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A monospecific serum which recognizes antigen HL-A2 (Mac) of the HL-A system was systematically absorbed with homogenates of fresh organs of three individuals possessing this antigen. Spleen was shown to be the richest in this antigen, followed in order by lung, liver, intestine, kidney, and heart. Aorta is rather poor while fat and brain contain practically none.

HLA markers (A, B, C, DRloci) were determined for the members of 52 unrelated families with at least one child suffering from congenital adrenal hyperplasia due to 21 hydroxylase deficiency, permitting genotyping. The gene frequencies of the 52 index cases were compared with those obtained from the parents' normal haplotypes and with those of a control reference panel. No significant differences were observed, except a clear decrease in the frequency of HLA-B8 among the haplotypes that carry the gene for congenital adrenal hyperplasia.

Purpose: To clarify the role of donor criteria we retrospectively analyzed a series of 5,129 cadaver kidney grafts harvested from January 1, 1989 to December 31, 1991. Materials and Methods: Graft survival was calculated and analyzed using a multifactorial approach. Results: Better graft survival was obtained with donors between 6 and 50 years old (80 percent versus 64 percent at 3 years), grafts performed from male donors (74 percent versus 69 percent at 3 years), donor deaths caused by cranial injury as opposed to cerebral hemorrhage (74 percent versus 70 percent at 3 years) and negative cytomegalovirus antibodies (75 percent versus 71 percent at 3 years). Conclusions: These factors may be used for kidney allocation.

We report here the DNA polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) typing of the HLA-DR B1, B3, B4, B5 and DQB1 loci for a sample of 103 Vietnamese Kinh from Hanoi, and compare their allele and haplotype frequencies to other East Asiatic and Oceanian populations studied during the 11th and 12th International HLA Workshops. The Kinh exhibit some very high-frequency alleles both at DRB1 (1202, which has been confirmed by DNA sequencing, and 0901) and DQB1 (0301, 03032, 0501) loci, which make them one of the most homogeneous population tested so far for HLA class II in East Asia. Three haplotypes account for almost 50% of the total haplotype frequencies in the Vietnamese. The most frequent haplotype is HLA-DRB1*1202-DRB3*0301-DQB1*0301 (28%), which is also predominant in Southern Chinese, Micronesians and Javanese. On the other hand, DRB1*1201 (frequent in the Pacific) is virtually absent in the Vietnamese. The second most frequent haplotype is DRB1*0901-DRB4*01011-DQB1*03032 (14%), which is also commonly observed in Chinese populations from different origins, but with a different accessory chain (DRB4*0301) in most ethnic groups. Genetic distances computed for a set of Asiatic and Oceanian populations tested for DRB1 and DQB1 and their significance indicate that the Vietnamese are close to the Thai, and to the Chinese from different locations. These results, which are in agreement with archaeological and linguistic evidence, contribute to a better understanding of the origin of the Vietnamese population, which has until now not been clear.

To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2–29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p<10−5) than HLA-identity (10% and 7%, respectively, p<0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4%, 3% and 4.4%, respectively, NS). C4BQO also conferred significant risk (11% vs 3% in non-C4BQO siblings, p<0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7% for HLA-identity, 9% for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41%, risk 56% after 8 years, p<10−7). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4+subjects had the highest risk (70% after 8 years, predictive value 58%, p<10−7) compared with islet cell antibody-positive DR3,4−(37% and 20%, respectively) and islet cell antibody-negative DR3,4+(5% and 3.6%, respectively). Furthermore, islet cell antibody-positive DR3,4+siblings progressed to diabetes at a younger age (risk 84% by age 22 years vs 20% in islet cell antibody-positive DR3,4−siblings, p<0.005). Siblings with moderate islet cell antibody levels who carry the DR3,4 antigens have been identified as a subgroup with increased risk and more rapid progression to Type 1 diabetes.

Abstract: The aim of the present study was to try to predict the number of cadaveric kidney transplantations (CKT) that will be performed in the year 1993. The raw data regarding the number of renal transplants that have been performed annually since 1975 in 31 countries, which were divided into six groups, were collected from published reports and confirmed by a questionnaire sent to all centers. The annual number of grafts was estimated using an exponential model, highly correlated with retrospective data (r 2>0.99). Predictions for 1993 were extrapolated. The growth of transplantation activity is limited by a shortage of available donor organs. The maximum number of grafts was arbitrarily set at 40 per million population, which is the maximum rate currently observed. The total number of CKT carried out between 1975 and 1986 was 114000; this will probably exceed 280000 in 1993. The yearly activity in 1987 exceeded 16500 and is expected to reach approximatively 26000 grafts in 1993.

DNA restriction fragments of the genes encoding HLA class II-beta antigens were compared in 34 patients with insulin-dependent diabetes mellitus and 34 HLA-DR-matched healthy individuals. Ninety-three fragments, determined by six restriction enzymes (EcoRI, EcoRV, HindIII, BamHI, Pvu II, and Taq I), were analyzed: (i) A DR Taq I 12.7-kilobase-pair fragment might be a marker for the extended haplotype HLA-B8, DR3. (ii) In controls, DR4 haplotypes are associated with two distinct clusters of DQ restriction fragments (DQR4 and DQR5). Almost all (94%) DR4 patients belong to the DQR4 and not to the DQR5 cluster. This suggests that, among HLA-DR4 haplotypes, only DQR4 haplotypes are involved in susceptibility to insulin-dependent diabetes mellitus. (iii) A DR Taq I 14.5-kilobase-pair fragment was found to be strongly associated with DQR4, mainly in DR3/DR4 heterozygous patients (P = 5 X 10(-4). However, these results must be interpreted with caution, taking into account the high number of statistical tests performed.

HLA-A and HLA-B markers have been determined in fibroblasts grown from tissues of triploid conceptuses and have been tested in the parents. Informative data on the origin of triploidy were obtained in eight cases: diandry I or dispermy in 4 cases, diandry II or dispermy in 2, digyny I or II in 2. This confirms that triploidy involved more frequently two sets of paternal chromosomes.

Since HLA-DRw15 (a subdivision of the HLA-DR2 specificity previously called DR2 long) is associated with dominant nonsusceptibility to insulin-dependent diabetes mellitus (IDDM), while HLA-DRw16 (another subdivision of HLA-DR2, previously called DR2 short) is positively associated with the disease, we looked for particular characteristics of HLA products encoded by the DR2 haplotypes of IDDM patients. The results show the following: (i) HLA-DQ molecules of HLA-DRw15-positive IDDM patients are different from those of HLA-DRw15-positive controls, suggesting that the HLA-DQ gene of DRw15 haplotypes is involved in a protective effect. (ii) HLA-DR and -DQ products of DRw16-positive IDDM are functionally indistinguishable from those of HLA-DRw16-positive controls. Furthermore, our data provide evidence that the residue at position 57 on the DQ beta chain could play a crucial biological role in antigen presentation to T cells as far as the DRw16 haplotype is concerned. This observation fits with the recent observation of correlation between DQ beta allelic polymorphism at position 57 and both susceptibility and resistance to IDDM.

Heterogeneity between two haplotypes in linkage disequilibrium with DR3: B8, C4AQOB1,BfS,DR3 and B18,C4A3BQO,BfF1,DR3, with regard to age at onset of Type 1 (insulin-dependent) diabetes mellitus, was investigated in 325 unrelated French patients (146 males and 179 females, age at onset 1 month to 29 years) who were genotyped for HLA-A, B, C, DR and Bf and 225 of whom were typed for the C4A, B complement components. A subgroup of 82 patients and 75 control subjects were tested for DRβ and DQβ DNA restriction fragment length polymorphism. The distribution according to age at onset and the mean ages at onset were compared between patients bearing B8, DR3 (n=58), B18,DR3 (n=62) or other DR3 haplotypes (Bx, DR3, n=70), the haplotype segments C4AQOB1.DR3 (n=41) or C4A3BQO,DR3 (n= 52) and the C4 null alleles C4AQO (N=48) or C4BQO (n=112) alone. The B8,DR3 haplotype, its smaller segment C4AQOB1,DR3 or C4AQO alone were associated with age at onset after 6 years (p<0.01, <0.08 and <0.02 respectively); on the other hand, the B18,DR3 haplotype, its segment C4A3BQO,DR3 or C4BQO alone were significantly more frequent in patients aged less than 6 years at onset (p<0.02, <0.01 and <0.01 respectively). Accordingly, the mean age of onset was significantly lower in the latter compared with the former patiens (p<0.02, <0.02 and <0.01 respectively). No age-related variation was observed in BX,DR3 patients and their mean age of onset was intermediate. The observed age distributions were sex dependent: that of C4AQO was mainly observed in males, that of C4BQO in females. Restriction fragment length polymorphism analysis in 37 patients and 32 control subjects positive for DR3 showed distinct patterns which correlated with DR3 and/or DQW2 borne by the B8 (n=11) and the B18 (n=18) haplotypes, respectively. BX,DR3 subjects exhibited either one or the other of these patterns. In the patients, the B18 associated fragments were found in most cases; whereas the B8 associated pattern was more frequent in the control subjects. These results provide evidence that a heterogeneous genetic background associated with two subsets of DR3 and/or silent alleles of the fourth component of complement could account for differences in the clinical expression of Type 1 diabetes.

The susceptibility determinants of Type 1 (insulin-dependent) diabetes mellitus are known to be associated with both HLA-DR3 and DR4. In our study we wished to determine if the parental origin of these antigens could influence susceptibility to the disease. We analysed the inheritance of DR3 and DR4 haplotypes from the father or mother (DR3p, DR4p, DR3m and DR4m, respectively), in the index cases and in the affected and non-affected siblings of 246 diabetic simplex and 41 multiplex families without affected parents. An independent series of 80 multiplex families (GAW 5) was also studied. Among the DR3,4 positive index cases and affected siblings, the paternal and maternal DR3 and DR4 antigens were not distributed randomly: 62% and 72%, respectively, had received DR4 from their father and DR3 from their mother (DR4p/DR3m), while only 38% and 28%, respectively, had received a paternal DR3 together with a maternal DR4 (DR3p/DR4m). This differed significantly from the 50% expected ratio (p<0.01) and was not observed in unaffected siblings. No excess of maternal DR3 in the absence of DR4 and no excess of paternal DR4 in the absence of DR3 were observed. The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.

HLA genotypes were ascertained in 53 French Caucasian families, comprising 68 juvenile onset insulin-dependent diabetic siblings. Among the 49 alleles detected at different loci in the HLA complex (A, C, B, Bf, DR) 4 appeared to occur at a significantly higher frequency among the 53 index cases than in a control series of 116 healthy individuals: HLA-B18 (p<10-3), DRw3, DRw4 and BfF1 (p<10-6). The excess of HLA identical affected siblings confirms genotype disequilibrium and supports the hypothesis of an HLA-linked gene(s) conferring susceptibility. There was no increase of homozygosity for HLA DRw3 and DRw4 whereas there was a marked excess heterozygosity for HLA DRw3/DRw4 in diabetic patients (32% versus 0% in the control series, p<0.001). These data provide evidence for the existence of two cooperating genes, linked to each of the HLA DR alleles.

HLA-DR2 allele is negatively associated with insulin-dependent diabetes and positively associated with multiple sclerosis (MS). A 2.2-kilobase-pair EcoRI DNA restriction fragment detected with a beta-chain HLA-DC cDNA probe was found to be strongly correlated with HLA-DR2 in the normal population, but was absent in HLA-DR2 insulin-dependent diabetic patients. This fragment was found in HLA-DR2 multiple sclerosis patients with the same frequency as in controls. A beta-chain HLA-DC 12-kilobase-pair BamHI fragment might differentiate multiple sclerosis patients from healthy individuals.

A method of analysis of HL-A compatibility in relation to the prognosis of kidney transplantation is described. It is based on the calculation of the probability of incompatibilities when the gene products of one or both of the defined HL-A loci are unknown in the donor, and on the assumption that cross-reacting antigens are not incompatible antigens. All of the 25 kidney grafts between HL-A genetically identical sibs have survived (P<0.001 when compared with HL-A genetically semi-identical grafts). Grafts between sibs sharing only one haplotype or between parents and children show a better prognosis when there is less than one calculated incompatibility. Among the 74 unrelated pairs, 70% of the matched pairs (less than two calculated incompatibilities) have functioned (P<0.01 when compared with mismatched pairs with 39% survival).

Laboratorie d’Immuno-Hématologie Unité INSERM U93 Center Hoyem Hopital Saint-Louis, 75475 Paris Cedex 10, France, and Unidad de Immunologia Hospital Clinico Barcelona 11, Spain

Segregation of HLA-DR2 among affected and unaffected offspring was studied in 66 HLA-genotyped families with Type 1 diabetes in whom at least one parent carried DR2. The frequency of DR2-positive parents (21%) was not different from that of control families (29%). Among the diabetic probands, the gene frequency of DR2 was significantly decreased compared with control subjects (0.05 versus 0.17, p < 0.001) as were DR5 (0.07 versus 0.17, p< 0.01) and DR7 (0.06 versus 0.13, p<0.003). Twenty probands carried DR2, in 11 of whom (55%) it was found in combination with either DR3 or DR4. The nine cases who carried another DR allele included one who was DR2 homozygous. Transmission of DR2 was reduced in affected offspring, and random in unaffected siblings, compared with the expected ratio. However, when the DR2 transmission was analysed separately for parents bearing DR2 with DR3, DR4 or another DR allele, it appeared that DR2 transmission to affected offspring was random when the parents carried neither DR3 or DR4, the transmission deficit being due to over-transmission of DR3 and DR4. The haplotype analysis showed that the haplotype A3, Cw7, B7, BfS, DR2, found in 19% of “non-diabetic” DR2 haplotypes was practically absent among “diabetic” DR2-haplotypes (4%). In conclusion, population and segregation analysis could not demonstrate a specific protective effect of DR2.

The complement proteins, Bf, C2, C4A and C4B, are closely linked to HLA. In 74 propositi and their families, and 97 controls genotyped for HLA-A, -B, -C, -DR, -Bf, a high incidence of the C4BQ0 variant was detected in the patient group (33% versus 12%, p< 0.00001); C4BQ0 was more frequent in propositi than in non-affected siblings (40 out of 74 versus 36 out of 92, p<0.05). When comparing the distribution of the phenotype C4BQ0 in Type 1 diabetic patients and normal control subjects, the difference was significant in patients bearing DR3 or DR4 (56% and 25%, respectively, p< 0.003). The main linkage disequilibria were observed among the 74 propositi: B18, BfF1, C4, A3, BQ0, DR3; B12, BfS, C4, A3, BQ0, DR4. The existence of a silent allele at the C4 B locus is known to be associated with a defective immune response.

Five different HLA-loci were tested in 53 families with one or more diabetic children. The alleles B15, B18, Cw3, Cw5, BfF1, DRw3, DRw4 were increased in diabetics, and significantly higher frequencies were found for several haplotypes with stronger linkage disequilibrium than in the control population. The strongest associations occured with the DRw3 and DRw4 alleles, suggesting the existence of several "high risk axes" carrying the diabetogenic gene (s) closely linked to the DR-locus. The excess of HLA-identity in multiple affected siblings of 12 families is in agreement with a recessive transmission. Yet the lack of homozygosity does not support a single-gene hypothesis. Moreover, the highly signficant excess heterozygosity DRw3/DRw4 in diabetics (32 %, p < 0.001) provides evidence for a pseudorecessive mechanism, two complementary acting genes being linked to each of the DR-alleles. In conclusion, the low frequency of DRw3/DRw4 heterozygotes in healthy siblings of diabetics (10 %) and their absence in controls, attribute the highest risk of diabetes to related as well as unrelated carriers of this combination.(Relative risk = 5.3 and 46.6, respectively)