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PubMed1990

[The polymorphisms of HTC-defined HLA specificities in the Shanghai Chinese population].

With reference sera and homozygous typing cells (HTCs) of 3rd Asia-Oceania Histocompatibility Workshop Conference, 56 healthy unrelated subjects in Shanghai were typed for HLA-A, B, C, DR, DQ, and Dw. This paper presents the results of HLA-Dw typing, its relationship to serological class II antigens, and the distribution of Dw in the population. The polymorphism patterns of Chinese Dw specificities were quite different from those in Caucasoids and Japanese. The predominant Dw phenotypes detected in Shanghai Chinese were Dw 2, Dw 3, DKT 2, Dw 7 c, (Dw7 + Dw 17) and Dw 23 (DB 5). And significant correlations were observed between Dw 1 and DR 1, Dw 2 and DR 2, Dw 3 and DR 3, Dw 7 c and DR 7, DB 7 and DRw 8, as well as Dw 23 and DR 9. SMY 129, a novel Dw specificity defined by local HTCs and co-studied by the laboratories joined for Dw typing in 3rd AOHWC showed its correlation with DR 5. Nevertheless, more than fifty percent of Dw specificities could not be assigned in the four correspondent designated serological antigens, DR 2, DR 5, DRw 8 and DR 9, respectively, which, together with other blank Dw specificities, gave a total blank Dw gene frequency as high as 43.2% in the population. It was suggested by further analysis that novel Dw specificities might be identified more effectively if efforts would be concentrated on DR 5 and DR 9, two antigen families which, in some way, might represent the characteristics of HLA system in Chinese. Besides, certain HTC-defined antigens, e.g. Dw 3 and the DR 4-related Dw specificities, have been revealed to be in linkage disequilibrium with other DR antigens in addition with the correspondent designated ones, resulting in some unique haplotype combinations in Shanghai Chinese. It seems to us that the particular patterns of polymorphisms of serum- and cell-defined HLA class II antigens would be helpful to elucidate the mechanisms by which certain diseases are in association with HLA in Chinese in a different manner as compared with that in Caucasoids.

Asian People↗

PubMed1999

Beneficial and detrimental human leucocyte antigen (HLA)-DR mismatches are not reflected by a differential effect of immunosuppressive drugs on the in vitro alloimmune response.

The introduction of molecular tissue typing techniques has led to an enormous increase in the number of human leucocyte antigen (HLA) alleles. This increasing polymorphism of the HLA antigens makes the selection of a well-matched unrelated donor a difficult task. Recent data suggest that some HLA mismatches are more immunogenic than others. This has led to the introduction of terms like beneficial or acceptable versus detrimental or taboo mismatches. The study considered whether the differential immunogenicity as reflected by graft survival studies can be detected in vitro as well. Mixed lymphocyte reaction (MLR) and primed lymphocyte tests (PLT) were performed with different HLA-DR mismatched combinations in the presence and absence of cyclosporine A and prednisolone. Differential effects of these immunosuppressive drugs were observed. Some reactions could easily be blocked by cyclosporine alone, whereas others need the addition of high doses of prednisolone as well before a significant inhibition was found. These differences were not only found between individual responders but also within one individual dependent on the stimulatory HLA-antigen involved. When the group of beneficial mismatches was compared with the group of detrimental mismatches, no differences were observed. Our data show that immunosuppressive drugs have a differential effect on in vitro alloimmune responses but these do not differentiate between beneficial and detrimental mismatches as defined by kidney graft survival.

Cyclosporine↗

PubMed1996

HLA class I-eluted platelets as an alternative to HLA-matched platelets.

BACKGROUND: Alloimmunized refractory thrombocytopenic patients often require HLA-matched platelet transfusions. As the HLA system is very polymorphic, sufficient HLA-matched donors are not available for every patient. STUDY DESIGN AND METHODS: In vitro elution techniques with citric acid incubation of platelets at pH 3.0 showed that platelets lose expression of HLA, whereas platelet-specific glycoproteins are preserved. This technique was modified for clinical use. Random-donor platelet concentrates were incubated with citric acid, subsequently washed, and transfused to two patients. RESULTS: Platelet-specific glycoproteins were unaffected, and HLA expression decreased generally to below 25 percent of the initial expression. One alloimmunized patient who was without compatible donors because of a rare HLA type underwent repeated transfusions with acid-treated platelets. In contrast to the results with random-donor platelet transfusions, posttransfusion increments up to 47 x 10(9) per L were obtained with acid-treated platelets, and profuse gastrointestinal bleeding was stopped, while multiple skin hemorrhages were resolved. No side effects were observed. A second patient developed a severe transfusion reaction without platelet increment after one transfusion with acid-treated platelets expressing 30 percent of the original HLA antigens. Further transfusions were not given. CONCLUSION: Standardization of the acid elution technique and validation of the technique in patients is necessary. The results suggest, however, that HLA-eluted platelets prepared under specified conditions may gain a place in platelet transfusion therapy.

Adult↗

PubMed1990

[Search for bone marrow donors for patients with hematologic-oncologic diseases].

In recent years, bone marrow transplantation (BMT) has been used as a curative treatment for patients with intractable hematopoietic disorders, such as leukemia. However, lacking other options, only 30 percent of patients will have an HLA-identical family-member bone marrow donor. For patients without HLA-identical family members, HLA-identical, MLC non-reactive unrelated donors have been used. However it is very difficult to find HLA-compatible donors from an unrelated donor registry, due to the highly polymorphic HLA-system. Therefore, we need approximately 6-12 months to find an HLA-matched donor who would agree to donate bone marrow.

Bone Marrow Transplantation↗

PubMed1996

[Role of genetic factors in the etiology of silicosis].

Examination of 15 systems of hereditary polymorphism including HLA system was conducted in 284 patients suffering from silicosis and 431 healthy subjects. The results provided genetic factors showing propensity to and resistance against silicosis. The data served as a base for silicosis risk groups formation among the staffers at occupational risk of silicosis, for occupational selection during placement to enterprises with silicosis danger.

Disease Susceptibility↗

PubMed2001

Genomics of unrelated-donor hematopoietic cell transplantation.

Unrelated-donor hematopoietic cell transplantation is a proven curative modality for hematologic malignancies. The success of unrelated-donor transplantation has been achieved through a better understanding of the immunobiology of the HLA system and through more precise and comprehensive matching of donors and recipients. The extensive polymorphism of HLA genes confers important biological implications affecting engraftment, graft-versus-host disease and overall survival. Although more-complete HLA identity of the donor and recipient is associated with optimal transplant outcome, new information suggests that not every HLA disparity is functionally relevant. Future advances in unrelated-donor transplantation must include the identification of tolerable HLA mismatches, so that more patients may benefit from this therapeutic modality. Furthermore, the role of cytokine-gene polymorphisms and minor histocompatibility genes in transplant outcome requires investigation. Delineation of the function of these markers as transplantation determinants may provide alternative means for optimizing the results of hematopoietic cell transplantation.

Animals↗

PubMed2006

HLA-E and immunobiology of pregnancy.

Recently, it has been suggested that non-classical antigens such as human leukocyte antigen (HLA)-G and HLA-E may interact with KIR receptors of NK cells which results into downregulation of immune response and helps in the maintenance of pregnancy. In the present study, we have investigated HLA-E polymorphism in normal fertile women and recurrent spontaneous aborters to assess the effect of HLA-E alleles on the success of pregnancy. Allele E*0101 was found to be significantly higher in patients with recurrent spontaneous abortion (chi(2) = 4.097 and P = 0.0430). Differential expression, peptide affinity, and stability of E*0101 may be one of the reasons.

Abortion, Habitual↗

PubMed1997

HLA class II DRB1, DQA1 and DQB1 polymorphisms in the Polish population from Wielkopolska.

HLA DRB1, DQA1 and DQB1 alleles were determined by DNA PCR-SSO typing in a sample of 99 individuals originating from Wielkopolska (midwestern Poland). A high number of alleles (38 DRB1, 8 DQA1 and 14 DQB1) was detected at each locus, many of them presenting notable frequencies in this population. The three HLA loci are thus characterized by very high heterozygosity levels (93% for DRB1, 85% for DQA1, and 88% for DQB1), which confirms the results found for other European populations. A total of 6 DRB1-DQA1-DQB1 haplotypes are detected with an estimated frequency higher than 5%, namely, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*0701-DQA1*0201-DQB1*0201, DRB1*0101-DQA1*0101-DQB1*0501, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*03011-DQA1*0501-DQB1*0201, and DRB1*1301-DQA1*0103-DQB1*0603. A genetic distance analysis between the Polish and other world populations tested for HLA class II indicates that the Wielkopolska community is close to geographically close, rather than linguistically related populations from Europe. More generally, a good agreement between genetics and geography is found for DRB1 and DQB1 polymorphisms in Europe, suggesting that these two loci are highly informative for assessing historical relationships among humans.

Alleles↗

PubMed2006

A family based linkage analysis of HLA and 5-HTTLPR gene polymorphisms in Sardinian children with autism spectrum disorder.

Autism spectrum disorders (ASD) are characterized by a broad range in clinical presentation. Although a definite genetic cause has not yet been fully demonstrated, family based studies suggest that a multigenic pattern may be responsible for susceptibility, but most results are conflicting and have yet to be replicated. The purpose of this investigation was to analyze the linkage of the human leukocyte antigen (HLA) and the human serotonin transporter coding (5-HTTLPR) genes with ASD in a group of 37 families of Sardinian ethnicity in insular Italy. In 50% of these families, ASD is linked to HLA, and in the other 50% it is linked to 5-HTTLPR polymorphic genes; in other words, linkage to one or the other was evident in all cases. Despite a very homogenous genetic pattern being generally reported for Sardinians, the linkage observed with HLA and 5-HTTLPR genetic regions indicated a statistically defined heterogeneity (p=0.002). No allelic HLA or 5-HTTLPR polymorphisms were specifically associated with ASD, suggesting these loci as markers of other genes mapped in their close proximity that may be more directly involved and thus may merit further analytical studies.

Adolescent↗

PubMed1986

The HLA-D-associated invariant chain binds palmitic acid at the cysteine adjacent to the membrane segment.

The highly polymorphic HLA-D antigens are associated with a nonpolymorphic polypeptide chain, designated invariant chain. This invariant chain is shown to incorporate fatty acid. Invariant chain metabolically labeled with [3H]palmitic acid releases its label after treatment with hydroxylamine indicating an ester linkage of the palmitic acid. The binding of fatty acid to the invariant chain inhibits the formation of S-S-linked dimers. This suggests that the sole cysteine residue of the invariant chain is blocked by binding of fatty acid. A peptide shared by [3H]palmitic acid- or [35S]cysteine-labeled invariant chain digests supports the hypothesis that the palmitic acid binds to the cysteine which is located close to the membrane-spanning domain on the cytoplasmic site. Inhibition of N-glycosylation with tunicamycin demonstrates binding of the fatty acid to the nonglycosylated precursor of the invariant chain. Additionally, blocking of fatty acylation by cerulenin inhibits further maturation of the invariant chain, as sialylation.

Antibodies, Monoclonal↗

PubMed2002

[Study on polymorphism of human leukocyte antigen-DRB1 allele in patients with endometriosis].

OBJECTIVE: To study the possibility of a correlation between occurrence of endometriosis (EM) and polymorphism of human leukocyte antigen (HLA) DRB1 allele. METHODS: Polymorphism of HLA-DRB1 allele were detected by polymerase chain reaction- sequence specific primers (PCR-SSP) testing 40 surgically proven EM patients and 50 normal control. RESULTS: At HLA-DRB1 15 allele, positive frequency of EM group was significant higher as compared with those of the normal control group [45.0% vs 26.0%, P < 0.05, relative risk (RR) = 2.1]. Other HLA-DRB1 allele positive frequency of EM group and control group had no significant difference. But for Polymorphism of DRB1 * 15 allele, positive frequency of EM group and control group had no significant difference [1501 : 35.0% vs 20.0%; 1502 : 10.0% vs 6.0%; P > 0.05]. CONCLUSIONS: The occurrence of EM may be associated with the presence of HLA-DRB1 allele, but hasn't associated about polymorphism of DRB1* 15 allele. HLA-DRB1 * 15 maybe one of some factors for the pathogenesis of endometriosis.

Adult↗

PubMed1983

An HLA-B locus probe clarifies endonuclease polymorphism of major histocompatibility complex class I genes.

A DNA probe specific for the HLA-B locus has been isolated from a broadly cross-reactive HLA class I genomic clone. Locus specificity of the probe appears to be derived primarily from a stretch of approximately 180 nucleotides comprising the last (7th) intron of the original B7 gene. Use of the probe to analyze Southern blots of genomic DNA from unrelated individuals provides the first direct demonstration of intragenic localization of an HLA allele-specific restriction endonuclease site. Availability of this probe should make practicable the study of HLA-B locus restriction fragment length polymorphism as genetic markers of disease susceptibility, and should provide a model for developing probes specific for other HLA class I loci.

Cloning, Molecular↗

PubMed1989

HLA-DR beta-chain polymorphism. Second domain polymorphism reflects evolutionary relatedness of alleles and may explain public serologic epitopes.

Nucleic acid sequences of the second domain encoding exons and the signal sequence encoding exons are presented for a number of HLA-DR beta-chain alleles. There is less polymorphism in these regions than is found in the first domain encoding exon, a result expected from previous amino acid sequence data. The distribution of the polymorphisms follows a locus and supertype pattern. This permits an easy assignment of gene relatedness that is useful for ordering the events which have taken place in the first domain. The relative nonpolymorphism of the second domains within evolutionarily related haplotypes makes them likely candidates for encoding the epitopes recognized by public serologic reagents.

Alleles↗

PubMed1996

Molecular genetic analysis of HLA-DRB, -DQA, and -DQB polymorphisms in Hungarians and distribution of the DRB1*03 allele in adults and newborns.

We describe here the genetic variability of HLA-DRB1, -DQA, and -DQB in 140 healthy individuals from Hungary, including 95 randomly selected adults and 45 newborns. Allele and haplotype frequencies as well as linkage disequilibria were calculated. It was found that HLA-DRB1*11, -DQA1*0501, and -DQB1*0301 predominate in Hungarians. This information may be helpful in the future for HLA and disease association studies. Simultaneously, we observed that the frequency of the DRB1*03 allele differs between adults and newborns. Since it is well known that bearers of HLA-DR3 (and/or B8) antigens may display significant changes in immune parameters, the lower frequency in adults indicates that children with the DR3 antigen are predisposed to immune diseases in adulthood.

Adolescent↗

PubMed1985

Epidermal synthesis and expression of HLA-DR on keratinocytes in lupus erythematosus.

It has been suggested that aberrant expression of HLA-DR plays an important role in the induction of an autoimmune reaction. In lupus erythematosus (LE), skin represents a major target for autoimmune attack. We therefore tested lesional and nonlesional skin from 11 patients with different clinical subtypes of LE for the presence of HLA-DR molecules on keratinocytes using a monoclonal antibody against a non-polymorphic HLA-DR determinant. In all lesions tested, HLA-DR-positive keratinocytes were present, whereas in nonlesional skin, these cells remained HLA-DR negative. To exclude the possibility of passive absorption of DR molecules, the de novo synthesis of HLA-DR was demonstrated by the presence of cytoplasmic HLA-DR gamma chains in keratinocytes. If aberrant HLA-DR expression is a primary event, it could facilitate the recognition of autoantigens on keratinocytes by immunocompetent cells. Alternatively, the synthesis of DR molecules could be induced as a secondary event by mediators derived from the inflammatory infiltrate.

Adult↗

PubMed1995

Immunogenetic study of couples with recurrent spontaneous abortions.

OBJECTIVES: Clinical observations suggest that genetic and immunologic disparity could be a factor in fecundity. The HLA system (HLA) is polymorphic and TLX (Trophoblast Lymphocyte Cross-Reactive), which is also polymorphic, seems to be linked to it. The immunologic hypothesis follows that excessive HLA and TLX-sharing could explain the rejection of a semi-allogenic blastocyst. Study objectives are therefore twofold; To determine whether or not there is significant HLA-sharing between spouses with unexplained recurrent spontaneous abortions (RSA) and to determine whether or not there is an association between some HLA specificities and RSA. STUDY DESIGN: The study includes only Caucasian couples that have had three successive spontaneous abortions. These were distributed in two groups: Group E: 18 couples either with known aetiology or with secondary RSA; Group U: seven couples with unexplained primary RSA; Control group C: 21 couples with at least two children and no spontaneous abortions. Tissue typing for HLA-A and B molecules was performed using serotyping methodology based on lymphocytotoxicity reaction. The different DRB1 alleles (class II) were determined by oligotyping with a non-radioactive reverse dot-blot methodology. RESULTS: Statistical comparison shows that the number of couples without shared specificity is not significantly different between the three groups for each locus independently and for the set of three. Our results show also that the allelic frequencies are not significantly different between the three groups. CONCLUSIONS: There is no higher HLA-sharing in couples with RSA than in fertile couples. Similarly, no particular HLA specificity can be associated with the RSA.

Abortion, Habitual↗

PubMed1994

The HLA-G gene is expressed at a low mRNA level in different human cells and tissues.

Recently, HLA-G transgenic mice were shown to exhibit transgene transcription in several extraembryonic tissues. To determine whether HLA-G mRNAs are also expressed in other human tissues, we have undertaken Northern blot and RT-PCR assays using HLA-G locus-specific probe and primers. These studies demonstrate that the HLA-G gene is transcribed in a variety of cells and adult tissues obtained from different individuals (peripheral blood leukocytes, placenta, skin, spleen, thymus, prostate, testicle, ovary, small intestine, colon, heart, brain, lung, liver, and kidney), as well as in fetal tissues (heart, lung, liver, and kidney). The HLA-G mRNA level observed in most tissues is orders of magnitude lower than the level of classic class I genes in the same tissues. RT-PCR studies have demonstrated that alternative splicing of the HLA-G primary transcript is different from tissue to tissue and could be regulated in a tissue-specific fashion. Sequencing of keratinocyte transcripts has confirmed previous observations: (a) three different alternative splicing transcripts are produced (a full-length transcript, an mRNA lacking exon 3, and a transcript devoid of exon 3 and 4) and (b) HLA-G polymorphism is limited in the coding regions. In view of this wide HLA-G tissue distribution, a new hypothesis dealing with possible HLA-G function is proposed.

Alternative Splicing↗

PubMed1997

HLA class I expression on the materno-fetal interface.

PROBLEM: The conditions that permit the genetically dissimilar (haplo-non-identical) human fetus to evade rejection by its mothers immune system have been the subject of intense interest for several years. As the placental cells, which are in contact with maternal blood or tissue, are devoid of HLA class II antigens, the interest has focused on the expression of HLA class I molecules. METHOD OF STUDY: Recent findings on the constitutive, transcriptional, and translational expression of HLA class I molecules on anatomically and morphologically different subpopulations of trophoblast cells will form the basis of this article. RESULTS: The expression of HLA class I molecules in the trophoblast cells, forming the materno-fetal junctional zone is inhomogeneous. It differs depending on the differentiation and location of trophoblast cells within the placenta and furthermore on the stage of gestation. On the transcriptional level HLA-A, -B, -C, -E, and -G could be detected on individual trophoblast populations, whereas only HLA-C and HLA-G seem to be translated to protein. CONCLUSIONS: The expression of HLA class I antigens by trophoblast cells is not simply suppressed. Instead, less polymorphic HLA-G and HLA-C antigens are carefully selected from the class I multigene family. This gives rise to the assumption that these two HLA class I molecules play an important role in the maintenance of pregnancy.

Female↗