21 and 1.9 micrograms/10(6) cells/24 h, respectively. From the present data we conclude that clusterin (as vitronectin and C3) is mainly produced in the liver and may be a useful marker in the evaluation of severity of liver disease and prognosis of patients with alcoholic cirrhosis.
Adult↗
Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency.
A low plasma concentration of mannan-binding protein (MBP) impairs opsonisation and phagocytosis. Three different mutations in the MBP gene have a dominant effect on MBP concentration. We investigated the frequency of the abnormal MBP alleles in 228 unrelated patients suspected of various non-HIV-related immunodeficiencies. The frequency of heterozygotes for the abnormal alleles was not different from that in the background population (36.0% and 37.4%, respectively). By contrast, the frequency of homozygotes for the abnormal alleles was significantly increased (8.3% and 0.8%, respectively; p = 0.0017). This finding implies that homozygotes for abnormal MBP alleles are predisposed to recurrent infections.
Alleles↗
Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein.
Mannan-binding protein (MBP) is a serum lectin participating in the innate immune defense by opsonizing various microorganisms for phagocytosis. Opsonization defect due to MBP deficiency and low levels of the protein can partially be explained by the dominant effect of three different mutations in the structural part of the MBP gene. Large interracial differences in the frequencies of these variants have previously been described, but they cannot explain the large interindividual variation in MBP serum concentration. We describe the existence of additional polymorphisms at positions -550 (H/L variants) and -221 (X/Y variants) in the promoter region of the gene. The promoter haplotypes, HY, LY, and LX, show associations with high, medium, and low levels of MBP serum concentrations, respectively. Moreover, this represents a genetic system with additive effect of haplotypes in which a low producing LX haplotype in the homozygous state down-regulates the basal expression of MBP as effectively as a single structural variant. Populations of pure Eskimos, Caucasoids, and black Africans show marked interethnic differences in the frequencies of promoter haplotypes regulating the expression of the normal peptide, with the HY haplotype frequency varying from 0.83 in Eskimos via 0.33 in Caucasoids to 0.08 in Africans. The LY haplotype frequency varies from 0.04 in Eskimos via 0.39 in Caucasoids to 0.23 in Africans. The LX haplotype frequency varies from 0.03 in Eskimos via 0.24 in Caucasoids to 0.23 in Africans. The effect of the promoter variants can explain almost all of the ethnic differences not explainable by the structural variants alone.
Base Sequence↗