Biomedical subjects

K I Welsh

Publications and source records attributed to K I Welsh.

At least 19 recordsLinked to original sources

PubMed2001

Ace gene I/D polymorphism and sarcoidosis pulmonary disease severity.

Previous studies of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in sarcoidosis have revealed both ethnic heterogeneity of I/D frequencies and controversy surrounding the association between the polymorphism and severity of disease. The objective of this study was, therefore, to clarify the role of the ACE I/D polymorphism in (1) disease susceptibility, (2) pulmonary disease severity (with particular reference to pulmonary fibrosis), and (3) pulmonary disease progression, in two distinct European sarcoidosis populations. Standard chest radiographic staging was performed on 118 UK and 56 Czech white patients with sarcoidosis at 2 yr from presentation. Pulmonary function data were analyzed, and patients were then categorized according to disease severity. A PCR-SSP assay was used to determine the ACE I/D genotype of each patient studied. The I/D allele frequencies from these patients were compared with frequencies from ethnically matched UK (n = 386) and Czech (n = 179) control subjects using a chi-square contingency table. No significant differences were seen in the distribution of the ACE I/D genotypes, allele frequencies or phenotype frequencies. Furthermore, no association was found between the ACE I/D polymorphism and pulmonary disease severity, fibrosis, and progression. We conclude that the ACE I/D polymorphism has no role in sarcoidosis susceptibility in European whites and that it is not a regulatory variant in this disease.

Adult↗

PubMed2001

Donor cytokine genotype influences the development of acute rejection after renal transplantation.

BACKGROUND: Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. Although rejection is mediated by recipient lymphocytes, both donor and recipient factors contribute to the local environment that influences the nature, severity, and duration of the rejection response. Cytokines are a major determinant of this milieu, and this study sought to explore the impact of donor cytokine and cytokine receptor gene polymorphisms on acute rejection after renal transplantation. METHODS: A total of 145 cadaveric renal allograft donors were selected for analysis according to the presence or absence of graft rejection in the first 30 days after transplantation. DNA was genotyped for 20 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reaction with sequence specific primers. Associations were assessed using contingency table analysis and the chi2 test, using a two-set design. RESULTS: A polymorphism at position -174 of the donor IL-6 gene was associated with the incidence (P=0.0002) and severity (P=0.000007) of recipient acute rejection. This finding was independent of HLA-DR matching. Acute rejection was not influenced by recipient IL-6 genotype, or by donor-recipient matching of IL-6 genotype. CONCLUSION: This study identifies donor IL-6 genotype as a major genetic risk factor for the development of acute rejection after renal transplantation. This provides evidence that donor-derived cytokines play a major role in determining outcome after transplantation, and will contribute to the development of therapeutic algorithms to predict individuals at particularly high risk of acute rejection.

Acute Disease↗

PubMed2001

CD1 genotyping of patients with Mycobacterium malmoense pulmonary disease.

Mycobacterium malmoense is an opportunistic mycobacterium that occasionally causes disease in non-immunosuppressed individuals. As only a few individuals exposed to these organisms actually develop clinical disease, it is possible there is a genetic component to susceptibility. CD1 molecules are capable of presenting antigens from more virulent mycobacteria to T cells; therefore, we were interested in discovering whether recently described polymorphisms in CD1 molecules modulated susceptibility to M. malmoense pulmonary disease. The CD1 system comprises five genes (CD1A, -B, -C, -D, and -E) located on chromosome 1 (1q22-23). CD1 molecules are structurally and functionally related to major histocompatibility complex (MHC) class I molecules and are expressed on dedicated antigen-presenting cells. The primary function of CD1 molecules is to present lipid and glycolipid antigens to T cells. We have developed an allele-specific polymerase chain reaction-sequence-specific primer (PCR-SSP) method of CD1 genotyping. Using this method, we compared the allele and haplotype frequencies of CD1 in 49 HIV-negative patients with M. malmoense pulmonary disease with those in 342 normal controls. The CD1A and CD1E alleles were nominally identified as CD1A*01, CD1A*02, CD1E*01 and CD1E*02, and the control gene frequencies were found to be 5%, 95%, 67% and 33%, respectively. No significant difference was observed between the patient and control cohorts. Positive linkage disequilibrium values of 0.73 were observed between CD1A*02 and CD1E*01 (P<0.0001; chi2 test), and 0.94 between CD1A*01 and CD1E*02 (P<0.0001; chi2 test). Typing was also performed for two previously described CD1D alleles (CD1D*01 and CD1D*02), although only CD1D*01 was detected.

Antigens, CD1↗

PubMed2001

Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP.

Scleroderma is a condition of variable phenotype characterised by fibrosis of the skin and internal organs. There is a range of disease-specific autoantibodies found in the sera of patients. The aims of this study were to: (1) investigate the role of the MHC and particularly HLA-DP in the production of autoantibodies; (2) investigate clinical associations with autoantibodies. We have performed HLA class II typing using PCR with sequence-specific primers on DNA samples from 202 scleroderma patients and 307 UK control subjects. All patients had well defined clinical phenotypes. Sera from patients were examined for the presence of disease specific autoantibodies in particular the anti-topoisomerase autoantibody (ATA), the anti-centromere autoantibody (ACA) and the anti-RNA polymerase autoantibody (ARA). There was a striking association between HLA-DPB1*1301 and ATA (Pcorr = 0.0001). In addition, ATA was associated with HLA-DRB1*11 and the anticentromere autoantibody (ACA) with HLA-DRB1*04, HLA-DRB1*08 (P = 0.001) and HLA-DQB1 alleles with a glycine residue at position 26. Very strong associations were detected between clinical phenotypes and autoantibodies. ATA was associated with pulmonary fibrosis (P = 0.00002), anti-RNA polymerase autoantibody (ARA) with renal involvement (P = 0.0000006) and diffuse skin disease (P = 0.00001), and ACA with limited skin involvement (P = 0.00002) and protection against pulmonary fibrosis (P = 0.0000003). We have identified a significant association between the ATA and HLA-DPB1*1301 which may provide an insight into how this autoantibody is formed. Patient clinical characteristics depend on the autoantibodies they carry.

Autoantibodies↗

PubMed2001

The role of cytokine polymorphisms in rejection after solid organ transplantation.

The importance of cytokines to the immune response is irrefutable. Their role in the biology of solid organ transplantation per se is also assured. Thus it is likely that subtle differences in cytokine composition, particularly at the initiation of an immune response, may have a major effect on the outcome of that response. This may be particularly relevant in solid organ transplantation, where it is possible that genetic polymorphisms which influence cytokine production may determine the outcome of a transplant. Indeed, it has been suggested that immunosuppression may be individualised on the basis of recipient or donor genotype. However, much of the early data regarding the importance of specific cytokine polymorphisms has not been reproduced, and the significance of this field remains controversial. Nonetheless, with the experience gained from earlier studies, some clear patterns for future studies are emerging.

Cytokines↗

PubMed2001

Rising incidence of post-transplant lymphoproliferative disease in kidney transplant recipients.

BACKGROUND: The purpose of this study was to determine whether the incidence of post-transplant lymphoproliferative disease (PTLD) has been increasing in renal transplant recipients in this centre. METHODS: Prospectively gathered data were analysed to establish trends in the epidemiology of PTLD in 1537 patients. RESULTS: Overall, PTLD occurred in 2.3 per cent of renal transplant recipients. An increase in its incidence coincided with the introduction of cyclosporin in the 1980s. However, there was a further increase in the incidence of PTLD in the 1990s when the only change in immunosuppressive policy was the abandonment of pretransplantation blood transfusion. The latter increase was particularly pronounced in patients with early-onset PTLD in whom it presented within 600 days after transplantation. CONCLUSION: The incidence of PTLD has been increasing in renal transplant recipients. The recent increase appears to be independent of cyclosporin and may reflect the reduction in pretransplant blood transfusion. Changes in the incidence of PTLD may also mirror changes in the epidemiology of non-Hodgkin lymphoma in the general population.

England↗

PubMed2001

Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production.

BACKGROUND: Class I human leucocyte antigens (HLA) -A, -B, -Cw and class II HLA-DRB1, -DQB1 alleles were determined in 131 British Caucasian patients with mucous membrane pemphigoid (MMP) using serological and DNA-based methods. OBJECTIVES: To analyse the class I and II alleles expressed in well-defined clinical and immunopathological subgroups of MMP, in order to establish whether specific alleles or haplotypes might in part explain disease susceptibility, clinical sites of involvement or disease severity. METHODS: Subgroups of patients were analysed according to the following clinical criteria: age of onset, sex, sites of clinical involvement (oral, ocular, skin, nasal, genital, pharyngeal, oesophageal, laryngeal, perianal), disease severity and history of autoimmune disease. Subgroups were also analysed according to the following immunopathological criteria: autoantibody profile, the presence of circulating antibasement membrane IgG or IgA antibodies and the detection of target basement membrane zone (BMZ) antigens (BP230 and BP180) by IgG autoantibodies. RESULTS: Class I HLA typing showed no significant disease or subgroup associations. Class II DRB1 typing showed a significantly increased allelic frequency in MMP vs. controls for DRB1*11 (RR = 2.08, Pc < 0.0000056). For DQB1, MMP vs. controls, there was a significantly increased allelic frequency for DQB1*0301 (Pc < 0.00000028) in both males and females; all clinical sites of involvement, with the exception of laryngeal, oesophageal and perianal sites and in patients with detectable circulating anti-BMZ IgG compared with those negative for IgG (P < 0.0096, Pc < 0.019). A positive trend was noted in patients with ocular involvement compared with no ocular involvement and in patients with a clinical score > or = 10 compared with < 10. We found no difference in DQB1*0301 allele frequency between subgroups with or without BP180 or BP230 target antigens. Haplotype frequencies showed an increase in DRB1*04, DQB1*0301 (Pc < 0.000066) and DRB1*11, DQB1*0301 (Pc < 0.000002) among patients compared with controls. CONCLUSIONS: The DQB1*0301 allele confers a predisposition to all subgroups of MMP and may have a role in T-cell recognition of basement membrane antigens, resulting in the production of anti-BMZ IgG autoantibodies. The positive trend between increased allelic expression of DQB1*0301 in patients with ocular disease and in those with a higher clinical score, further suggests a role for this allele in disease severity.

Adult↗

PubMed2001

MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy.

MHC class I chain gene A (MICA) is a non-classical Class I gene which is expressed on the surface of epithelia without beta 2-microglobulin. The gene is found in the major histocompatibility complex (MHC) in tight linkage disequilibrium with human leucocyte antigen-B (HLA-B). Its precise function is unknown, but it interacts with gamma delta T cells of the intestinal immune system. This region of the MHC has been implicated in inflammatory bowel disease (IBD) pathogenesis by recent association mapping studies and this study was performed to examine the prevalence of MICA gene polymorphisms in IBD, in particular in type 2 peripheral arthropathy (PeA), which also has a strong HLA-B association. An assessment of the prevalence of MICA polymorphisms in IBD was made. Blood from 50 ulcerative colitis (UC) and 50 Crohn's disease controls was taken and MICA status determined using allele-specific PCR for 16 known alleles of MICA. A further 91 UC patients were recruited to confirm the results of this stage, and then the polymorphisms were studied in 52 type 1 and 45 type 2 PeA patients. The MICA status of these groups was compared with 118 blood and organ donor controls with appropriate correction for multiple comparisons. UC overall was associated with possession of MICA*007 in 32% compared to 11% of controls (P(c) = 0.017). This association was confirmed in a second cohort of 91 patients (23% versus 11%, P = 0.02). These were independent of HLA class I status. Type 2 IBD PeA was associated with MICA*008 in 98% compared to 73% of controls (P = 0.0001). MICA*007 is associated with susceptibility to UC in our population and MICA*008 with type 2 IBD PeA. Further work is now required to assess the distribution and expression of MICA throughout the gut in health and disease.

Case-Control Studies↗

PubMed2001

Histocompatibility leucocyte antigens and closely linked immunomodulatory genes in autoimmune thyroid disease.

OBJECTIVES: Associations between autoimmune thyroid disease and antigens of the major histocompatibility complex (MHC) have long been recognized. Graves' disease (GD) is associated with the histocompatibility leucocyte antigen (HLA) haplotype A*01-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 (or B8/DR3) whereas autoimmune hypothyroidism (AIH) has been weakly associated with HLA DRB1*03, *04 and *11/*12 alleles (or DR3, DR4 and DR5). However, the presence of important immunoregulatory genes within the HLA Class II and III regions raises the possibility that these genes harbour the primary susceptibility locus. This study examines genetic variation across the MHC in UK Caucasoid subjects with autoimmune thyroid disease. PATIENTS AND METHODS: DNA extracted from venous blood samples from 215 patients with autoimmune thyroid disease (GD 135, AIH 77) and 267 control subjects was analysed. Genotyping was performed using polymerase chain reaction and sequence specific primers for HLA Class I and II alleles and polymorphisms within the TAP1, TAP2, tumour necrosis factor (TNF), lymphotoxin alpha (LTalpha), heat shock protein (HSP)70-1, HSP70-2 and HSP70-Hom genes. RESULTS: For GD, the strongest association was with DRB1*03 [56% patients positive vs. 24% controls, P = 2 x 10(-10), odds ratio (OR) 4.0]. Positive associations were also seen for DRB1*03 linked alleles, B*0801, DRB3*01/02, DQA1*05, DQB1*02 and DPB1*0101 (OR 2.3-3.4). Specific TNF and LTalpha alleles were strongly associated with GD (Pc = 3 x 10(-5) and 0.001) and weak associations were seen for HSP70-1 + 190C and HSP70-2 + 1267G polymorphisms (Pc = 0.05 and 0.01). These associations were not significant when DRB1*03 status was considered. Patients with AIH showed only a weak association with DQB1*03 (P = 0.02). CONCLUSIONS: These results show that, of the polymorphisms tested within the MHC, GD is most strongly associated with DRB1*03, and associations with other immunoregulatory genes previously described in Caucasian subjects most likely reflect linkage disequilibrium. AIH differs from GD, being less influenced by the MHC region.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Endothelial cell protection against ischemia/reperfusion injury by lecithinized superoxide dismutase.

BACKGROUND: Organs used for transplantation may experience long periods of cold ischemic preservation and consequently oxygen free radical-mediated damage following reperfusion. Lecithinized superoxide dismutase (lec-SOD) is a novel free radical scavenger that has been shown to bind with high affinity to cell membranes. The aim of this study was to determine whether lec-SOD bound to endothelial cells under organ preservation conditions to mediate direct antioxidant activity at the endothelial cell surface and thus offer protection against the harmful effects of ischemia/reperfusion injury. METHODS: An in vitro study was performed on large vessel endothelial cells (HUVEC) and a human microvascular endothelial cell line HMEC-1, to investigate the potential therapeutic benefits of incorporating lec-SOD into organ preservation solution. A cold hypoxia/reoxygenation system was developed to examine lec-SOD binding affinity to endothelial cells, protection against hypoxia/reoxygenation-induced cell death, and neutrophil adhesion. RESULTS: Lec-SOD bound to endothelial cells with higher affinity than unmodified recombinant human superoxide dismutase (rhSOD) and significantly protected both HUVEC and HMEC-1 from cell death following 27 hours of cold hypoxia (P < 0.01). Furthermore, neutrophil adhesion to the endothelium stimulated by hypoxia and reoxygenation was significantly inhibited by treatment with lec-SOD but not by lecithin or rhSOD (P < 0.01). Analysis by flow cytometry demonstrated that E-selectin and ICAM-1 were up-regulated by hypoxia/reoxygenation that was inhibited in part by lec-SOD. CONCLUSIONS: The results from this study suggest that incorporation of lec-SOD into organ preservation solutions provides effective protection to endothelial cells against cold ischemia and reperfusion injury following transplantation.

Antioxidants↗

PubMed2001

A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis.

BACKGROUND AND AIMS: We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A). METHODS: An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease [IBD]) and 99 healthy subjects (HS) were genotyped. In stage 2, 59 PSC patients (49 IBD), 84 patients with uncomplicated ulcerative colitis, and 72 HS were genotyped. RESULTS: In stage 1, 5A carriage rate (90.4% vs. 72.7%; P = 0.012) and 5A allelic frequency (65.4% vs. 48.5%; P = 0.005) were increased, and 6A homozygosity was reduced in PSC (9.6% vs. 27.3%; P = 0.012). In stage 2, 5A allelic carriage was increased in PSC (93.2% vs. 76.4% in HS; P = 0.0092) and 6A homozygosity was reduced (6.8% vs. 23.8% in HS; P = 0.0092). Portal hypertension was associated with 5A homozygosity in PSC (P = 0.035; odds ratio [OR], 3.88). In the combined data set, 5A allelic frequencies (63.5% vs. 49.4%; P = 0.001; OR, 1.78) and 5A carriage rates (91.9% vs. 74.2%; P = 0.0002; OR, 3.92) were increased, and 6A homozygosity was reduced in PSC (8.1% vs. 25.7%; P = 0.0002; OR, 0.25). Overall, portal hypertension was associated with 5A homozygosity (P = 0.0192; OR, 3.12). CONCLUSIONS: Stromelysin polymorphism may influence susceptibility and disease progression in PSC.

Adult↗

PubMed2001

Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine.

OBJECTIVE: To compare fluoxetine, a selective serotonin reuptake inhibitor, with nifedipine as treatment for primary or secondary Raynaud's phenomenon. METHODS: Twenty-six patients with primary and 27 patients with secondary Raynaud's phenomenon were assigned randomly to receive 6 weeks of treatment with fluoxetine (20 mg daily) or nifedipine (40 mg daily). Following a 2-week washout period, each group was crossed over to the other treatment arm. The primary outcome variable was the frequency of attacks of Raynaud's phenomenon. Self-reported attack severity, thermographic recovery from cold challenge and plasma levels of von Willebrand factor and soluble P-selectin were also measured. RESULTS: There was a reduction in attack frequency and severity of Raynaud's phenomenon in patients treated with either fluoxetine or nifedipine, but the effect was statistically significant only in the fluoxetine-treated group (P=0.0002 for attack severity and P=0.003 for attack frequency). Subgroup analysis showed that the greatest response was seen in females and in patients with primary Raynaud's phenomenon. A significant improvement in the thermographic response to cold challenge was also seen in female patients with primary Raynaud's phenomenon treated with fluoxetine but not in those treated with nifedipine. There was no significant treatment effect on von Willebrand factor or soluble P-selectin. No significant adverse effects occurred in the fluoxetine-treated group. CONCLUSION: This pilot study confirms the tolerability of fluoxetine and suggests that it would be effective as a novel treatment for Raynaud's phenomenon. Larger and placebo-controlled trials are warranted to assess fluoxetine's therapeutic potential further in this vasospastic condition.

Adult↗

PubMed2001

Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation that is associated with structural damage of the lung and fibrosis. Although the etiology of IPF is unknown, it is likely to involve an interaction between environmental and multiple genetic components. Animal models of pulmonary fibrosis have shown that proinflammatory mediators are critical at both the inflammatory and fibrotic stages of the disease. Genetic variants exist in genes encoding proinflammatory mediators, as well as in genes encoding their receptors, which makes these genes candidates for the pathogenesis of IPF. In the present study, we examined 12 biallelic polymorphisms in the genes for tumor necrosis factor (TNF)-alpha (+488[G/A], -238[G/A], -308[G/A]), lymphotoxin (LT)-alpha (+720[C/A], +365[C/G], and +249[A/G], determining haplotypes LT-alpha1 to LT-alpha4), tumor necrosis factor-receptor 2 (TNF-RII) (gb:M32315: 676[T/G], 1663[A/G], 1668[T/G], 1690[C/T]), and interleukin- (IL)-6 (promoter -174[G/C], intron 4[A/G]). We also examined the haplotypes determined by the three biallelic polymorphisms in each of the TNF-alpha and LT-alpha genes. As compared with a normal control population, the IPF group showed no significant deviations in genotype, allele, or haplotype frequencies. Surprisingly, in the IPF population, but not in the control population, an increased frequency of cocarriage of the IL-6 intron 4G and the TNF-RII 1690C alleles was observed, despite the location of the two genes on different chromosomes. Moreover, using impairment of carbon monoxide transfer (DL(CO)) adjusted for duration of dyspnea as a marker of rapidity of disease progression, we found that the IL-6 intron 4GG genotype was the only genotype independently associated with lower DL(CO) levels. These findings, if independently confirmed, will be the first to suggest that disease progression in IPF may be linked to a particular genetic marker or to functional polymorphisms in other genes near that marker.

Antigens, CD↗

PubMed2001

Human leukocyte antigen-DRB1 position 11 residues are a common protective marker for sarcoidosis.

Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susceptibility to sarcoidosis, a chronic granulomatous disease of undetermined etiology. To clarify the role of HLA in sarcoidosis we determined HLA-DR and -DQ alleles in case-control samples from three European populations (United Kingdom, Czech, and Polish) and compared these results with those published for three additional populations (Italian, Japanese, and Scandinavian) to determine whether the HLA-DR and/or -DQ alleles act as ethnic-dependent, or ethnic-independent modifiers of disease risk. Although variations were apparent in the alleles associated with susceptibility, reductions in the frequency of alleles associated with protection were remarkably consistent in the six populations. Previously detected associations between single-nucleotide polymorphisms at the TAP2 locus and sarcoidosis were shown to be due to linkage disequilibrium with the HLA-DR locus. The protective HLA-DR alleles, which encode the DR1 and DR4 antigens, were found to share characteristic small hydrophobic residues at position 11, which were replaced by small hydrophilic residues in the remaining, nonprotective, HLA-DR alleles. This residue position is within a pocket of the HLA-DR complex antigen binding groove (designated P6), where it is the only variable amino acid and therefore determines the peptide binding preferences of this pocket. A highly significant reduction in the frequency of individuals carrying HLA-DR alleles with a hydrophobic residue at position 11 was observed in the sarcoidosis cases in the three populations we examined. This suggests this HLA-DR residue is an important protective marker in sarcoidosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection.

The inflammatory disease human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM/TSP) occurs in only 1-2% of HTLV-I-infected individuals and is associated with a high provirus load of HTLV-I. We hypothesize that a person's risk of developing HAM/TSP depends upon the efficiency of their immune response to the virus, which differs between individuals because of polymorphism in genes that influence this response. Previously we showed that the possession of HLA-A*02 was associated with a lower risk of HAM/TSP, and with a lower provirus load in healthy carriers of HTLV-I. However, HLA-A*02 did not account for all the observed difference in the risk of HAM/TSP. Here we present evidence, in the same study population in Japan, that HLA-Cw*08 was also associated with disease protection (probability value, two-tailed test = 0.002) and with a lower proviral load in healthy carriers. Possession of the A*02 and/or Cw*08 genes prevented 36% of potential HAM/TSP cases. In contrast, HLA-B*5401 was associated with a higher susceptibility to HAM/TSP (probability value, two-tailed test = 0.0003) and with a higher provirus load in HAM/TSP patients. At a given provirus load, B*5401 appeared to increase the risk of disease. The fraction of HAM/TSP cases attributable to B*5401 was 17%. Furthermore, individuals who were heterozygous at all three HLA class I loci have a lower HTLV-I provirus load than those who were homozygous at one or more loci. These results are consistent with the proposal that a strong class I-restricted CTL response to HTLV-I reduces the proviral load and hence the risk of disease.

Alleles↗

PubMed2000

The impact of recipient cytokine genotype on acute rejection after renal transplantation.

BACKGROUND: Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. As cytokines are major regulators of the immune system, genetic variation in cytokine production or activity may influence susceptibility to acute rejection. This study sought to determine the impact of recipient cytokine and cytokine receptor polymorphisms on acute rejection after renal transplantation. METHODS: A total of 209 cadaveric renal transplant recipients were selected for analysis according to the presence or absence of graft rejection in the first 30 days after transplantation. DNA was genotyped for 22 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reaction with sequence specific primers. Results were stratified by incidence and severity of rejection, and by HLA-DR mismatching. RESULTS: No association between any polymorphism and the incidence or severity of acute rejection was detected. In particular, no association was seen with tumor necrosis factor or interleukin-10 genotype, either alone or in combination. CONCLUSIONS: We have failed to demonstrate any association between recipient cytokine genotype and acute rejection after cadaveric renal transplantation. Although more extensive studies may disprove these findings, it would seem premature to use recipient cytokine genotyping to predict transplant outcome, or to guide immunosuppressive therapy after transplantation.

Acute Disease↗

PubMed2000

A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer.

Exposure to UV radiation is a major risk factor for the development of malignant melanoma. DNA damage caused by UV radiation is thought to play a major role in carcinogenesis induction. Multiprotein pathways involved in repairing UV-DNA damage are the base excision, the nucleotide excision, and the homologous double-stranded DNA repair pathways. This study used a sequence-specific primer PCR (PCR-SSP) genotyping method to investigate the association between polymorphisms in DNA repair genes from these pathways with the development of malignant melanoma. The patient cohort was comprised of 125 individuals with malignant melanoma with lesions or staging suggesting a high risk of relapse or metastatic disease. The control population consisted of 211 individuals. We found the presence of a T allele in exon 7 (position 18067) of the XRCC3 gene was significantly associated with melanoma development (P = 0.004; odds ratio, 2.36; relative risk, 1.74). This gene codes for a protein involved in the homologous pathway of double-stranded DNA repair, thought to repair chromosomal fragmentation, translocations, and deletions. These results may provide further insights into the pathogenesis and the mechanism of UV-radiation induced carcinogenesis as well as having a role in prevention.

Adult↗

PubMed2000

Detection of HLA-specific IGG antibodies using single recombinant HLA alleles: the MonoLISA assay.

BACKGROUND: Because of the presence of confounding antigens, the assignment of HLA antibody specificity is difficult in highly sensitized patients, and the definition of an acceptable HLA mismatch requires a significant workload per patient. We describe a new ELISA method, monoLISA, for detection of immunoglobulin (Ig)G HLA antibody using single recombinant HLA class I monomers bound to microtiter plates. METHODS: HLA-A2 and -B8 monomers were synthesized and used as screening targets for 85 sera from renal patients. The sera contained various IgG and IgM HLA-specific antibodies, including anti-A2 and anti-B8,defined in a conventional complement-dependent cytotoxicity test (CDC). Investigations were performed to determine possible effects on antibody binding of differential monomer peptide presentation as well as lack of glycosylation. RESULTS: A good correlation was found between CDC-defined specificities and the reactivity observed with HLA monomers. MonoLISA attained means of 100% sensitivity and 92.5% specificity compared with CDC. Neither the presence of different peptides, nor the absence of glycosylation of the monomer affected the ability of monoLISA to detect antibody. CONCLUSION: This study demonstrates that the mono-LISA method for HLA antibody detection is valid. Because this has the potential to reduce the work involved in screening sensitized patients awaiting transplantation for HLA antibodies, resources aimed at increasing the number of constructed monomers would be well targeted.

Alleles↗