HLA in Japanese Insulin-Dependent Diabetes Mellitus

Ninety-four Japanese patients with insulin-dependent diabetes mellitus (IDDM) and 388 healthy randomly selected Japanese were HLA typed. Significantly increased frequencies of Bw54, Cwl, DR4, B17 (Bw58), DR3 and DRw9 were observed. Simultaneously, the frequencies of Bw52 and DR2 in the patients were found to be significantly low as compared with those in helathy Japanese controls. It was suggested that one of the susceptibility genes to IDDM, which is associated with B8, DR3 haplotypes in Caucasoids, might be associated with B17 (Bw58), DR3 haplotypes in Japanese and in Chinese. Another susceptibility gene to IDDM associated with DR4 in Caucasoids might be associated with both DR4 and DRw9 in Japanese. A very rare variant of properdin factor B allotypes (BF*FT or BF*F075) was shown to be associated significantly with Japanese IDDM and with Bw52, DRw9 haplotypes.     

The Study of HLA, ICA and Autoantibodies in Japanese Type 1 Diabetes Mellitus

HLA, ICA (islet cell antibody) and autoantibodies were studied in 65 Japanese patients with type 1 diabetes mellitus to elucidate the existence of immuno-genetic heterogeneity. Patients with autoantibodies had increased frequencies of HLA DRw9 antigen and of HLA haplotype of Bw61-DRw9, and a slow decay of ICA, while patients without autoantibodies had increased frequencies of HLA DR4 antigen and of HLA haplotype of Bw54-DR4, and a rapid decay of ICA. These findings support the concept of immunogenetic heterogeneity in Japanese type 1 diabetes mellitus.     

HLAs in children with minimal change disease and other types of nephrotic syndrome in the southern part of Turkey

The aim of this study was to investigate the human leukocyte antigen (HLA) profile of children with nephrotic syndrome in the southern part of Turkey. Seventy-eight children with nephrotic syndrome were studied for the frequency of class I and class II human leukocyte antigens. Forty-seven of them were steroid sensitive nephrotic syndrome (minimal change disease-MCD) and 31 were other types of nephrotic syndrome. The results were compared with 133 healthy subjects for HLA groups. HLA B13, Cw5, Cw7, DR4, DR7, DRw10, Drw15(2) and DQ2 in the MCD group and HLA A31, B8, B13, B17, Cw2, Cw6, Cw7, DRw10 and DRw12 in the non-MCD group were found significantly increased when compared to healthy controls. MCD patients with frequent relapses had higher frequencies of both Cw6 and DR1 (p < 0.005) and MCD patients with infrequent relapses had a higher frequency of Cw7 (p < 0.05). In conclusion, HLA groups may help in the early diagnosis of these variants.     

Membranoproliferative glomerulonephritis in sibs.

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a chronic renal disease with variable clinical expression and several distinct morphological subtypes. Two sibs, aged 10 and 13, presented with clinical and laboratory findings of MPGN at the time of admission. After an interval of one year, the diagnosis of MPGN was established by renal biopsies. The complement pathway was unremarkable. HLA typing in the unrelated parents and the two male sibs revealed common HLA A2,A11,Bw60, DR2,DQw1 antigens in the brothers. Of these antigens, A2 has been reported previously in cases of MPGN. The other antigens regarding this disease need to be evaluated from the standpoint of genetic importance.     

Human leucocyte class I and II antigens in coeliac disease: a study in an Austrian paediatric population

Regional variations in the human leucocyte antigen (HLA) distribution patterns of coeliac disease (CD) have been reported. This study focuses on phenotype frequencies of a cohort of Austrian paediatric CD patients in comparison with those recorded in the literature. HLA class I and II typing was performed in 136 CD patients and 667 healthy controls from the general population of the same geographical area. The HLA phenotypes of our controls agreed with those published for Caucasians. In our patients the relative risks (RR) were 6.43 for DR3 and 2.52 for DR7, the aetiologic fractions being 0.58 respectively 0.24. The highest RR (7.78) was found for DR3/DR7 heterozygotes. The RR for DR5 was increased in heterozygosities, either with DR3 (3.34) or DR7 (5.53), yet not for DR5 alone. Of our patients, 10% were lacking both DR3 and DR7 as well as B8, 82% of them were positive for DQw3. In these DR3 and DR7 negative patients, DR4 and DR5 were significantly more frequent than in the others. DR5 was also significantly more common in these patients compared to controls lacking the same antigens, whereas this did not hold true for DR4. Prospective studies are required to determine any link between these HLA heterogeneities and long-term progression of the disease.     

幼年类风湿关节炎人类白细胞抗原-DR基因与疾病相关性的研究

为研究幼年类风湿关节炎（ＪＲＡ）的遗传学发病特点及与疾病的相关性，应用聚合酶链反应技术（ＰＣＲ）序列特异性引物和序列特异性寡核苷酸斑点杂交法，检测５０例类风湿关节炎患儿。结果：ＪＲＡ全身型３５．０％的患儿具有ＨＬＡ－ＤＲ８基因，与对照组相比，差异有非常显著意义（Ｐ＜０．０１）。多关节型中的类风湿因子（ＲＦ）阳性组８３．３％的患儿携带ＤＲ２，而ＲＦ阴性组中只有２２．２％的患儿携带ＤＲ２，二者差异有非常显著意义（Ｐ＜０．００１）；ＤＲ１、ＤＲ１０试验组有增高的趋势。少关节型的ＨＬＡ－ＤＲ呈多态性分布，９１．７％的患儿为ＨＬＡ－Ｂ２７位点阳性且全部为男性。结论：ＨＬＡ－ＤＲ８或ＤＲ４是导致ＪＲＡ全身型的易感因素，ＨＬＡ－ＤＲ２与ＲＦ高度联锁是导致多关节型发生的因素，少关节型中未发现与之相关的ＤＲ基因，但与Ｂ２７位点相关。提示患儿的检测结果可能是强直性脊柱炎的早期表现。     

Classification of Type 1 and Type 2 Diabetes Mellitus from Studies of ICA, HLA and Insulin Secretory Capacity

We studied ICA, HLA and insulin secretory capacity in 87 children with positive urinary screening and more than 2 points in the oral glucose tolerance test in order to establish criteria by which they could be classified into type 1 or type 2 diabetes mellitus. Fifty-five non-obese, ketosis-prone insulin dependent diabetic children were used as controls for type 1 diabetes mellitus. Our conclusions were as follows: 1. Type 1 diabetics were non-obese (on insulin therapy), ICA positive, ketosis-prone, had an insulin secretory capacity (Z IRI) of less than 100/nU/ml, and most of them possessed HLA-Bw54-DR4 or DRw9, DRw53 but did not possess Bw52-DR2 haplotype. 2. In the patients who were treated by dietary regimens alone for certain periods, however, insulin secretory capacities gradually deteriorated and they finally became insulin dependent. The children of this group who were not obese during insulin therapy and possessed an HLA haplotype identical to that in type 1 diabetes, regardless of ICA, might be classified as having slowly progressive type 1 diabetes. 3. The major difference between type 1 and slowly progressive type 1 diabetes was a family history of diabetes. Genetic factors might modify the clinical course of type 1 diabetes mellitus. 4. If the sensitivity of ICA or related autoantibodies to islet cells can be detected more readily, it should become easier to distinguish between type 1 and 2 diabetes.     

Human lymphocyte antigen DR types in relation to early clinical manifestations in diabetic children

Human lymphocyte antigen (HLA)-DR-typing was performed in 117 insulin-dependent diabetics with age at onset between 0.5 and 17 years (mean +/- SD, 9.0 +/- 3.9); 115 of 117 patients were DR3- and/or DR4-positive. DR4 was very common, seen alone or in combination with other DR types in 82.9% of the patients. Only two children were DR2-positive, but they also were DR4-positive. A comparison between DR3 and DR4 patients showed that DR4 patients manifested a seasonal variation of onset (most common onset during spring and autumn), had more severe signs and symptoms of the disease at onset, and were less likely to have a partial remission than patients with DR3. The results support the hypothesis that insulin-dependent diabetes mellitus is a genetically heterogeneous disease.     

Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter

BACKGROUND: Current theory on the etiology of Langerhans cell histiocytosis (LCH), formerly Histiocytosis-X, is that abnormality(ies) of the immune system are responsible for dysregulation of Langerhans cells (LC) in patients' lesions. Among the known abnormalities in LCH patients are increased amounts of tumor necrosis factor alpha (TNF-alpha) and other cytokines in the lesions. PROCEDURE: We investigated the human leukocyte antigen (HLA) phenotypes of 29 patients and 37 healthy family members to determine if any haplotypes segregate with the presence or locations of the disease. The lymphocyte subsets for 22 patients and 11 family members were also determined. RESULTS: Patients with single bone, multiple bone, or multi-system LCH had different relative proportions of HLA types. Patients presenting with single bone disease had an especially high frequency of the DR4 type. In this patient group, every Caucasian patient had either Cw7 or DR4. Lymphopenia was documented in patients who had been off therapy as well as those who only had surgical curetage of their lesions. Family members also had low numbers of T lymphocytes. There were fewer mutations of the TNF-alpha promoter in patients than in the general population. CONCLUSIONS: Although there is an increased percentage of LCH patients with DR4 and/or Cw7 there was also an increased prevalence of this antigen as well as lymphopenia among unaffected family members. Additional genetic and/or environmental factors are necessary to explain this association. TNF-alpha promoter mutations are not responsible for the increased production of this cytokine.     

The importance of CTLA-4 polymorphism and human leukocyte antigen genotype for the induction of diabetes-associated cytokine response in healthy school children

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease associated with the destruction of pancreatic beta cells and genetically linked to human leukocyte antigen (HLA) class II DR3-DQ2 and DR4-DQ8 haplotypes. The +49A/G polymorphism of the immunoregulatory cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is also associated with T1D. Genetic and environmental risk factors precede the onset of T1D, which is characterized by a T helper 1 cell-dominating cytokine response to diabetes-related autoantigens. AIM: To investigate immunological differences between healthy children with and without CTLA-4 +49A/G and HLA genetic susceptibility for T1D. STUDY DESIGN: Young, 7-15 years of age, healthy subjects (n = 58) were investigated to test whether CTLA-4 +49A/G genotype was associated with enzyme-linked immunospot assay T-cell responses to T1D-related autoantigens. Because T1D is primarily HLA-DQ associated, we stratified the healthy subjects by HLA genotypes associated with the disease. RESULTS: Peptide of heat shock protein 60 induced a higher interferon-gamma (IFN-gamma) response in subjects with risk-associated CTLA-4 polymorphism (GG genotype) (p = 0.02) while glutamic acid decarboxylase 65-induced interleukin-4 (IL-4) secretion was lower in GG genotype subjects (p = 0.02). CONCLUSION: The increased IFN-gamma response and lower IL-4 response toward diabetes-related autoantigens shown in CTLA-4 +49 GG risk subjects show a possible mechanism for the association between CTLA-4 and T1D.     

Fatal pneumococcal meningitis in a 1-year-old child with homozygous C2 deficiency

The 1-year old girl died of recurrent bacterial meningitis. Streptococcus pneumoniae was isolated from the cerebrospinal fluid. The analysis of the immune system revealed only a defect of the complement system. The following results were obtained: 1. No function of the classical complement pathway. 2. Reduced function of the alternative complement pathway. 3. No functional C2 activity. 4. No C2 protein. The parents had half normal C2 titers. HLA typing was only possible for the parents with the following results: A1, A32(w19), B18, DR2, DRw11(5) (father) and A3, A10, B18, B7, DR2 (mother). These data are compatible with a B18, DR2 haplotype of the child which is found in most cases of homozygous C2 deficiency. Our patient list another example for the high risk of recurrent severe infectious diseases in persons with a total complement defect.     

Influence of HLA DQ 2/8 genotypes in predisposing type 1 diabetes in siblings of a Saudi family with paternally inherited chromosomal translocations

Type 1 diabetes is one of the most widely studied complex genetic disorders and the genes in human leukocyte antigen (HLA) locus are reported to account approximately 40%-50% of familial aggregation of type 1 diabetes. Genetic markers are helpful in assessing the risk of type 1 diabetes in the general population as well as in close relatives of a patient with type 1 diabetes. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The major susceptibility genes for type 1 diabetes are in the HLA region, and over 90% of patients carry genotypes DR4, DQ8 and/or DR3, DQ2. Absence of the above alleles makes type 1 diabetes very unlikely, especially if the subject carries protective genotypes such as DR2 and/or DQ6. In this brief report of a consanguineous Saudi family, four offsprings inherited one or both of balanced reciprocal translocations from their father. Two offsprings, one with a translocation and the other without, developed type 1 diabetes during early childhood. Both these diabetic children were found to have HLA genotype DQ 2/8, whereas the father and the youngest daughter, both carrying two sets of balanced translocations as well as the protective HLA genotype DQ6, were free of diabetes during several years of observation. This underscores the influence of HLA genotype DQ 2/8 in the susceptibility and DQ6 in the protective effect on type 1 diabetes even in individuals with gross chromosomal abnormalities.     

Genetics of insulin-dependent diabetes mellitus in children

Insulin-dependent diabetes in children is a heritable disease, although it does not fit into any simple genetic model. Research is not facilitated by the lack of knowledge of the different etiological mechanisms and the inability to classify the disease. Human leucocyte antigens (HLAs) coded for in the major histocompatibility complex on the 6th chromosome have given the most important insights into the genetics of diabetes, and these genes probably provide the majority of genetic susceptibility to type-I diabetes. Several facts indicate that there are at least two loci of importance, one associated with HLA B8, DR3 and another with HLA B15, DR4, which probably are usually included in extended haplotypes in linkage disequilibrium. There seems to be a substantial DNA polymorphism and further studies may detect fragments that are even more strongly associated with diabetes than the DR type. A combination of more detailed immunological, perhaps virological or other environmental investigations on diabetic patients and their families, together with the use of specific DNA probes for the HLA region, might reveal the susceptibility genes.     

Molecular detection of genetic defects in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A study of 27 families

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OHase) deficiency is inherited as an autosomal recessive trait. Patients can present with the salt wasting, simple virilizing or a non-classical form of the disease. The gene for P450C21, the enzyme carrying 21-OHase activity, has been mapped to the major histocompatibility complex on chromosome 6p. Using molecular hybridisation techniques we have studied the genetic defect in 27 families with one or more affected off-spring diagnosed and treated at the University Hospital of Essen. DNA samples were digested with restriction endonucleaseTaqI,PvuII,BglII, andEcoRI and analysed by Southern blot hybridisation with the cDNA probe pC21/3c. Eleven of 40 haplotypes associated with the salt wasting form were found to have a large deletion of 30 kb affecting the 5 end of the active 21-OHase gene and the 3 end of the closely linked pseudogene. Results in another 11 cases are compatible with gene conversion; 18 cases were not informative. The 30 kb deletion was associated with a combination of the HLA antigens Bw47 and DR7 in 7 of 11 cases. In the haplotypes with gene conversion, no linkage disequilibrium to HLA antigens was found. No apparent gene alterations were detected in simple virilizing and non-classical haplotypes. The direct detection of the genetic defect in 55% of the salt wasting haplotypes may help to improve predictive testing in families with CAH.     

The challenge of childhood diabetes mellitus in India

The prevalence of DM is about 0.4/1000 children with a lower incidence in the rural areas. Children comprise 3–5% of the total diabetics. A study of 55 pediatrie cases of DM (1980-84) showed that only 22 (40%) had ketoacidosis on admission. Ten (18.2%) had onset of illness before 4 years of age. HLA antigen studies in childhood IDDM have shown a positive linkage disequilibrium with Bw21 (RR-12.7), and DR3 (RR=16.6). Prevalence of islet cell antibodies (ICA) was 30.9% (n = 110) as compared with 0.8% in controls. Antibodies against Coxasckie B2 virus were increased (75.5% vs 46.4% in controls). The C-peptide content was substantially low. Malnutrition related DM occurs in adolescents in some parts of India. It is characterized by moderate hyperglycemia, low serum glycerol, relative insulin insensitivity, and pancreatic malformation/calcification in about 1/4 of subjects. There is no association with HLA antigens or ICA, and the precise etiology is unclear. Mortality was 3.6% in patients admitted in our hospital but is higher in other regions due to poverty and relative lack of health care facilities.     

Pattern of human leukocyte antigens in Turkish children with celiac disease

BACKGROUND: Regional variations in the human leukocyte antigen (HLA) distribution patterns of celiac disease (CD) have been reported. The aim of the present study was to assess the distribution of HLA class I and class II in Turkish children with CD and to compare the findings with a control group. METHODS: Human leukocyte antigen typing was performed in 33 children with CD and in 77 healthy individuals, who served as controls, by using standard National Institutes of Health lymphocytotoxicity techniques. RESULTS: A positive association was found between HLA A2 (42 vs 19% for sick subjects compared with healthy controls, respectively), B8 (39 vs. 9% for sick subjects compared with healthy controls, respectively), CW7 (45 vs. 25% for sick subjects compared with healthy controls, respectively), DR3 (70 vs. 17% for sick subjects compared with healthy controls, respectively), DR7 (30 vs. 13% for sick subjects compared with healthy controls, respectively) and DQ2 (52 vs. 34% for sick subjects compared with healthy controls, respectively). The combinations of DR3-DQ2 (30 vs. 12% for sick subjects compared with healthy controls, respectively), DR3-DR4 (21 vs. 1% for sick subjects compared with healthy controls, respectively) and DR7-DQ2 (21 vs. 6% for sick subjects compared with healthy controls, respectively) were also found to be significantly important in children with CD. The highest relative risk (RR) was for HLA B8 in class I (RR 6.50), for DR3 (RR 11.30) in class II and for combination of DR3-DR4 (RR 20.46). The highest etiologic fraction (EF) was for the DR3 antigen (EF 0.55). CONCLUSIONS: The present study emphasizes that HLA genotypes are an important background to CD development, but some additional susceptibility factors remain to be identified.     

Contrasting features of insulin dependent diabetes mellitus associated with neuroectodermal defects and classical insulin dependent diabetes mellitus

The Wolfram, or DIDMOAD, syndrome is a rare congenital disease that is associated with diabetes insipidus, insulin dependent diabetes mellitus of an early onset, bilateral optic atrophy and deafness. Urological disorders are usually present as well. We have studied nine patients belonging to five different families. All of the family members were HLA typed (including DR), and islet cell as well as antinuclear antibody determinations were carried out. Although individuals with insulin dependent diabetes mellitus are very prone to have either HLA-DR3 or -DR4 antigens, none of our patients had DR3 antigens and only one was DR4 positive. On the other hand, three of our patients were typed as HLA-DR2 positive. This antigen is uncommon in classical insulin dependent diabetes. In one of the families, the affected siblings did not share the same HLA haplotype. Islet cell and antinuclear antibodies were not found in any of the cases and six of the patients had a small, but significant, insulin secretory reserve. On the basis of some of the clinical features it was also possible to further distinguish between the DIDMOAD syndrome and the classical insulin dependent diabetes mellitus. The differences encountered between classical and DIDMOAD insulin dependent diabetes mellitus--the presence/absence of HLA linkage, HLA-DR2, -DR3 and -DR4 associations, islet cell or antinuclear antibodies, the tendency to ketosis and diabetic retinopathy--indicate that their etiopathogenies are triggered by distinct mechanisms.     

A Study of HLA in Japanese Patients with Rheumatic Fever

HLA was analysed to study an aspect of genetic background of susceptibility to rheumatic fever. The frequency of HLA was determined in 66 Japanese patients with rheumatic fever and compared with 95 healthy Japanese controls by chi-square method with Yates' correction. The frequency of Bw35 was increased significantly in rheumatic fever group compared with control group (Pc < 0.01). An association between Bw35 and rheumatic fever may imply that rheumatic fever is an autoimmune disease. And the susceptibility to rheumatic fever may be controlled by immune response genes, which have a linkage disequilibrium with Bw35 as an immunogenetic background.     

Contrasting Features of Insulin Dependent Diabetes Mellitus Associated with Neuroectodermal Defects and Classical Insulin Dependent Diabetes Mellitus

ABSTRACT. The Wolfram, or DIDMOAD, syndrome is a rare congenital disease that is associated with diabetes insipidus, insulin dependent diabetes mellitus of an early onset, bilateral optic atrophy and deafness. Urological disorders are usually present as well. We have studied nine patients belonging to five different families. All of the family members were HLA typed (including DR), and islet cell as well as antinuclear antibody determinations were carried out. Although individuals with insulin dependent diabetes mellitus are very prone to have either HLA-DR3 or -DR4 antigens, none of our patients had DR3 antigens and only one was DR4 positive. On the other hand, three of our patients were typed as HLA-DR2 positive. This antigen is uncommon in classical insulin dependent diabetes. In one of the families, the affected siblings did not share the same HLA haplotype. Islet cell and antinuclear antibodies were not found in any of the cases and six of the patients had a small, but significant, insulin secretory reserve. On the basis of some of the clinical features it was also possible to further distinguish between the DIDMOAD syndrome and the classical insulin dependent diabetes mellitus. The differences encountered between classical and DIDMOAD insulin dependent diabetes mellitus—the presence/absence of HLA linkage, HLA-DR2, -DR3 and -DR4 associations, islet cell or antinuclear antibodies, the tendency to ketosis and diabetic retinopathy—indicate that their etiopathogenies are triggered by distinct mechanisms.     

Coeliac disease, enamel defects and HLA typing

The presence of dental enamel defects in coeliac disease and their relation to hypocalcaemia or a particular HLA class in 82 Italian children with coeliac disease was studied. Demarcated opacities or hypoplasia were detected in 23 subjects (group 1) while minimal or no dental lesions were found in the remaining 59 patients (group 2); in 189 normal controls, enamel lesions were significantly less frequent than in patients with coeliac disease (14.8% versus 28.0%; p < 0.005). No statistically significant differences were found for age at diagnosis and calcium concentrations between groups 1 and 2. Regression analysis showed a correlation between age at diagnosis and number of teeth with enamel defects. In our patients, the presence of HLA DR3 antigen significantly increased the risk of dental lesions, while genotype DR5,7 seemed to protect against enamel defects. A logistic regression analysis of the variables age, serum calcium concentrations, number of affected teeth, type of enamel defect and DR antigens showed that only DR antigens discriminated coeliac disease patients with from those without enamel defects.