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PubMed1998

Distribution of HLA class II alleles among Spanish patients with pemphigus vulgaris.

Twenty-six unrelated Spanish Caucasian individuals affected by pemphigus vulgaris (PV) were HLA typed and frequencies compared with those of 200 ethnically matched healthy controls. Twenty-three out of 26 patients were HLA-DR4. The frequency of HLA-DR14 was also increased (31%; controls: 4%). Of the 23 patients positive for HLA-DR4, 21 carried the DRB1*0402 allele. Therefore, the frequency of HLA-DRB1*0402 among patients was 81% (4% in controls; P=4.7x10(-27), OR=100.8). Interestingly, HLA-DR13, a frequent HLA-DR specificity in the Spanish general population (27%), was absent among the PV patients (P=0.009; Pc=0.1; OR=0.05). Taking together these data, we can conclude that, in the Spanish population, PV is preferentially and strongly associated with HLA-DRB1*0402, whereas DRB1*13 seems to confer a protective effect in our population.

Alleles↗
PubMed1998

Genomic identification of the minor histocompatibility antigen HA-1 locus by allele-specific PCR.

Graft-versus-host disease (GvHD) can be a major complication of allogeneic bone marrow transplantation even in recipients of HLA genotype-identical transplants. Disparities in minor histocompatibility antigens (mHags) between donor and recipient are a potential risk for the development of GvHD. A mismatch for the mHag HA-1 can cause GvHD in adult recipients of allogeneic bone marrow from HLA-identical donors. The mHag HA-1, first identified by HLA-A*0201-restricted cytotoxic T cells (CTLs), was recently chemically characterized as a nonapeptide. On the cDNA level, the HA-1 locus has two alleles, HA-1H and HA-1R, which differ in two nucleotides, resulting in a single amino acid substitution. Here we report on the genomic structure of the HA-1 locus. Isolation and sequencing of cosmid DNA encoding the HA-1 peptide sequence revealed that the HA-1 alleles are encoded by two exons. Two different primer sets were designed, each consisting of allele-specific primers and a common primer, and both sets containing intronic sequences. We performed genomic DNA typing of three families consisting of 24 HLA-A*0201-positive individuals. The predicted allele-specific products correlated in all cases with the mHag classification by CTLs and by RT-PCR. We demonstrate for the first time the genomic identification of the mHag HA-1 locus. Prospective genomic typing for the HA-1 alleles will improve donor selection and identify HLA-A*0201-positive recipients with a high risk for HA-1-induced GvHD.

Adult↗
PubMed1994

Familial testicular carcinoma: in search of genetic triggers.

Two cases of testicular tumours in non-twin brothers of a cancer-prone family are described. Cytogenetic studies of these two patients and human leucocyte antigen (HLA) typing of the family failed to identify any genetic defects. The authors propose using linkage analysis for further genetic studies but would require additional families for this to be performed.

Adult↗
PubMed1993

Genomic MHC haplotyping of mutant cell lines using a novel marker.

The aim of this study was to characterize MHC mutant cell lines by studying haplospecific markers within the MHC and specifically in the 250 kilobase (kb) region between the HLA B and TNF loci. This region has been difficult to define because of the lack of appropriate markers. Spontaneous MHC mutants were isolated after immunoselection with an anti-HLA A2 monoclonal antibody and complement. Ten mutants were characterized using serological or allelic and genomic DNA markers within the HLA A to HLA DQ region of the MHC. Most mutants lost at least the 3 megabases of DNA from HLA A to HLA DQ viz the whole haplotype carrying HLA A2. Variants which have lost either HlA A alone or HLA A and HLA B were also found. The results show that it is possible to map the extent of the deletion between HLA B and TNF. Haplospecific scanning patterns for the CL region appear particularly useful.

Cell Line↗
PubMed1994

PCR SSCP reveals haplotype related polymorphism of PERB1: a new marker for MHC beta block typing.

Many new Major Histocompatibility Complex (MHC) genes have been discovered in the last 5 years. Defining the polymorphism of these new genes may elucidate their function and their relevance to diseases with MHC associations. Polymerase chain reaction and single stranded conformation polymorphism (PCR SSCP) analyses were used to detect sequence polymorphisms of PERB1 demonstrated by comparing the available genomic sequence of four haplotypes. This study showed that PCR SSCP of PERB1 is reproducible. In addition, PERB1 alleles segregate within families together with MHC haplotypes. Typing results from the Forth Asia and Oceania Histocompatibility Workshop (4AOHW) cell panel indicate that the identified polymorphisms of PERB1 are "haplotypic', i.e., unrelated individuals carrying the same MHC ancestral haplotypes carry the same PERB1 SSCP pattern. Interestingly, PERB1 SSCP patterns allow the distinction of ancestral haplotypes which share HLA-B serological specificities, such as HLA-B44 and therefore this analysis can be used to further define MHC haplotypes and thus to improve our understanding of the evolution of this complex.

Alleles↗
PubMed1979

Neisseria meningitidis bacteremia in association with deficiency of the sixth component of complement.

The serum of a 26-year-old black man with a recent episode of meningococcemia complicated by meningitis and arthritis was found to lack hemolytic complement activity. The sixth component of complement was not detected by functional or immunochemical assays whereas other components were normal by hemolytic assay. His fresh acute-phase serum lacked complement-mediated bactericidal activity against the homologous strain of Neisseria meningitidis, but the addition of fresh normal serum or purified C6 restored bactericidal activity as well as hemolytic activity. The absence of C6 activity could not be accounted for on the basis of an inhibitor. Opsonization and chemotaxis functioned normally. Histocompatibility typing of family members did not demonstrate evidence for genetic linkage of C6 deficiency with the major histocompatibility loci. This report represents the first published case of C6 deficiency associated with bacteremic Neisseria infections in which antimeningococcal bactericidal antibodies have been definitively demonstrated against the homologous strain in the acute phase of the illness.

Adult↗
PubMed1984

A study of lymphocytotoxins in families of patients with systemic lupus erythematosus.

Lymphocytotoxic antibodies are a common feature in the sera of patients with systemic lupus erythematosus. This family study, however, has not confirmed the previous findings of an increased incidence in the sera of their relatives. Adsorption studies suggest that when lymphocytotoxins occur in the sera of normal subjects and relatives of patients they have a different specificity and thus significance.

Antilymphocyte Serum↗
PubMed1990

Genes associated with rheumatoid arthritis and mild inflammatory arthritis. I. Major histocompatibility complex class I, II, and III allotypes.

Patients with mild inflammatory arthritis (IA) were compared with patients with definite rheumatoid arthritis (RA) for abnormal frequencies of major histocompatibility complex (MHC) antigens and haplotypes to determine whether a genetic predisposition either to RA or to mild self-limiting arthritis/arthralgia was present in the patients with IA. In general the MHC antigens with abnormal frequencies found in patients with IA differed from those in patients with RA and were mainly at the A and B loci. In patients with IA the frequencies of HLA-A24, A25, B27, and B35 antigens were significantly higher than those of controls and HLA-DR5 and C4A4 were slightly raised. In contrast, in patients with RA abnormal frequencies of the MHC antigens DR4 and DR2 and the extended haplotypes associated with them [B62 BfS C4A3 C4B3 DR4 GLO2] and [B7 BfS C4A3 C4B1 DR2] confirmed the observations reported on other white populations. Thus MHC antigen associations with IA and RA differ sufficiently to suggest a different genetic basis for the two conditions.

Arthritis↗
PubMed1987

Marrow transplantation: what determines success or failure of hematologic reconstitution?

The technique of marrow transplantation serves to replace diseased marrow by normal hemopoiesis. Successful restoration of hemopoiesis is predicated upon the ability of the preparative regimen to ablate both the diseased marrow and the host immune system and upon the capacity of the injected undifferentiated self-renewing stem cells to produce progeny. If these conditions are met, hemopoiesis and an immune system consisting almost exclusively of donor cells will be established although a minority of patients may show a mixture of host and donor cells. If not, graft failure may ensue, a clinical syndrome having at least two etiologies: spontaneous graft resistance and transfusion-induced sensitization. The present report contrasts the immunological findings made with successful hemopoietic engraftment to those seen with graft failure.

Animals↗
PubMed1992

Selection of unrelated bone marrow donors: does the current procedure warrant complete MHC class II identity?

Bone marrow transplantation from unrelated donors is being used increasingly for the treatment of patients with leukemia and several other hematologic disorders. Selection of unrelated bone marrow donors currently relies on serological HLA identity and negative mixed lymphocyte reactions between donor/recipient pairs. As serological HLA-DP typing is not feasible, we used the HLA-DPB1 oligonucleotide typing method to investigate whether the current selection procedure can guarantee complete MHC class II identity. In 40 consecutive patients, one third (62/193) serologically HLA-A, -B, -C, -DR and -DQ identical donors were found to be MLC negative with a relative response below 5%. HLA-DPB1 oligonucleotide typing of these MLC negative donors revealed that again only one third (20/62) was also identical for DP with their presumptive recipients. In the majority of pairs a disparity in graft-versus-host direction or in host-versus-graft direction of at least one allele was seen. These data indicate that in spite of the strict MLC criteria used, the current procedure did not warrant complete MHC class II identity. This implies that oligotyping for DPB1 can improve matching and should be introduced for typing of volunteers. We speculate that DP differences may contribute to the higher incidence of graft-versus-host disease or graft rejection in unrelated transplants.

Bone Marrow Transplantation↗
PubMed1990

C4 reference typing report.

Human C4 is most polymorphic at the protein level, distinction between allotypes of the C4A and C4B proteins resting on electrophoretic migration patterns and difference in hemolytic activity. The aim of the C4 reference typing has been the definition of reference variants, the assignment of rare variants, and the investigation of duplicated, deleted, or non-expressed and hybrid genes. Samples from 136 individuals, predominantly with known segregation, from 16 laboratories were investigated by standard electrophoretic techniques, for their relative hemolytic activity, reactivity with monoclonal antibodies and Rg/Ch reagents, alpha-, and beta-chain types, relative electrophoretic migration distance, as well as the C4/21-OH-TaqI RFLPs. The results were evaluated in three groups; they consisted in the definition of the eight most common C4 alleles, and the ten Rg/Ch standard phenotypes in group I. In group II twelve C4A and fourteen C4B duplications among 96 complotypes, as well as eighteen deleted/non-expressed C4A and twenty-two C4B alleles, and hybrid alleles were seen by correlation of lytic activity, electrophoretic mobility, and monoclonal and/or Rg/Ch reactivity. Group III consisted of the newly defined allotypes A 8, A 7, A 58, A 55, A 45, B 45, B 35, and B 22, furthermore of alleles subdividing the A 1/A 91, and the B 13/B 12/B 11 regions. The reference typing has allowed reclassification of the majority of described C4 allotypes and resulted in a revision of the C4 nomenclature.

Blood Grouping and Crossmatching↗
PubMed2006

A uniform genomic minor histocompatibility antigen typing methodology and database designed to facilitate clinical applications.

BACKGROUND: Minor Histocompatibility (H) antigen mismatches significantly influence the outcome of HLA-matched allogeneic stem cell transplantation. The molecular identification of human H antigens is increasing rapidly. In parallel, clinical application of minor H antigen typing has gained interest. So far, relevant and simple tools to analyze the minor H antigens in a quick and reliable way are lacking. METHODOLOGY AND FINDINGS: We developed a uniform PCR with sequence-specific primers (PCR-SSP) for 10 different autosomal minor H antigens and H-Y. This genomic minor H antigen typing methodology allows easy incorporation in the routine HLA typing procedures. DNA from previously typed EBV-LCL was used to validate the methodology. To facilitate easy interpretation for clinical purposes, a minor H database named dbMinor (http://www.lumc.nl/dbminor) was developed. Input of the minor H antigen typing results subsequently provides all relevant information for a given patient/donor pair and additional information on the putative graft-versus-host, graft-versus-tumor and host-versus-graft reactivities. SIGNIFICANCE: A simple, uniform and rapid methodology was developed enabling determination of minor H antigen genotypes of all currently identified minor H antigens. A dbMinor database was developed to interpret the genomic typing for its potential clinical relevance. The combination of the minor H antigen genomic typing methodology with the online dbMinor database and applications facilitates the clinical application of minor H antigens anti-tumor targets after stem cell transplantation.

Alleles↗