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PubMed1997

Quantification of the relative contribution of major histocompatibility complex (MHC) and non-MHC genes to human immune responses to foreign antigens.

Understanding the extent to which genetic factors influence the immune response is important in the development of subunit vaccines. Associations with HLA gene polymorphisms appear insufficient to explain the range of variation in immune responses to vaccines and to infections by major pathogens. In this study of Gambian twins we report that regulation of the immune response to a variety of antigens from Plasmodium falciparum and Mycobacterium tuberculosis is controlled by factors which are encoded by genes that lie both within and outside the major histocompatibility complex (MHC). We define the relative contribution of these genes, which varies for different antigens. The cumulative genetic contribution of non-MHC genes to the total phenotypic variance exceeds that of the MHC-encoded genes.

Antibody Formation↗

PubMed2003

Acne in infancy and acne genetics.

Acne is a disease that can be seen in the first year of age, early childhood, prepubertal age and puberty. Neonatal acne is due mainly to considerable sebum excretion rate, and infantile acne because of high androgens of adrenal origin in girls and of adrenal and testes in boys. These pathogenic mechanisms are characteristic in these ages. Important factors like early onset of comedones and high serum levels of dehydroepiandrosterone sulfate are predictors of severe or long-standing acne in prepubertal age. Hereditary factors play an important role in acne. Neonatal, nodulocystic acne and conglobate acne has proven genetic influences. Postadolescent acne is related with a first-degree relative with the condition in 50% of the cases. Chromosomal abnormalities, HLA phenotypes, polymorphism of human cytochrome P-450 1A1 and MUC1 gene are involved in the pathogenesis of acne. Several other genes are being studied.

Acne Vulgaris↗

PubMed2002

Peptide-based vaccines in the treatment of specific allergy.

The efficacy of conventional allergen-specific immunotherapy (SIT) for allergic conditions and venom hypersensitivity is well documented. However it's use is limited due allergic side effects including anaphylaxis and the difficulty of standardising proteins in complex allergenic mixtures. The aim of new therapeutic strategies is to circumvent these limitations and approaches include allergen non-specific therapy, such as anti-IgE and anti-cytokine therapy and other allergen specific techniques including the peptide based vaccines (PBV), modified allergens (allergoids) and DNA vaccines. PBV are small linear peptide fragments containing T cell epitopes which are designed to reduce the ability to cross link antigen-specific IgE. Studies in animal models have confirmed proof of principle demonstrating the induction of hyporesponsiveness using high doses of peptides. However, the principle limitation to clinical use of PBV is the polymorphism of HLA class II molecules. There are ongoing clinical studies using peptide-based vaccines for cat, bee and grass allergies--looking at both immunological mechanisms and clinical outcome measures. The mechanisms underlying the efficacy of PBV appear to be similar to those described for classical immunological tolerance. Thus, the peptides may induce anergy due to absence of co-stimulation, activation-induced cell death, a switch from a Th2 to a Th1 cytokine profile, the induction of regulatory T cells or combinations of these mechanisms. Successful immunotherapy, in bee sensitive individuals, is associated with the elaboration of IL-10. Clonal deletion is unlikely as an overall mechanism as there is evidence that the subsequent in vitro response to associated, non-injected, peptides can be suppressed. Mechanistic studies continue to provide insight into the mode of action of whole allergen and peptide-based immunotherapy. Clinical studies designed on the basis of these observations hold the promise of safer vaccines with improved efficacy. Whether this strategy can be used for allergy to complex allergen mixtures such as dust mites will need further evaluation.

Allergens↗

PubMed2026

Chimeric vaccine based on Iraqi HLA alleles against a predominant local Escherichia coli phylogroup.

INTRODUCTION: Escherichia coli remains amongst the most globally important pathogens implicated in severe clinical manifestations. The progressive rise in multidrug-resistant strains highlights the urgent need for new vaccines. Therefore, this study was designed to develop a new multi-epitope vaccine containing the most conserved epitopes across E. coli pathotypes. Consequently, the study aimed to investigate the immunoadjuvant role of faecal microbiota transplantation in enhancing vaccine efficacy. METHODS: Eighteen of the most conserved B-cell and T-cell epitopes of FimH, LptD, and BamA proteins were selected and included in a single construct. During the epitope selection process, HLA alleles predominant in the Iraqi population, as reported in previous studies, were used as criteria for selecting T-cell epitopes. The chimeric protein was expressed in BL21 E. coli and purified using affinity chromatography. Vaccine cross-protective immunity and protection were tested in in vivo experiments. Different formulations were used in the experimental evaluation: three doses of 100 μg of purified chimeric protein, injected intraperitoneally alone or encapsulated in PLGA nanoparticles, after faecal microbiota transplantation with and without gut microbiota modulation mediated by a cocktail of antibiotics. IgG1, IL-4, INF-γ, and NLRP3 levels were measured at 30 and 75 days after the first immunisation dose. Immunised mice were challenged with the local B2 UPEC phylogroup, and protection efficacy was considered 48 h later. Finally, the histological effects of the different chimeric protein formulations on the liver were assessed. RESULTS: All vaccine formulations except those after faecal microbiota transplantation without gut microbiota modulation induce significant increases in IgG1, IL-4, and INF-γ levels at different times. Only vaccination after faecal microbiota transplantation with gut microbiota modulation elicited robust NLRP3 levels at 30 and 75 days after, and this was linked to the highest reduction in bladder bacterial load by 813-fold compared to the other formulations, as well as the mildest effect on liver histological changes. DISCUSSION: These results demonstrated that the chimeric vaccine provides preliminary protection against a local B2 UPEC isolate. Furthermore, modulating gut microbiota via faecal transplantation markedly enhances the immunogenicity and protective efficacy of vaccination, suggesting its adjuvanticity.

Animals↗

PubMed2003

Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning.

Inflammatory bowel disease (IBD) includes two clinical subtypes: Crohn disease (CD) and ulcerative colitis (UC). The general prevalence is about 1.0-2.0 % in Western countries. It is predominantly regarded as a multifactorial disorder involving environmental factors and polygenic defects. The view was confirmed by a lot of evidences from clinical attributions and animal models, especially from epidemiological investigations. So the etiological study of IBD has been focused on searching for susceptibility genes by positional cloning, which consists of two steps: linkage analysis and association analysis. Linkage analysis has been an important method of searching for susceptibility genes to polygenic diseases as well as single-gene disorders. IBD, as a polygenic disease, has been widely investigated by linkage analysis for susceptibility gene since 1996. The paper reviewed 38 articles, which covered almost all original researches in relation to IBD and linkage analysis. So far, several loci, such as 16q, 12q, 6p and 3p, have been identified by the studies. The most striking is 16q12 (IBD1), which linked only with CD not UC in the majority of studies. Association analysis, as one essential step for positional cloning, is usually carried out by genotyping candidate genes selected by means of linkage analysis or other methods, for figuring out the frequencies of alleles and comparing the frequencies between IBD group and healthy control group to identify the specific allele. It has been established that IBD is implicated in immune disorder. So the studies were centered on the genes of NOD2/CARD15, HLA-II, cytokine, cytokine receptor and adhesion molecule. This paper reviewed 14 original articles on association between NOD2 and IBD that have been published since 2001. All results, with the exception of one report from a Japanese group, provide evidences that the three kinds of variants of NOD2 are susceptibility factors for IBD. This article also comprehensively analyzed 18 original researches of HLA gene polymorphism in IBD. We found extensive discrepancy among the conclusions and a novel hypothesis was put forward to explain the discordance. Most studies published recently on association between IBD and cytokine gene polymorphism were reviewed.

Carrier Proteins↗

PubMed2000

MHC: function and implication on vaccine development.

The purpose of this State of the Art review is to present an overview of structural and functional aspects of human MHC molecules and how polymorphisms in HLA molecules determine the nature of the antigenic peptides bound and how such may impact upon rational vaccine development. The following areas will be discussed: elements of immune recognition, class I and class II structure and function, the class I antigen processing pathway, class II antigen processing and presentation, functional divergence among T-cells recognizing class I or class II MHC molecules, and rational vaccine development. While the first section will review our current understanding of MHC structure and function, the latter part will draw on my own work with Hepatitis C Virus (HCV) antigens.

Epitopes↗

PubMed2002

In-cell PCR method for specific genotyping of genomic DNA from one individual in a mixture of cells from two individuals: a model study with specific relevance to prenatal diagnosis based on fetal cells in maternal blood.

BACKGROUND: During recent years, much attention has been paid to the possibility of using fetal cells circulating in the pregnant woman's blood for prenatal diagnosis of genetic or chromosomal abnormalities. Although successes have been achieved in enrichment procedures for fetal cells from maternal blood samples, the use of such an approach for genotyping by molecular biology techniques in a more routine setting has been hampered by the large contamination of maternal nucleated blood cells in the cell isolates. Therefore, a new method based on in-cell PCR is described, which may overcome this problem. METHODS AND RESULTS: Mixtures of cells from two different individuals were fixed and permeabilized in suspension. After coamplification of a DNA sequence specific for one of the individuals and the DNA sequence to be genotyped, the two PCR products were linked together in the fixed cells positive for both DNA sequences by complementary primer tails and further amplification steps. In a model system of mixtures of male and female CD71-positive cells from umbilical cord blood attached to immunomagnetic particles, a Y-chromosome-specific sequence (TSPY) was linked to a polymorphic HLA-DPB1 sequence only in the male cells, leading to the correct HLA-DPB1 genotyping of the male by DNA sequencing of a nested, linked TSPY-HLA-DPB1 PCR product. CONCLUSION: This approach might be usable on mixed cell populations of fetal and maternal cells obtained after conventional cell-sorting techniques on maternal peripheral vein blood.

Antigens, CD↗

PubMed2004

Genetic impact of pathogenesis and prognosis of ANCA-associated vasculitides.

Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and the Churg-Strauss syndrome (CSS) are small vessel vasculitides associated with anti-neutrophil cytoplasmic antibodies (ANCA). Cytoplasmic (c)-ANCA mainly target proteinase 3 (PR3) and are often observed in WG patients, while perinuclear (p)-ANCA predominantly bind to myeloperoxidase (MPO) and are common in patients with MPA and CSS. It is suspected that a genetic background contributes to disease formation since the diseases are more prevalent in Caucasian populations. This article provides a detailed review of the genetic impact of the pathogenesis and prognosis of ANCA-associated vasculitides. Alpha-1 anti-trypsin is the physiological inhibitor of PR3 and carriage of the defective allele PI*Z was observed as the first genetic risk factor for the development of PR3-ANCA-associated vasculitis. Expression analyses have revealed that PR3 surface expression is genetically determined. Elevated levels of PR3 expression have been observed in WG patients and high levels of PR3 expression corresponded to increased risk of disease relapses. Furthermore, the non-carriage of CTLA-4 allele 86 was associated with WG formation, while homocygotic carriage of the CCR5 allele delta 32 seemed to prevent ANCA-negative WG. MPO-ANCA vasculitides were associated with certain alleles of CD18 polymorphisms. Lack of or only weak allelic associations of ANCA-vasculitides with polymorphic cytokine, HLA, and Fcgamma receptor genes have been shown. Although, in practice, it is sometimes difficult to differentiate between WG and MPA, the diseases appear to be based on different genetic backgrounds.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed1989

Automated DNA sequencing methods involving polymerase chain reaction.

Polymerase chain reaction (PCR) as a method for preparing DNA templates has been used for several DNA sequencing applications. An in situ procedure for directly sequencing PCR products by the dideoxy-termination method has been developed by using fluorophore-labeled sequencing primers. Completed sequence reactions were combined and loaded into a single electrophoretic lane of a fluorescence-based DNA sequence analyzer. DNA targets devoid of a universal primer sequence could be sequenced with labeled universal primers by incorporating a universal primer sequence into the PCR product. With this method, the sequence of a 351-bp region in the bacteriophage lambda genome was fully analyzed in a single lane with automatic base identification accuracy of greater than 99%. An unknown sequence, 1.7 kb long, also was sequenced by this procedure, in combination with a "PCR gene walking" strategy. Comparison of the 1110 bases in overlapping sequence data from both strands yielded only two single-base ambiguities. Automated DNA sequence analysis of the highly polymorphic HLA-DQA-1 (alpha) region in the human genome can be performed with this simple methodology. Use of this PCR-sequencing method to analyze DNA extracted from a one-month-old blood sample from an individual who is heterozygous at this locus allowed unambiguous assignment of genotype.

Autoanalysis↗

PubMed1987

Class II genes of the human major histocompatibility complex. Organization and evolutionary relationship of the DR beta genes.

The genes of the polymorphic HLA-DR molecules are located within the human major histocompatibility complex. We have studied the HLA-DR genes of an HLA homozygous individual typed to be DR4, Dw4, and DRw53. Fourteen cosmid and phage clones from genomic libraries were isolated and grouped into three clusters comprising a total of 165 kilobases. These clusters contain four DR beta genes. Nucleotide sequence determination showed that two of the genes encode beta chains that carry the DR4 and DRw53 specificities, respectively, while the other two genes are presumably pseudogenes. Comparisons of the nucleotide sequences of all four DR beta genes of the DR4 haplotype show that the genes are extensively similar, approximately 90% in both exons and introns. All four genes are equally similar to each other. These observations are consistent with the notion that the genes arose by duplications that were followed by homogenization through gene conversion. The existence of more than one DR beta gene homologue but only a single DR alpha gene homologue in mouse, rabbit, and cattle suggests that the DR beta gene duplications occurred at or early during mammalian speciation.

Base Sequence↗

PubMed1993

Human T cell clones reactive against U-small nuclear ribonucleoprotein autoantigens from connective tissue disease patients and healthy individuals.

SLE and mixed connective tissue disease (MCTD) are characterized by the presence of high titers of autoantibodies against uridine-rich RNA-small nuclear ribonucleoprotein (snRNP) Ag. Because the presence of such snRNP-reactive autoantibodies has recently been shown to be associated with polymorphisms of HLA, this study was undertaken to determine whether snRNP-reactive T cells could be identified and characterized from patients. PBMC were stimulated with affinity-purified snRNP Ag and cloned by limiting dilution in the presence of rIL-2 and rIL-4, snRNP-reactive human T cell clones were generated from three patients and two healthy blood donors who possessed disease-associated HLA genotypes. The cell surface phenotype of clones determined by flow cytometry was CD3+, CD4+, CD45RO+, TCR V alpha beta+. TCR V beta analysis, performed using V beta-specific primers and polymerase chain reaction, revealed that the T cell lines generated were clonal; a limited number of TCR V beta genes were expressed among the clones tested. All clones tested by mAb blocking of Ag-induced proliferation were restricted by HLA-DR. Several T cell clones were identified that were specific for B'/B or D polypeptides. These results demonstrate that snRNP-reactive T cells can be isolated from SLE and MCTD patients in vitro, and that Ag-driven expansion of such T cells could play a role in the immunopathogenesis of these diseases in vivo.

Adult↗

PubMed1998

[Distribution of HLA class I antigen in Finno-Ugrian populations of Russia (Mordovians and Maris)].

Distributions and gametic associations of HLA I antigens were studied in two Finno-Ugrian populations of Russia: Mordovians (300 subjects, including 148 Erzyas and 152 Mokshas) and Maris (137 subjects). Regarding the Mordovian population, Erzya and Moksh subpopulations significantly differed from each other only in the frequency of the A9 antigen. However, the Mari and Mordovian populations differed from each other considerably. Maris exhibited higher frequencies of antigens A9, B27, and B40 and lower frequencies of B5, B8, and B16 compared to Erzyas, as well as higher frequencies of A3, A28, B27, and B40 and lower frequencies of A10, B5, B8, B16, and B18 compared to Moksha. In addition, Erzyas, Mokshas, and Maris differed from one another in the gametic associations revealed. In general, our data indicated that the three populations, which display characteristic features of both Caucasoid and Mongoloid races, differ from one another with respect to the HLA genetic polymorphism. In all of the three populations, a positive association of the B27 antigen with spondylarthropathies (SAPs) was revealed. This confirms the hypothesis that B27 is involved in the pathogenesis of some rheumatoid diseases.

Chromosome Mapping↗

PubMed2002

Restriction fragment length polymorphism and polymerase chain reaction: HLA-DQA1 and polymarker analysis of blood samples from transfusion recipients.

The effect of blood transfusion on DNA profiles of an individual is a significant issue in the forensic context. In the present study, the effects of blood transfusion in 5 recipients were studied by performing restriction fragment length polymorphism and polymerase chain reaction HLA-DQA1 and Polymarker (LDLR, GYPA, HBGG, D7S8, and GC) assays (Roche Molecular Systems, Branchburg, NJ) on serial posttransfusion blood samples. Pretransfusion and posttransfusion DNA profiles of all 5 recipients were consistent with no evidence of the donor genetic material. Currently used DNA profiling techniques in forensic science are reliable and informative for paternity and identity purposes in situations involving transfusion of 1 or 2 U of blood up to 24 hours posttransfusion.

Blood Transfusion↗

PubMed2004

Genetic polymorphism and linkage disequilibrium of the HLA-DP region in Basques from Navarre (Spain).

In this work, a sample of 116 individuals from an autochthonous Basque population (northern Navarre, Spain) was typed at the DNA level for HLA-DPA1 and HLA-DPB1 loci, with the aim of analysing the genetic polymorphism and the linkage disequilibrium (LD) of the HLA-DP region. In this Basque subpopulation, the most frequent alleles were *0103 (0.767) and *0201 (0.185) for DPA1 locus, whereas for DPB1 locus the *0401 allele was predominant (0.307). Accordingly, the most frequent haplotype was DPA1*0103-DPB1*0401 (0.300), which showed a significant LD. However, the haplotypes that most differentiated the sample of Navarre from other worldwide populations already analysed were DPA1*0105-DPB1*1901 (0.011) and DPA1*0201-DPB1*7601 (0.021), both of which showed a strong LD. Analysis of the relationships between populations based on data provided by HLA-DPA1 and HLA-DPB1 loci revealed a high genetic affinity between the Basque samples (North Navarre and Guipúzcoa), which, in turn, tend to plot separately from the remaining European populations. Gene frequency clines for DPB1*01, DPB1*04 and DPB1*11 alleles among European populations are reported for the first time. These alleles showed maximum values of F(ST) (0.033, 0.034 and 0.025, respectively). Various evolutionary forces were considered in discussing the origin of the spatial structuring of the gene frequencies: (i) gene flow, argued from the hypotheses of Post-glacial recolonization from southern Europe or the demic diffusion of farmers from the Near East into Europe, and (ii) the existence of selective pressures that could have generated genetic microdifferentiation.

Gene Frequency↗

PubMed1985

Polymorphic restriction endonuclease sites linked to the HLA-DR alpha gene: localization and use as genetic markers of insulin-dependent diabetes.

Polymorphic restriction endonuclease sites within the HLA-DR alpha gene have been defined, localized, and used as genetic markers in the analysis of susceptibility to insulin-dependent diabetes mellitus (IDDM). Hybridization of Bgl II-digested human genomic DNA with a cDNA clone for the HLA-DR alpha chain (pDR alpha-1) has revealed three allelic restriction fragment lengths: 3.8 kilobase pairs (kb), 4.2 kb, and 4.5 kb. Hybridization of EcoRV-digested human genomic DNA with the same probe has revealed two allelic polymorphic restriction fragment lengths: 9.2 kb and 13.0 kb. By analysis of double digests of genomic DNA from individuals homozygous for each of the allelic variants, the polymorphic restriction sites were found to be clustered near the 3' end of the HLA-DR alpha gene. The observed correlations of DR alpha Bgl II restriction site variants with serologically determined DR specificities suggest linkage disequilibrium between the DR alpha and DR beta loci. The 3.8-kb fragment is correlated with the DR1 type (Pc = 4.4 X 10(-4)); and the 4.2-kb fragment, with a subset (B8,DR3) of the DR3 type (Pc = 5.1 X 10(-4)) and with the DR6 type. The segregation pattern of HLA-DR alpha polymorphic Bgl II restriction fragments was analyzed in six IDDM families. The observed association of IDDM with the Bgl II 4.2-kb DR alpha restriction variant is higher than with existing serological markers and supports the utility of this approach in elucidating IDDM inheritance.

Alleles↗

PubMed1989

HLA-DR and -DQ epitopes and monoclonal antibody specificity.

The polymorphism of the HLA system-originally studied serologically using antisera from multiparous women and cellularly using the mixed lymphocyte reaction-has now been further revealed by the use of monoclonal antibodies and, at the most basic level, by the nucleotide and amino acid sequences of the different alleles. In this article, Steven Marsh and Julia Bodmer examine the specificity of mainly well-known HLA-DR and HLA-DQ monoclonal antibodies and postulate the positions of their binding sites, or at least of the polymorphic sites determining their patterns of reactivity. The publication together of all available amino acid sequences of the first domain of the DR beta and DQ alpha and the DQ beta chains (updated and corrected where necessary in collaboration with their authors) provides a useful tool with which to identify binding sites of other antibodies and perhaps to attempt to correlate their position in the structure with their function. Outlines of strategies to produce a wider range of polymorphic antibodies are discussed.

Amino Acid Sequence↗

PubMed2000

TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.

OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

Adult↗

PubMed1997

No independent associations of LMP2 and LMP7 polymorphisms with susceptibility to develop IDDM.

Results from a recent study suggested that polymorphisms within the HLA class II genes LMP2 and LMP7 were associated with the susceptibility for developing IDDM, and that this association could not be explained by linkage disequilibrium to HLA-DR or -DQ genes. We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene. In addition, we typed IDDM families in which at least one parent was homozygous for a DRB1-DQA1-DQB1 haplotype and performed a transmission/disequilibrium test of these LMP polymorphisms. Our data suggest that none of these LMP2 or LMP7 polymorphisms are independently associated with IDDM susceptibility, in contrast to what has been previously reported by others. Further, our results suggest that one partial explanation for the previously reported independent association between IDDM and these LMP polymorphisms may have been that patients and control subjects were not matched for DRB1*04 subtypes. Our results emphasize the need for a complete matching for DRB1, DQA1, and DQB1 alleles between patients and control subjects when attempting to detect independent effects of other polymorphisms in the HLA complex on IDDM susceptibility or protection.

Cysteine Endopeptidases↗