Biomedical subjects
E D Albert
Publications and source records attributed to E D Albert.
Nomenclature for factors of the HLA system, 2000.
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Nomenclature for factors of the HLA system, 2000.
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MICA, MICB and C1_4_1 polymorphism in Crohn's disease and ulcerative colitis.
MICA and MICB belong to a multicopy gene family located in the major histocompatibility complex (MHC) class I region near the HLA-B gene. They encode for MHC class I molecules, which are induced by stress factors like infection, heat shock or neoplastic transformation and which are mainly expressed on gastrointestinal epithelium. They are recognized by gammadelta T lymphocytes and natural killer (NK) cells. Additionally they are located within a linkage region on chromosome 6p around HLA-B and TNFalpha. Thus the polymorphic MICA and MICB genes are excellent candidate genes for providing the genetic background of inflammatory bowel disease. A strong association of allele A6 of the MICA exon 5 trinucleotide microsatellite polymorphism with ulcerative colitis has been found in Japanese patients. Therefore, we have analysed the MICA exon 5 polymorphism, the MICB intron 1 dinucleotide polymorphism and in addition the tetranucleotide polymorphism C1_4_1, which is located between the MICA gene and the HLA-B gene, in patients of Caucasoid origin with Crohn's disease (n=94) and ulcerative colitis (n=94). In this study we could not find any associations of particular alleles of the MICA, MICB and C1_4_1 polymorphisms with Crohn's disease or ulcerative colitis. We could also not discover any associations of specific two-point or three-point haplotypes with these diseases. Thus it is unlikely that the MICA and MICB genes are involved in causing susceptibility for inflammatory bowel disease, although it cannot be excluded that a weak association could be identified in a larger patient sample.
Identification of a novel HLA-B*2722 allele from a Filipino cell.
We present the novel HLA-allele B*2722 amplified and sequenced from a Filipino individual. This DNA was included several times in the International Cell Exchange, UCLA, and typed at the time as B*27 or B*2706 by the majority of the participating laboratories. The second HLA-B allele of this person is B*3802. B*2704/06 or B*2704/06/10 were suggested by approximately one-third of the laboratories. As we were investigating the intron 3 sequences of B*27 alleles, we also sequenced exon 4 of this Filipino DNA and found a single nucleotide exchange in exon 4 (pos. 704) which was not in concordance with the previous B*2706 typing. Our sequencing results showed that the coding sequence of B*2722 is identical to B*2706 in exon 1, 2 and 3. In exon 4 the B*2722 sequence is identical to B*2704. HLA-B*2704 differs from B*2706 in one base at position 704, a G in B*2704 and a C in B*2706, respectively.
Nomenclature for factors of the HLA system, 2000.
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An update on HLA association of Mi-2 autoantibodies: the association with a tryptophan at position 9 of the HLA-DRbeta chain is strong but not absolute.
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Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: the German BABYDIAB study.
AIMS/HYPOTHESIS: Islet autoantibodies precede the clinical onset of Type I (insulin-dependent) diabetes mellitus. The cumulative development of such autoantibodies in infants followed from birth and in particular infants with high-risk HLA genotypes is poorly defined, but such information is essential to design trials to prevent islet autoimmunity. METHODS: HLA genotypes were determined in offspring of parents with Type I diabetes who were followed from birth for at least 2 years (median follow-up: 3.1 years) and who were characterised for the expression of insulin, GAD65, IA-2 and islet cell autoantibodies at birth, 9 months, 2 and 5 years of age. RESULTS: The HLA genotypes DRB1*03/04(DQB1*57non-Asp) and DRB1*04/04(DQB1*57non-Asp) were present in 7.1% and 5.0% of offspring of parents with Type I diabetes. The frequency of both genotypes was increased in offspring who developed islet autoantibodies within the first 2 years of life (27.3% vs 5.5%, odds ratio 6.3 [p = 0.002] and 22.7% vs 4.2%, odds ratio 6.6 [p = 0.003]) and half of all offspring who developed antibodies had these genotypes. Other genotypes were not associated with an increase in risk. By life-table analysis, the cumulative risk of developing islet autoantibodies by the age of 2 years was 20% (95% CI 9.4,30.6) for offspring carrying either the DRB1*03104(DQB1*57non-Asp) or the DRB1*04/04(DQB1*57non-Asp) genotype compared with 2.7% (95% CI 1.2,4.2) for offspring without these genotypes (p < 0.0001). CONCLUSION/INTERPRETATION: These data show that early appearance of islet autoantibodies is remarkably frequent for DR3/4 heterozygous and DR4/4 homozygous offspring and indicate that primary prevention could be considered once available in an offspring cohort selected for these genotypes.
Nomenclature for factors of the HLA System, 1998.
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Nomenclature for factors of the HLA system, 1998.
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Unusual association of the DRB4 null allele, DRB4*0103102N, with HLA DRB1*0402 in a sample of Austrian patients.
Tissue typing for HLA class II antigens is routinely performed by serological, and/or DNA-based methods. Accuracy, absence of cross-reactivity and controllable level of resolution are striking advantages of molecular methods. However, a disadvantage of molecular typing, compared to serological methods, is the identification of unexpressed alleles. Whereas serology allows a more or less direct insight into antigen presence, molecular biology is an indirect method and results must also be interpreted by considering the biological pathways of protein expression. We believe that identification of nonexpressed MHC alleles is of importance for transplantation, since nonexpressed MHC allele positive individuals could give rise to antibody formation against the respective expressed MHC product in donor tissue. Usually, the nonexpressed DRB4*0103102N is encountered in association with DRB1*0701-DQB1*03032, which facilitates correct DNA typing. Here we describe the unusual association of this unexpressed DRB4*0103102N, with DRB1*0402-DQB1*0302 in a sample of Austrian patients.
Nomenclature for factors of the HLA system, 1998.
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Predictive value of human leukocyte antigen class II typing for the development of islet autoantibodies and insulin-dependent diabetes postpartum in women with gestational diabetes.
Gestational diabetes mellitus (GDM) is a risk factor for the development of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus postpartum. To evaluate whether there is any association of human leukocyte antigen (HLA) class II alleles (DR and DQ) with GDM and the postpartum development of IDDM, we analyzed 184 women with GDM from Germany for HLA class II alleles, islet autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), and protein tyrosine phosphatase IA-2 autoantibodies (IA-2A), and the postpartum development of diabetes. No elevation in the frequency of any HLA class II alleles was observed in GDM patients compared to 254 nondiabetic unrelated subjects. DR3 allele frequency was significantly increased in 43 women with islet autoantibodies [corrected P value (Pc) = 0.02], in particular in those with GADA (Pc = 0.002), or in the 24 women who developed IDDM postpartum (Pc = 0.005). In women with GADA, DR4 and DQB1*0302 were significantly elevated (Pc = 0.009). Twenty-five (59.5%) islet antibody-positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4-containing genotype. The cumulative risk to develop IDDM within 2 yr postpartum in GDM women with either DR3 or DR4 was 22% compared to 7% in women without those alleles (P = 0.02) and rose to 50% in the DR3- or DR4-positive women who had required insulin during pregnancy (P = 0.006). Combining the determination of susceptible HLA alleles (DR3, DR4) with islet autoantibody measurement increased the sensitivity of identifying GDM women developing postpartum IDDM to 92%, but did not improve risk assessment above that achieved using GADA measurement alone, which was the strongest predictor of IDDM. These results indicate that women with GDM who have islet autoantibodies at delivery or develop IDDM postpartum have HLA alleles typical of late-onset type 1 diabetes, and that both HLA typing and islet antibodies can predict the development of postpartum IDDM.
Juvenile arthritis: genetic update.
Juvenile arthritis (JA) is a term that covers a number of different disease entities, of which only three present with significant Human Leukocyte Antigen (HLA) associations. (1) Pauciarticular JA with late onset and a strong male proponderance is associated with HLA-B27 and represents the group of juvenile spondyloarthropathies related to adult ankylosing spondylitis. (2) Early onset pauciarticular JA with a preponderance of females and a frequent occurance of chronic iridocyclitis and the frequent presence of anti-nuclear antibodies is associated with alleles from three different regions of the HLA system: HLA-A2, which shows a very strong correlation with early age of onset; DR8, DR11 and DR12 as well as DQA1*0401, *0501, *0601 and finally DPB1*0201. These alleles show no linkage disequilibrium in the control population. (3) Rheumatoid factor positive polyarticular JA is associated, as is adult rheumatoid arthritis, with DR4. Concerning the possible mechanisms of the immunopathogenesis, it is speculated that the normal function of HLA molecules, namely the presentation of antigenic peptides, plays a major role. Data collected on HLA associations in early onset pauciarticular JA have been interpreted as indicating that alleles of the DQA1 locus (*0401, *0501, *0601) are probably responsible for presenting the hypothetical arthritogenic peptides. It is speculated that the pathogenic process includes the presentation of HLA-A2 or HLA-DPB1*0201 derived peptides presented by DQ molecules. It is clearly stated that typing for HLA alleles has very little or no importance for clinical diagnosis and prognosis.
HLA region microsatellite polymorphisms in juvenile arthritis.
A number of microsatellite polymorphisms located in the MHC region of the human chromosome 6 have been analysed in a large group of patients with juvenile arthritis (JA) (n = 177) and in 157 controls. There have been no significant associations for the alleles of the microsatellite polymorphisms D6S-105, D6S-510, TNFA, TNFC, TNFD, TNFE, HSP. Allele frequencies and HLA associations were listed for the non-associated microsatellite loci. The microsatellite locus DQ CAR, which is localized between DQA1 and DQB1, shows a significant positive association with JA for the allele DQ CAR 121 and a negative association for the allele DQ CAR 111. The allele DQ CAR 121 is strongly associated with DQA1*0501 and with DQB1*0301 both in the normal controls and in the patient population. This pair of DQA/DQB alleles corresponds to the DQ molecule DQ7 on the cell surface, which has been described to be strongly associated with JA. Investigations of the two and three-point haplotypes of DQ CAR with alleles of its neighboring loci have shown that the association with DQ CAR 121 is secondary to the association with DQ7 previously observed. Thus, using eight HLA linked microsatellite polymorphisms in the region from HLA-A to HLA-DQ, we have not found any evidence for further loci which might be involved in the coding for susceptibility for JA.
In vivo and in vitro immune variables in patients with narcolepsy and HLA-DR2 matched controls.
We investigated cytokine levels (interleukin [IL]-1beta, IL-1ra, IL-2, IL-6, tumor necrosis factor [TNF]-alpha, TNF-beta) in plasma and secreted by mitogen-stimulated blood monocytes and lymphocytes; T-cell subsets; and natural killer cell activity in patients with narcolepsy and in human leukocyte antigen (HLA)-DR2 matched controls. The only significant finding was higher IL-6 secretion by monocytes of patients than by those of the HLA-DR2-positive controls. In conclusion, we found no major abnormalities of T-cell function in patients with narcolepsy, but slight alterations of monocyte function deserving further investigation.
High serum IgE concentrations: association with HLA-DR and markers on chromosome 5q31 and chromosome 11q13.
BACKGROUND: Linkage studies mapped a locus regulating total serum IgE concentrations in a noncognate fashion to chromosome 5q31 and a locus for atopy to chromosome 11q13. In contrast, antigen-driven IgE production seems to be largely controlled by major histocompatibility complex class II genes. OBJECTIVE: We therefore analyzed the association between the phenotype of high IgE serum levels and six microsatellite markers on chromosomes 5q31 and 11q13, as well as HLA-DRB1, in a random sample of the adult East German population. METHODS: One hundred twenty-nine persons identified as "cases" (serum IgE level > 200 kU/L) and 266 control subjects (serum IgE level < or = 200 kU/L) were genotyped for five 5q31 microsatellites (D5S436, D5S393, D5S210, IL-4, and IL-9) and an 11q13 microsatellite (FCERIB). Cases and controls were also typed for HLA-DRB1. Allele frequencies were compared between cases and controls by means of a two-sided Fisher's exact test. RESULTS: None of the markers was significantly associated although a weak association to the markers within the IL-9 gene and the FCER1B gene and to the HLA-DRB1*01 allele was found when specific IgE-positive cases were compared with negative controls. CONCLUSIONS: The weak associations observed after stratification for specific IgE might point to a contribution of genes in these regions to the development of allergy.
Nomenclature for factors of the HLA System, 1996.
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