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HLA A, B, C and DR were typed in 73 Korean patients with Tourette disorder meeting the diagnostic criteria of DSM III-R and compared with 291 normal subjects. Relatively higher frequencies were found in HLA A11 and A26(10) with lower incidences in HLA A24(9) and B13. A family history of tic disorders was associated with a lower frequency of HLA A24(9).
HLA molecules serve as identity markers for immunocompetent cells which respond to pathogens and transplant tissue antigens to distinguish self from non-self. The continuous discovery of new HLA polymorphisms which are associated with various diseases or are involved in graft rejection continuously increases the number of HLA antigens which need to be identified for each individual. We defined the HLA class I and HLA class II antigens with the NIH standard microcytotoxicity system and compared the results with those obtained using the commercially available automated Patimed system. Our results show that serological identification of HLA antigens with the Patimed system is reliable. It can be recommended for routine as well as for research purposes.
IgA and IgG antigliadin antibodies were measured in 498 patients with insulin dependent diabetes mellitus and no history of intestinal malabsorption. Thirty patients had abnormal concentrations of antigliadin antibodies; 22 of these had an intestinal biopsy carried out and 16 of the 22 had subtotal villous atrophy suggestive of coeliac disease (prevalence 3.2%). There were no significant differences between patients with coeliac disease and diabetes and diabetic patients with normal IgA antigliadin antibodies in any of the nutritional variables measured, duration of diabetes, and mean insulin requirement. The mean age of onset of diabetes and attainment of expected height for age were both significantly lower in the patients with both diseases. Typing HLA classes I and II was done in 242 patients. The incidence of HLA-B8, DR3, and DQW2, which are commonly associated with both the diseases, is increased when both are present.
We studied iron overloading and HLA types in 24 sibships of patients with idiopathic hemochromatosis, of which 15 had at least two subjects with overt forms. HLA types of 84 unrelated patients were also investigated. Among siblings there was a significant association (P less than 0.0001) between the presence of hemochromatosis and the possession of the same two HLA haplotypes. The fact that overt forms of hemochromatosis depend on the presence of two specific homologous chromosomes strongly supports a recessive mode of transmission for the overt disease. The haplotypic equilibrium demonstrated in the unrelated patients group is another supporting argument. The lod-score value (2.239 for theta = 0.005) in six families available for study further supports the conclusion that a hemochromatosis gene is closely linked to the HLA-A locus. HLA typing in families with hemochromatosis could provide a means of early detection of subjects at risk before appearance of any sign of iron overload.
It has recently been demonstrated that umbilical cord blood from genotypically human leukocyte antigen (HLA)-matched donors can provide sufficient numbers of progenitor cells for hematopoietic reconstitution. This technique has been successfully applied in the treatment of two children affected with Fanconi anemia (FA). Fetal cells from the potential sibling donors were first tested to determine that the fetus was not affected with FA. Unaffected fetal cells were then tested for HLA type. Cord blood from compatible donors can be harvested at birth and used immediately or frozen for subsequent use in hematopoietic reconstitution. We now show that fetal cell DNA amplification and hybridization for DQ typing can be an important adjunct procedure to verify serologically determined HLA class II types and/or to establish class II haplotype identity with the affected sibling.
Several laboratories have recently observed that common HLA typing sera contain antibodies to various nonHLA antigens, including leukemia-associated antigens and normal platelet, granulocyte, or B-lymphocyte-specific alloantigens. In order to study the possible effects of these antibodies on HLA typing data in leukemia, several of these sera were adsorbed with HLA typed platelets, purified B-lymphocytes, cultured lymphoblasts, or mononuclear cells from patients with active leukemia of various types, and retested for residual activity against previously reacting cells. The results indicate that many of the reactions of leukemia cells to HLA typing sera represent reactions to nonHLA antibodies, many of which are directed against antigens common to cultured lymphoblasts, leukemia cells of several types, and normal B-cells. In the absence of family studies or prior serum adsorption, caution should be used in interpretation of all data related to HLA antigens in leukemia.
I present an overview of HLA typing, a method of evaluating donor-recipient compatibility. The major histocompatibility system in man, the HLA region, considered to control the immunologic response to transplantation and perhaps to certain diseases, is discussed in relation to chromosomal location, chromosomal mapping, association with other markers, nomenclature of the gene products (the HLA antigens), inheritance of the HLA antigens, and methods of determining these antigens. Use of HLA typing is currently most applicable in the correlation of certain diseases with HLA antigen frequency, in evaluating donor-recipient pairs for renal and bone marrow transplantation and for transfusion of platelets and granulocytes and in paternity testing.
MOTIVATION: Allele typing for Human Leukocyte Antigen (HLA) genes has many important clinical applications. Popular short-read typing can only accurately distinguish alleles at the coding sequence level, which potentially limit our understanding of the effect of variants in non-coding region. Long read data has been proved to be useful in typing HLA alleles in full resolution, but only a few tools are publicly available and with significant limitations in practical application. RESULTS: We developed FuFiHLA, a lightweight open-source software, to type HLA alleles. Currently it supports typing alleles of six HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, and HLA-DQB1) from long reads. Evaluation using 233 PacBio HiFi WGS samples from HPRC shows that FuFiHLA achieves 99.6% accuracy in the full field allele typing and QV as 51.8 for consensus allele sequence construction. Additional testing on four Nanopore R10 reads demonstrates slightly reduced accuracy in the fourth field. AVAILABILITY: FuFiHLA is available at https://github.com/jingqing-hu/FuFiHLA under MIT License.
A quick and reliable method for HLA typing of human cadavers has been established. Retinal pigment epithelial cells (RPE) were obtained from cadaver bulbi 8-36 h post mortem (n = 24). After 24 hours, cell growth correlated inversely with the time lapse between the donor's death and bulbus explantation. Cultivated human RPE were stimulated by different Y-interferon (IFN) concentrations and examined by FACS analysis for the expression of MHC class I and II molecules. A concentration of 100 units/ml human Y-IFN was sufficient to induce maximal class I antigen expression by about 90% of cells after 3 days. At 50 units/ml Y-IFN, the cells showed maximal class II antigen expression for HLA-DR, whereas 100 units/ml I-IFN was required for maximal HLA-DQ expression. Higher concentrations of Y-IFN induced a further HLA-DP expression. However, serological HLA typing was performed after cell stimulation with 250 units/ml Y-IFN for 3 days. A concentration of 500 units/ml Y-IFN yielded equivalent results, but 750 units/ml Y-IFN led to poor identification of class I MHC specificities. Unclear serological results on class I specificities were clarified by 1D-isoelectric focusing (1D-IEF), thus allowing full HLA typing of all donor bulbi examined. In summary, successful HLA typing of cultivated RPE is dependent on both the Y-IFN concentration and the time lapse between stimulation and typing of the RPE. The method provides a much improved basis for cadaver cornea grafting.
Corneas used for transplantation are typically obtained from donors up to 48 hr post mortem. By this time, standard HLA typing usually is impossible because of the lack of viable lymphocytes in spleen and peripheral blood. To increase the number of HLA-typed corneas, we developed a method in which the retinal pigment epithelial (RPE) cells of the donor eye are isolated, cultured in the presence of 1000 IU/ml interferon-gamma (IFN-gamma), and, after 4 d, are typed for HLA Class I and Class II antigens in the standard NIH cytotoxicity assay. Sixty five donors were typed simultaneously using peripheral blood lymphocytes and RPE. One hundred and sixteen out of 120 HLA-A antigens, 125/127 HLA-B, 106/108 HLA-C, and 92/100 HLA-DR antigens were identical using the same technique. Donor age, sex, cause of death, time of enucleation post mortem, and time of RPE preparation post mortem, as well as duration of culture period prior to stimulation with IFN-gamma did not correlate with the results of HLA typing. These data show that RPE cells can substitute for lymphocytes in post mortem HLA typing. Consequently, every donor with corneas suitable for transplantation can be prepared for matched transplantation.
OBJECTIVES: To re-evaluate the associations of HLA types with Japanese patients having hyperthyroid Graves' disease, HLA types and clinical findings were correlated. DESIGN: Four independent clinical findings (ophthalmopathy, family history, age at onset and size of goitre) and two autoantibody titres, thyrotrophin binding inhibitor immunoglobulin (TBII) and anti-thyroid microsmall antibody (anti-M), were analysed. PATIENTS: Eighty-eight Japanese patients with hyperthyroid Graves' disease and 186 control subjects were assessed. MEASUREMENT: Serological HLA typing was performed on 73 antigens in HLA-A, -B, -C, -DR and -DQ loci. HLA-D and -DP (29 antigens) were determined by the restricted fragment length polymorphism (RFLP) methods. TBII and anti-M were measured by commercially available kits. RESULTS: Patients with potent antibody titres had HLA antigens commonly seen among all the patients with Graves' disease. Interestingly, however, HLA-B35 and -Cw11 were found to relate with negative and/or weak TBII, and HLA-B7 and absence of HLA-Aw19 with negative anti-M. Significant associations were observed between HLA-DRw8 and large goitre and absence of ophthalmopathy, and between HLA-DQw4 and a negative family history of diffuse goitre (corrected P less than 0.05). Several other antigens were also found to be significant. Among these antigens, four pairs of MHC classes I and II were found to relate to the clinical findings independently. HLA-DQw4 and negative -A31 pair was closely related to ophthalmopathy, negative family history and late onset of disease. The HLA-B5 and -Dw12 pair was associated with ophthalmopathy, positive family history and early onset of disease. The HLA-A11 and negative -DPw2 pair was associated with ophthalmopathy, negative family history and early onset of disease. The HLA-Bw46 and -DRw8 pair did not increase in frequency above that seen with HLA-DRw8 alone. These four antigen groups (HLA-DRw8, HLA-DQw4 and negative-A31, HLA-B5 and -Dw12, and HLA-A11 and negative -DPw2) were observed in the majority (68%) of patients with Graves' disease and at a significantly higher incidence than in the control group (P less than 0.05). CONCLUSION: There are four subpopulations of Japanese patients with hyperthyroid Graves' disease. This is one of the reasons why the association of HLA types in Japanese patients is rather weak when they are studied as one group.
Congenital adrenal hyperplasia (C.A.H.) due to 21-hydroxylase deficiency is an HLA-linked recessive disorder. HLA-A and B antigens are expressed on amniotic cells. Prenatal diagnosis of C.A.H. by HLA typing of families and amniotic cells was attempted in two at-risk families. In one family HLA typing indicated that the fetus would have C.A.H., and this prediction was confirmed after birth. In the second family, HLA typing indicated that the fetus would be an unaffected, phenotypically normal carrier of the disease gene, and this prediction was also confirmed after birth.
A study of 18 unrelated families with idiopathic haemochromatosis (I.H.C.) was undertaken to define the relative values of HLA typing and serum-ferritin estimation in the early detection of the disease. Sharing of both HLA haplotypes with the proband indicated a high risk of I.H.C. in siblings; but HLA typing was of limited value in detecting affected offspring. Non-identical HLA indicated a low risk of I.H.C. in both siblings and offspring. The presence of HLA A3 was not clinically useful as a marker for I.H.C., since this antigen was also present in 40% of unaffected relatives. In contrast, the serum-ferritin concentration was elevated in 96% of patients with I.H.C. and in only 5% of unaffected relatives. HLA typing provides some indication of the risk of I.H.C. in first-degree relatives, but the combination of serum-ferritin, serum-iron, and transferrin saturation remains the most reliable screening regimen for early diagnosis of I.H.C.
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.
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.
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.
In 1990, 4,234 BMT were performed in Europe; 2,097 autologous BMT (388 AML) and 2,137 allogeneic BMT (494 AML). Although an established therapy with leukemia free survival (LFS) at five years of 41% +/- 5% (EBMT results) its value compared to alternative therapies remains controversial. During the year 1985, the EBMT conducted a prospective evaluation study. In 12 centres 168 patients with AML were registered at the time of HLA-typing. Basic patient data and treatment intention were recorded. 79 patients were HLA-typed at diagnosis. 68 patients in 1st CR and 21 at other stages. Follow-up of these patients was obtained as of January 1, 1991. Three-year LFS is 44% for patients with an HLA-identical donor and 21% for those without (p = 0.02). Of the 68 patients HLA-typed in first CR, 40 had an HLA-identical donor and 28 no donor. Three-year LFS is 42% and 35%. resp. (n.s.). The difference in results between patients typed at diagnosis and first CR patients illustrates the problem of selection. We conclude that patient registration early in the disease can give insight into the process of selection. Allogeneic BMT incorporated prospectively at diagnosis into therapy offers a survival advantage for patients in this age category compared to alternative therapies.
The frequency of HLA types in a selected group of 40 patients with myasthenia gravis in relation to the effect of thymectomy and also to gender, and thymus histology was studied. As generally described we found a significant increase in the frequency of HLA-A1, HLA-B8, HLA-DR3 and HLA-DQ2 in the total group. There were no further differences between subgroups of patients, which demonstrates that HLA type is not indicative for the effect of thymectomy in myasthenia gravis.