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At least 757 records · Page 42Linked to original sources
PubMed1987

Syngeneic anti-idiotypic antisera to murine monoclonal antibodies to monomorphic and polymorphic determinants of HLA class I antigens.

BALB/c mice were immunized with syngeneic anti-HLA class I monoclonal antibodies. The latter included the anti-HLA-A2, A28 monoclonal antibody (MoAb) CR11-351, the MoAb Q6/64 to a determinant restricted to HLA-B antigens and the MoAb CR10-215 and CR11-115 to the same (or spatially close) monomorphic determinant. Anti-idiotypic antibodies could be detected in bleedings obtained 3 days after the first booster, increased in titer in bleedings obtained after the second booster, and persisted at high levels in subsequent bleedings. The four anti-HLA class I MoAb did not differ in their ability to elicit syngeneic anti-idiotypic antibodies. Cross-blocking studies with a panel of anti-HLA class I, anti-HLA class II, and anti-human melanoma-associated antigen (MAA) MoAb showed that the anti-MoAb CR10-215 and anti-MoAb CR11-115 antisera contain only antibodies to private idiotopes, whereas the anti-HLA MoAb CR11-351 and anti-MoAb Q6/64 antisera also contain antibodies to public idiotopes. The latter are expressed by the anti-HLA class I MoAb CR11-351, Q1/28, Q6/64, and 6/31, and by the anti-HLA class II MoAb Q5/6, Q5/13, 127, and 441. Public idiotopes were not detected on the nine anti-MAA MoAb tested. Public idiotopes do not interfere with the binding of anti-HLA MoAb with the corresponding antigenic determinants. On the other hand private idiotopes are located within the antigen-combining site, because anti-idiotypic antisera specifically inhibit the binding of the corresponding immunizing anti-HLA class I MoAb to cultured human lymphoid cells in a dose-dependent manner. Analysis by isoelectric focusing of the anti-HLA class I MoAb antisera showed that the spectrotype of the anti-MoAb CR11-351 antiserum comprises four components that focus in the pH 6.9 to 6.2 range, the spectrotype of anti-MoAb Q6/64 antiserum comprises three components that focus in the pH 6.5 to 6.1 range, the spectrotype of the anti-MoAb CR10-215 antiserum comprises three components that focus in the pH 6.4 to 6.1 range, and the spectrotype of the anti-MoAb CR11-115 antiserum comprises three components that focus in the pH 6.6 to 6.4 range.

Animals↗
PubMed1993

Genetic polymorphism of HLA-DR in the Japanese population.

As a result of carrying out sequence analyses on the HLA-DR genes of several Japanese donors, we found three new DRB1 alleles, DRB1-12b, DRB1-14c, and DRB1-JX6, that had not been identified using immunological procedures. Sequence-specific oligonucleotide (SSO) probes directed against various DRB1 alleles, including the above three, enabled DNA typing of all the DRB types in the Japanese population and calculation of their gene frequencies based on this typing to be carried out for the first time. The SSO-DNA typing yielded higher DR13 and DR14 gene frequencies than those reported by serological workshops. Next, we applied this DR-DNA typing to the analysis of Japanese patients with juvenile rheumatoid arthritis (JRA) and found that DRB1*0405 was the allele susceptible to rheumatoid factor-positive polyarticular JRA, which is one of the four types of JRA that has been classified clinically. Analysis of the DR types of patients who suffered unexplained recurrent spontaneous abortion (URSA) using DNA typing demonstrated that 1) URSA is not correlated with any particular DR type and 2) no difference between the DR sharing rate of patients and normal couple was detected, which contradicts the results obtained in some serological studies.

Alleles↗
PubMed2002

Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study.

OBJECTIVE: To test the hypothesis of an association between a polymorphism in the matrix metalloproteinase 3 (MMP-3) gene promoter and the susceptibility, severity, and progression of rheumatoid arthritis (RA), and to further document the association between HLA-DRB1 alleles encoding the shared epitope (SE) and the severity and progression of RA. METHODS: Patients with early RA (n = 103) were included in this prospective study. A total radiographic damage score (TDS; by the Sharp/van der Heijde method) was used to quantify RA severity at baseline and after 4 years of followup. The 5A/6A biallelic polymorphism in the MMP-3 gene promoter was analyzed using fluorescence-based polymerase chain reaction (PCR). HLA-DRB1 genotyping was performed using PCR methods. Control subjects (n = 127) were unrelated healthy individuals. RESULTS: MMP-3 allele carriage rates and allele and genotype frequencies did not differ between patients and controls. The MMP-3 6A/6A genotype was associated with the highest TDS both at baseline and after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. The DRB1 SE+/+ genotype was associated with the highest TDS after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. Patients homozygous for MMP-3 6A and DRB1 SE had the highest progression of the TDS. CONCLUSION: This study provides the first evidence of an association between a polymorphism in the MMP-3 gene promoter and the severity and progression of RA, but not RA susceptibility. Investigation of this polymorphism could be combined with that of DRB1 gene polymorphism to improve the predictive accuracy and management strategy in early RA.

Alleles↗
PubMed2006

The relation between size at birth and risk of type 1 diabetes is not influenced by adjustment for the insulin gene (-23HphI) polymorphism or HLA-DQ genotype.

AIMS/HYPOTHESIS: Associations have been described between higher birthweight and increased risk of type 1 diabetes, and of insulin (INS) and human leucocyte antigen (HLA) genotypes that protect against diabetes with larger size at birth. We studied simultaneously the effects of size at birth, INS and HLA genotypes on the risk of type 1 diabetes to test whether the relation between size at birth and risk of type 1 diabetes would be strengthened after adjustment for INS and HLA genotypes. SUBJECTS AND METHODS: We designed a population-based case-control study in Norway with 471 cases of childhood-onset type 1 diabetes and 1,369 control subjects who were genotyped for the INS -23HphI polymorphism (surrogate for INS variable number of tandem repeats) and HLA-DQ alleles associated with type 1 diabetes. Data on birthweight and other perinatal factors were obtained from the Medical Birth Registry of Norway by record linkage. RESULTS: The data fitted a multiplicative model for the protective INS class III allele both within the INS locus and for the model with INS- and HLA-DQ-conferred risk of type 1 diabetes. We found no overall significant association between weight or head circumference at birth and the risk of type 1 diabetes, and adjustment for INS and HLA genotype did not influence this result. There was also no evidence for association of INS or HLA with size at birth among control subjects. CONCLUSIONS/INTERPRETATION: In contrast to suggestions from previous indirect studies, direct adjustment for INS and HLA genotypes did not lead to a stronger relation between birthweight and the risk of type 1 diabetes.

Adolescent↗
PubMed1990

Multigenic basis for type I diabetes. Association of HRAS1 polymorphism with HLA-DR3, DQw2/DR4, DQw8.

We analyzed extended haplotypes composed of DNA loci on the short arm of chromosome 11 for segregation with insulin-dependent (type I) diabetes mellitus. The markers for these loci are tyrosine hydroxylase, insulin, and c-Ha-ras-1 proto-oncogene (HRAS1). We report, in a study of 27 families, that a specific haplotype (H), containing a 3-kilobase (kb) HRAS1-Taq I DNA polymorphism, segregated differentially in diabetic and nondiabetic siblings (P = 0.005). A parallel population study showed that the 3-kb HRAS1-Taq I polymorphism is increased in frequency in type I patients having two strong HLA-susceptibility haplotypes compared with other type I patients or healthy control blood donors (P less than 0.010 and P less than 0.025, respectively). The polymorphic variable, enhancer, and promoter regions flanking the human insulin gene on the H haplotype were not associated with type I diabetes. These results indicate that the HRAS1 locus or genes in linkage disequilibrium with this locus are involved in the pathogenesis of HLA-DR3/4 type I diabetes mellitus.

Base Sequence↗
PubMed1977

Structural heterogeneity of C2 Complement protein and its genetic variants in man: a new polymorphism of the HLA region.

A zymogram method, following thin-layer isoelectric focusing in a polyacrylamide gel, allows resolution of the lytic activity of serum C2 complement protein in a spectrum of molecular forms. This spectrum is characteristic in each of the species studied (man, rhesus monkey, guinea pig, and hamster). Moreover, two different alternative patterns are observed in man: each of the six major lytic bands characteristic of the most common pattern (herein designated C2(1) is duplicated in the least common pattern (C2(2-1), with an additional band displaced cathodally by not more than 0.04 pH unit. Distribution of phenotypes C2(1) and C2(2-1) in a Caucasion population is in agreement with the hypothesis that they are controlled by two alleles, C2(1) and C2(2), with frequencies 0.96 and 0.04 +/- 0.01. Segregation studies show that the two alleles are codominant and identify a locus in the HLA region. No recombinants with HLA-B were detected among 27 informative meioses, generating a cumulative lod score of 6.321 at equals 0. These findings suggest that the individuals with the C2-deficient trait might be interpreted as homozygotes for a third and rarest amorph C2 degrees of the same locus.

Animals↗
PubMed1987

DNA polymorphisms associated with HLA-B-like genes and evidence for a duplication of B40 genes detected with an HLA-B-specific DNA probe.

Analysis of polymorphic DNA endonuclease restriction fragments by Southern blotting indicates that the genetic complexity of the HLA class I gene family is larger than the complexity indicated by serologically defined HLA-A, -B and -C gene products (Orr et al., 1982). There are correlations between polymorphic restriction endonuclease fragments in a limited number of HLA class I alleles; in fact, a few alleles in the population have been correlated with the presence of polymorphic DNA fragments (Cann et al., 1983; Cohen et al., 1983; Orr & De Mars, 1983; Lucotte, Coulondre & Salmon, 1985; Driesel et al., 1985). Recently, probes shown to be specific for HLA-A and HLA-B genes (Grumet et al., 1983; Koller et al., 1985) were constructed from the 3'-untranslated region of these genes.

HLA Antigens↗
PubMed2002

Codominant expression of the polymorphic MICA alloantigens encoded by genes in the HLA region.

The HLA-related, polymorphic MHC class I-related chain A (MICA) gene encodes a 383-amino acid polypeptide, with three extracellular domains (alpha1, alpha2 and alpha3), a transmembrane region and a cytoplasmic tail. We have previously shown that freshly isolated endothelial cells, fibroblasts, keratinocytes and monocytes express MICA, while peripheral blood CD4+, CD8+ or CD19+ lymphocytes do not. This polymorphic MICA molecule is a target for specific alloantibodies in sera from kidney, heart and lung transplant recipients, although its possible role during graft rejection remains to be demonstrated. In this study we investigated whether there is codominance in the expression of MICA. We isolated RNA from a heterozygous cell line (HCT116), previously shown by sequencing-based typing to be MICA*001/MICA*00902, as well as 12 clones derived from it. Thereafter, we retrotranscribed the RNA into cDNA, and performed a molecular typing using MICA-sequence specific oligonucleotides (SSOP). Using this approach, we detected the RNA encoding MICA*001 and MICA*00902 in all the clones and in the parental cell line, indicating that MICA is codominantly expressed. This codominant expression was further confirmed by cloning and sequencing plasmids encoding these two alleles produced from the same HCT116 RNA preparation. We also produced the two recombinant MICA proteins (MICA*001 and MICA*00902). They reacted with rabbit anti-MICA polyclonal antibodies by ELISA and Western blot, indicating that the plasmids carrying the cDNA inserts probably encode functional MICA proteins. This strongly suggests that, like the HLA class I and class II proteins, MICA is codominantly expressed. The codominant expression of the polymorphic, HLA-like MICA alloantigens may have implications for the immune response elicited by the allograft in organ transplantation.

DNA Probes↗
PubMed2000

Polymorphism of HLA-A, -B, -DRB1, -DQA1 and -DQB1 haplotypes in a Croatian population.

We describe for the first time extended haplotypes in a Croatian population. The present study gives the HLA-A, -B, -DRB1, -DQA1 and -DQB1 allele and haplotype frequencies in 105 families with at least two offspring. All individuals were studied by conventional serology for HLA class I antigens (A and B), while class II alleles (DRB1, DQA1, DQB1) were typed using the PCR-SSOP method. HLA genotyping was performed by segregation in all 105 families. For extended haplotype analysis, 420 independent parental haplotypes were included. Fourteen HLA-A, 18 HLA-B, 28 DRB1, 9 DQA1 and 11 DQB1 alleles were found in the studied population. Most of the DRB1 alleles in our population had an exclusive association with one specific DQA1-DQB1 combination. This strong linkage disequilibrium within the HLA class II region is often extended to the HLA-B locus. A total of 10 HLA-A, -B, -DRB1, -DQA1, -DQB1 haplotypes were observed with a frequency </= 1.0%. The three most frequent haplotypes were HLA-A1, B8, DRB1*0301, DQA1*0501, DQB1*0201; HLA-A3, B7, DRB1*1501, DQA1*0102, DQB1*0602 and HLA-A24, B44, DRB1*0701, DQA1*0201, DQB1*02. These results should provide a useful reference for further anthropological studies, transplantation studies, and studies of associations between HLA and diseases.

Croatia↗
PubMed1991

Polymorphism of HLA-DRw52-associated DRB1 genes as defined by sequence-specific oligonucleotide probe hybridization and sequencing.

We have used group-specific DNA amplification and sequence-specific oligonucleotide probe (SSOP) hybridization to study DRB1 sequence polymorphisms associated with DR3, DRw11(5), DRw12(5), DRw13(w6), DRw14(w6) and DRw8 alleles. Group-specific amplification of DRw52-associated DRB1 alleles was achieved using a 5' amplification primer designed to hybridize with a first hypervariable region (HVR) sequence common to all known alleles in this group, together with a 3' intron primer. Prospective SSOP typing of DR3, DRw11, DRw12, DRw13, DRw14 and DRw8 alleles was performed in 318 individuals, including 124 patients, 46 family members and 148 unrelated marrow donors. Among the 395 DRw52-associated DRB1 alleles tested in our study, a subtype corresponding to the previously defined alleles DRB1*0301-2 (DR3), DRB1*1101-4 (DR5), DRB1*1201-2 (DR5), DRB1*1301-5 (DRw6), DRB1*1401-2 and 1404 (DRw6), and DRB1*0801-4 (DRw8) could be assigned in all but 6 individuals (1.9%) tested. In addition to the 22 known alleles, we identified two new DRw6-associated alleles, DRB1*13.MW(1) and DRB1*14.GB(1). DRB1*13.MW typed serologically as DRw13 and was identical to DRB1*1301 except at codon 71 where AGG encodes arginine instead of GAG encoding glutamic acid. DRB1*14.GB represents a DRB1*1402 variant whose sequence at codon 86 encodes valine (GTG) instead of glycine (GGT). These results demonstrate that SSOP methods represent an efficient and precise approach for typing DRB1 alleles and for identifying potential novel variants previously unrecognized by conventional typing methods.

Alleles↗
PubMed2000

[Correlative study on HLA-DR2 allelic polymorphism and systemic lupus erythematosus in the Han nationality in Hunan province].

Fifty-eight systemic lupus erythematosus (SLE) patients and 59 normal controls of the Han nationality in Hunan province were involved in this study to analyze the correlation between HLA-DR2 group specific amplification in combination with HLA-DRB generic amplification PCR/SSCP technique to detect the sequence variation within exon 2 of HLA-DR2 alleles outside the sequence specific primer matching positions. The results were that HLA-DR2 was strongly correlated with SLE (RR = 2.71, P < 0.01); and HLA-DRB1 * 1501 was the allele correlated with disease (RR = 3.01, Pc < 0.05). In addition, PCR/SSCP showed that there was not any novel sequence variation in exon 2 of HLA-DR2 alleles in the Han nationality in Hunan province.

Alleles↗
PubMed1990

DNA restriction fragment length polymorphism of HLA-DR2 haplotypes in normal individuals and in patients with rheumatoid arthritis.

A strong association between HLA-DR4 and rheumatoid arthritis (RA) has been found in a number of populations. In contrast, the incidence of DR2 is decreased in patients with RA, suggesting that this specificity may confer some protection against the disease. A number of subtypes of DR2 have been defined by serology, by responses in mixed lymphocyte culture reaction, and, more recently, by restriction fragment length polymorphism. These subtypes of DR2 are in linkage disequilibrium with different subspecificities of DQw1. It is thus likely that the distribution of these subtypic DR,DQ haplotypes in DR2 positive patients with RA may be important in understanding the genetic basis of susceptibility/resistance to RA. In this paper a study of the subtypes of DR2,DQw1 haplotypes in 18 patients with RA, who required sodium aurothiomalate as a disease remitting drug, and unrelated healthy individuals is reported. Three subtypes of DR2 haplotypes, DRw15 (Dw2),DQw1.2(DQw6), DRw15(Dw12),DQw1.12(DQw6), and DRw16(Dw21),DQw1, AZH (DQw5), were analysed with a cDNA probe for the DQ beta gene. The data show that DR2 positive patients with RA carried either the DRw15(Dw2),DQw6 or DRw15(Dw12),DQw6 haplotype. No patient with RA was positive for the DRw16(Dw21),DQw5 subspecificity. In contrast, six of 29 (21%) normal healthy DR2,DQw1 positive individuals carried the DRw16(Dw21),DQw5 haplotype. These data together with earlier results on the distribution of the DR4,DQw7 haplotype in patients with RA support the hypothesis that DQB1 chain polymorphism may be important in determining susceptibility to severe RA.

Arthritis, Rheumatoid↗