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PubMed2004

Preimplantation HLA typing and stem cell transplantation: report of International Meeting, Cyprus, 27-8 March, 2004.

There has been progress in the application of stem cell transplantation for the treatment of an increasing number of severe congenital and acquired bone marrow disorders that are currently restricted by the availability of human leukocyte antigen(HLA)-matched related donors. Preimplantation HLA typing has recently been introduced to improve the access to stem cell therapy for inherited bone marrow failures, and its possible use for the treatment of common sporadic malignant and non-malignant bone marrow disorders has also been explored. This paper describes the current experience of preimplantation HLA typing, reviewed by the International Meeting on the subject, which includes preimplantation HLA typing in 147 cycles, 109 of which were carried out as part of preimplantation genetic diagnosis (PGD) for Fanconi anaemia, thalassaemia, Wiscott-Aldrich syndrome, hyperimmunoglobulin M syndrome, hypohidrotic ectodermal dysplasia with immune deficiency, and X-linked adrenoleukodystrophy, and 38 for the sole purpose of HLA typing for leukaemias and aplastic and Diamond-Blackfan anaemias. The applied method resulted in the accurate pre-selection and transfer of HLA-matched embryos, yielding 25 clinical pregnancies and the birth of 14 HLA-matched children to the siblings who required stem cell transplantation.

Bioethics↗
PubMed1981

HLA typing in retinitis pigmentosa.

HLA serological typing was performed on 173 patients with retinitis pigmentosa (RP) of all hereditary types. No significant difference was found in the frequency of any HLA (A, B, C) antigen, when comparing autosomal dominant and recessive RP patients with a control population.

HLA Antigens↗
PubMed1996

[HLA typing of donor corneas with extended post mortem time].

In case of high-risk patients cornea transplantation should be carried out using HLA-matched donor corneas to minimize the risk of rejection. HLA typing using blood lymphocytes of the donor is impossible because of the long post-mortem times. Alternatively, HLA typing can be performed using retinal pigment epithelium (RPE). Nevertheless, this method is limited by increasing post-mortem times. The aim of the present study was the optimization of culture conditions for RPE cells isolated from donor eyes with long post-mortem times. The HLA type should be evaluated during an acceptable period of organ preservation of the corresponding cornea. In different steps the method for isolation of the cells was optimized and a growth medium for RPE cells was established. Various supplements, including uvea-conditioned medium, were assessed using growth assays. The optimization of culture conditions led to an increase in the estimation of the complete HLA I and HLA II antigens from 36% to 74%. The time needed for the typing-procedure could be reduced from 38 to 17 days (average). At present 30% of the donor tissue with long post-mortem times can be typed in less than 14 days.

Cell Division↗
PubMed1997

Immune response to neutralizing epitope on human cytomegalovirus gylcoprotein B in Japanese: correlation of serologic response with HLA-type.

Antigenic domain 1 (AD-1), located between amino acids 608 and 625 of human cytomegalovirus (CMV) gB protein, is the major domain recognized by neutralizing antibodies. Amino acids 552 to 630 are essential for the binding of neutralizing antibodies. We developed an enzyme-linked immunosorbent assay (ELISA) to detect antibodies against a fusion protein containing amino acid residues 549 to 644 of the gB polypeptide and maltose binding protein (MBP). Of 180 seropositive samples, 106 (58.9%) showed positive immuno-reactivity against the fusion protein. None of the seronegative samples reacted with the fusion protein. Among 57 seropositive individuals typed for HLA, subjects with HLA-DR9 had a higher positive rate against the fusion protein (13/14=92.9%) than those without HLA-DR9 (25/43=58.1%). In addition, subjects with HLA-DR15 had a lower positive rate against the fusion protein (7/16=43.3%) than those without HLA-DR15 (31/41=75.6%). Mean OD values of HLA-DR15-positive individuals were significantly lower than those of HLA-DR15-negative individuals. Thus, among CMV-infected individuals, HLA-DR9 may be associated with responders for neutralizing antibodies and HLA-DR15 may be associated with non/low-responders.

ATP-Binding Cassette Transporters↗
PubMed1980

A family with hereditary ataxia: HLA typing.

In a previously unreported family with olivopontocerebellar atrophy, the kindred contained over 600 individuals in five generations. Of 83 offsping of affected individuals who over over 38.8 years of age (the mean age of the onset of disease in this family), 47 had ataxia; there was autosomal dominant transmission. Clinical findings included lower bulbar palsies, hyperreflexia, ataxia, incoordination, scanning and explosive speech, and, in some, slow motor-nerve conduction velocities. There was cortical and cerebellar atrophy of pontine nuclei, inferior olives, and XII nuclei, and loss of Purkinje cells in the cerebellum. Seventy-three individuals of the III and IV generations were typed for HLA histocompatibility antigens. A maximum lod score of 1.97 was found at male recombination fraction 0.18 and female recombination fraction 0.36. When the lod score values reported in other studies were combined with the values in this family, the maximum lod score was found to be 4.681 at a recombination frequency of 0.22.

Adult↗
PubMed1999

Oligonucleotide arrays for high resolution HLA typing.

The methodology and applications of oligonucleotide array technology are reviewed. An oligonucleotide array system for typing HLA-B alleles is described. Oligonucleotide probes representing all known polymorphisms in exons 2 and 3 of HLA-B are immobilized on glass slides. Exons 2 and 3 are amplified from human genomic DNA using fluorescent-labeled primers and subsequently allowed to hybridize to an oligonucleotide array on glass supports. The presence of positive hybridization is detected by fluorescence scanning. HLA-B alleles are assigned by quantitative analysis of hybridization patterns. Proof of principle has been established in blinded testing of heterozygous DNA samples.

HLA Antigens↗
PubMed1977

Family studies and HLA typing in ankylosing spondylitis and sacroiliitis.

The families of 21 ankylosing spondylitis (AS) and 16 sacroiliitis (SI) patients were investigated and typed for HLA markers. The association of HLA B27 with AS was confirmed, but no strong evidence for the same or other HLA markers being associated with SI was found. Inheritance patterns in families were analyzed according to the multifactorial and monofactorial models. It is proposed that a major gene associated or interacting with the B27 product controls the susceptibility to AS, and that this gene behaves as a dominant with incomplete penetrance. The problem as to whether linkage disequilibrium maintained by selective pressure, or functional epistasis between the "disease gene" and the B27 antigen may be the acting mechanism of association, remains to be elucidated.

Arthritis↗
PubMed1988

Antibody levels to mycobacteria in relation to HLA type: evidence for non-HLA-linked high levels of antibody to the 65 kD heat shock protein of M. bovis in rheumatoid arthritis.

We previously reported DR2 and DR7-associated regulation of antibody binding to mycobacteria in rheumatoid arthritis sera (RA), but not in tuberculosis (Tb). An extensive analysis of antibody to mycobacteria in matched normal sera, in relation to both HLA class I and class II has revealed no class II correlations, confirming that the original findings were due to RA. There was however a very strong association between IgM binding to M. tuberculosis and Cw1 (P = 0.0004). RA patients have strikingly raised levels of IgG (but not of IgA or IgM) binding to the 65 kD heat shock protein of M. tuberculosis, recently implicated in the pathogenesis of adjuvant arthritis in the rat. Remarkably, levels in RA were significantly higher even than in tuberculosis. Levels of this antibody showed no HLA associations. Thus the 65 kD antigen does not account for the DR7, and DR2 associations of IgM and IgA binding to mycobacteria reported previously, but does suggest a role for cross-reactive autoimmunity in RA.

Adolescent↗
PubMed1988

[HLA typing in Ullrich-Turner syndrome].

33 female patients with established anomaly of gonosomes were examined for the problem of a possible connection of the disease with certain types of HLA. An accumulation of individual specificites of HLA cannot be proved summarizingly; there are no significant differences to the control group. Remarkable and at present not yet to be interpreted is, however, the exclusive occurrence of the HLA-A1 in the 45,X-karyotype and iso-X-chromosomes, which needs further investigations.

Female↗
PubMed2000

Storage and utilization of HLA genomic data--new approaches to HLA typing.

Currently available DNA-based HLA typing assays can provide detailed information about sequence motifs of a tested sample. It is still a common practice, however, for information acquired by high-resolution sequence specific oligonucleotide probe (SSOP) typing or sequence specific priming (SSP) to be presented in a low-resolution serological format. Unfortunately, this representation can lead to significant loss of useful data in many cases. An alternative to assigning allele equivalents to suchDNA typing results is simply to store the observed typing pattern and utilize the information with the help of Virtual DNA Analysis (VDA). Interpretation of the stored typing patterns can then be updated based on newly defined alleles, assuming the sequence motifs detected by the typing reagents are known. Rather than updating reagent specificities in individual laboratories, such updates should be performed in a central, publicly available sequence database. By referring to this database, HLA genomic data can then be stored and transferred between laboratories without loss of information. The 13th International Histocompatibility Workshop offers an ideal opportunity to begin building this common database for the entire human MHC.

Base Sequence↗
PubMed2025

Learning predictive signatures of HLA type from T-cell repertoires.

T cells recognize a wide range of pathogens using surface receptors that interact directly with peptides presented on major histocompatibility complexes (MHC) encoded by the HLA loci in humans. Understanding the association between T cell receptors (TCR) and HLA alleles is an important step towards predicting TCR-antigen specificity from sequences. Here we analyze the TCR alpha and beta repertoires of large cohorts of HLA-typed donors to systematically infer such associations, by looking for overrepresentation of TCRs in individuals with a common allele.TCRs, associated with a specific HLA allele, exhibit sequence similarities that suggest prior antigen exposure. Immune repertoire sequencing has produced large numbers of datasets, however the HLA type of the corresponding donors is rarely available. Using our TCR-HLA associations, we trained a computational model to predict the HLA type of individuals from their TCR repertoire alone. We propose an iterative procedure to refine this model by using data from large cohorts of untyped individuals, by recursively typing them using the model itself. The resulting model shows good predictive performance, even for relatively rare HLA alleles.

Humans↗
PubMed1979

HLA types and immunity in multiple sclerosis.

HLA types and levels of humoral and cell-mediated immune responses to several antigens were studied in a large group of patients with multiple sclerosis, and in controls. Patients were more likely than controls to have the DRw2 antigen. They had higher mean antibody titers to measles but not to cytomegalovirus, herpes 1, or herpes 2, and had less competent cell-mediated responses. Antibody titers to measles were lower and cell-mediated immune responses were more effective in patients with the DRw2 antigen in patients than in patients without it. This apparent specificity for measles suggests that the etiology of multiple sclerosis is related to the immune response to measles or related viruses.

Antibodies, Viral↗
PubMed1980

Detection of heterozygotes for congenital adrenal hyperplasia: 21-hydroxylase deficiency-a comparison of HLA typing and 17-OH progesterone response to ACTH infusion.

We have studied nine families in which at least one member has congenital adrenal hyperplasia, to compare the predictive value of HLA typing and the 17-hydroxy progesterone response to ACTH as methods for detection of heterozygotes. In each of six families, two children were affected and were HLA genotypically identical. None of the unaffected siblings were HLA identical with their affected siblings. When the 17-OHP response to ACTH and the HLA haplotypes of parents and unaffected siblings were compared, there was a 79% concordance for identification of heterozygotes. Two siblings were carriers according to HLA typing, but had normal 17-OHP responses consistent with the carrier state. Three individuals with recombinations involving the HLA region of chromosome number 6 were detected. Analysis of these recombinant individuals provided additional evidence suggesting that the 21-OH degrees gene is closely associated with the B-locus of HLA. When an affected individual has been identified, HLA typing is a direct and reliable method for determining the carrier state among family members.

Adrenal Hyperplasia, Congenital↗
PubMed1994

Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay.

We examined HLA Class II antigens in 116 Japanese IDDM patients [84 typical IDDM (T-IDD); 32 slowly progressive IDDM (S-IDD)] by the hybridization protection assay (HPA) which is a novel HLA typing method based on hybridization of acridinium-ester-labeled DNA probes to amplified DNA. We detected HLA-DRB1, -DQA1 and -DQB1 genes by this method which is capable of analyzing over 50 samples within 4 h with high sensitivity. Positive associations were found in DRB1*0405, DRB1*0802, DRB1*0901, DQA1*0301, DQB1*0303 and DQB1*0401, negative correlations in DRB1*0403, DR2, DR12, DRB1*0801 or 03, DQA1*0101 or 02, DQA1*0501, DQB1*0301 and DQB1*0602 alleles. The absence of aspartic acid (Asp) at position 57 of the DRB1 chain and the presence of arginine (Arg) at position 52 of the DQA1 chain correlated positively with both types of IDDM. There were no significant differences in HLA between T-IDD and S-IDD. These results suggest that the absence of Asp at position 57 of the DRB1 chain and the presence of Arg at position 52 of the DQA1 chain are significant Japanese IDDM patients and that DRB1*0802, in which the amino acid at position 57 is aspartic acid, may play a role in the pathogenesis of IDDM. Also, T-IDD and S-IDD have common bases in the HLA gene.

Adolescent↗
PubMed1986

HLA typing and autoantibodies in hepatitis B surface antigen-negative chronic active hepatitis.

HLA types, serum autoantibodies and serum globulin levels were surveyed in 46 patients with HBsAg-negative chronic active hepatitis. Patients with chronic active hepatitis with viral risk factors were less likely than those without viral risk factors to be HLA type B8 (10% vs 44%) or to have autoantibodies (antinuclear and/or anti-smooth muscle antibodies) (38% vs 84%). Thirty patients (10 with and 20 without viral risk factors) were treated with glucocorticosteroids. Of the 11 patients who were HLA-B8, 100% responded to treatment. Of the 20 patients who were ANA positive, 80% responded. The data suggest that the presence of HLA-B8 may be a useful predictor of response to anti-inflammatory treatment and may define a genetic subset of HBsAg-negative chronic active hepatitis that will benefit from glucocorticosteroid therapy.

Adult↗
PubMed1994

[Comparison of HLA typing and retyping data in patients with bone marrow transplantation].

Comparing HLA data from 851 patients with serological HLA-A, -B, -DR and/or PCR-SSO HLA-DRB, -DQB reevaluated HLA types produced 107 (12.5%) different results. The high discrepancy of HLA data from patients confirm the demand for a serological HLA-A, -B and a DNA HLA-DRB, -DQB reevaluation before starting an unrelated donor search for bone marrow transplantation. The reliability of serological HLA-DRB, -DQB typing was evaluated as 97.8%, whereas DNA HLA-DRB, -DQB typing was 99.5%.

Bone Marrow Transplantation↗
PubMed2005

[Extending preimplantation genetic diagnosis to HLA typing: the Paris experience].

Preimplantation genetic diagnosis (PGD) consists in the genetic analysis of one or two cells. These cells (blastomeres) are sampled from embryos, obtained by in vitro fertilization, at the third day of development. Since 1998, the bioethical laws (1994) and their decrees restricted PGD practices in France, strictly to the avoidance of the birth of a child affected with a genetic defect. In parallel, works on blood cord transplantation, taken at the birth of a compatible HLA sibling, showed very encouraging results, particularly for the treatment of Fanconi anemia. In 2001, Verlinsky et al., have reported the first PGD for Fanconi anaemia combined with HLA typing, allowing the birth of a healthy child, HLA-identical with his affected sister. The "designer baby" concept was born. The French law, which allowed PGD under specific conditions, i.e. when the genetic defect has been characterized in one parent at least, recently extended PGD to HLA typing when embryos are at risk of a genetic disorder. Article L.2131-4-1 (August 2004) allows the practice of HLA typing for PGD embryos when an elder sibling is affected with a genetic disorder and need stem cell transplantation. The HLA-matched offspring resulting from PGD can give cord blood at birth to supply the necessary therapy. This double selection give rise to serious ethical problems, but technical difficulties and legal restrictions will probably limit the development of such a procedure.

Adult↗