A likelihood approach to HLA serology.

A likelihood approach to HLA serology has been developed in which the aim is not to define a recognition set for a serum but to describe the serum's ability to react with each and every antigen in the test cells, this ability being quantified in terms of the probability of a positive reaction. For a given set of probabilities, one for each antigen, it is possible to derive the probability of the observed set of reactions (the likelihood of the set of probabilities). The maximum possible value of the likelihood for any possible combination of the probability set can then be sought, but this requires a maximization of likelihood with respect to 60-100 independent parameters. Theoretical considerations of the shape of the likelihood surface prove that, in this particular case, this is a feasible proposition. This approach allows the recognition of three groups of antigens: those for which there is considerable evidence of a specificity, those for which there is either no specificity or a very weak specificity, and those for which there is insufficient evidence on which to base a conclusion. The existence of a specificity can be tested using a log likelihood ratio as a statistic, but the usual assumption of a chi 2 distribution of this statistic cannot automatically be made in this situation. Therefore, the distribution is estimated by simulation. A serologist using this approach would receive considerably more information as to the serum's reaction patterns and valid statistics for the existence, or not, of a specificity.     

HLA haplotype study of 53 juvenile insulin-dependent diabetic (I.D.D.) families

Fifty-three families with at least one IDD patient were genotyped for 5 markers of the HLA complex including Bf and DR. In 8 families one of the parents was also affected and in 12 families more than two children were diseased. In total, 76 patients were genotyped. Their haplotypes were compared with those of 106 unrelated controls (the parents of 53 genotyped families).

• 1) 

  Three haplotypes or segments of them (A2, Cw3, B15, BfS, DR4; Aw30, Cw5, B18, BfF I, DR3; and Al, Cw7, B8, BfS, DR3) were found more frequently in IDD patients.
• 2) 

  Measured by the 6 formula, the association of the postulated IDD susceptibility gene was very strong with the D-end of two of these haplotypes: BfF1, DR3 and BfS, DR4. However, the association was weak with the DR3 of the haplotype Al, Cw7, B8, BfS, DR3.
• 3) 

  An excess of HLA-identical affected siblings was found.
• 4) 

  An excess of DR3/DR4 heterozygotes was observed. By contrast, the observed frequency of patients homozygous for DR3 or DR4 was not increased, but even slightly decreased.

The data support a model of inheritance comprising at least two closely linked specifically "diabetic" loci (most of the time marked by B18, BfFl, DR3 and B15, BfS, DR4) and a non-specifically "diabetic" haplotype favouring auto-immunisation (most of the time marked by B8, BfS, DR3). This model is discussed in the light of the presented data and of those of the literature.     

HLA-DR2 in two sibships with insulin-dependent diabetes mellitus.

We report two families selected from 124 genotyped Caucasian insulin-dependent diabetes mellitus (IDDM) families because of unusual features. In both families, all offspring are affected and four out of six bear the allele HLA-DR2 which is an uncommon phenotype among diabetic patients. Onset before the age of 1 year in all the patients of one family, association with optic atrophy in the other, and the existence of pairs of affected sibs of different HLA types in both, are infrequent findings and support the evidence of heterogeneity in IDDM.     

THE HLA-DRB1*0405 HAPLOTYPE IS MOST STRONGLY ASSOCIATED WITH IDDM IN ALGERIANS

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is strongly associated with HLA-DR3-DQ2 and DR4-DQ8. In order to investigate the HLA class II associations with IDDM in Algerians, we have used polymerase chain reaction (PCR) and sequence specific oligonucleotide analysis (SSO) to identify DQA1, DQB1, and DRB1 alleles, haplotypes and genotypes in 50 unrelated IDDM patients and 46 controls from a homogeneous population in Western Algeria. Both DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) haplotypes were found at increased frequencies among the patients compared to controls (45% vs. 13%, RR = 5.5, P_c < 10^-5 and 37% vs. 4%, RR = 12.9, P_c < 10^-4, respectively). Among the latter, in contrast to other Caucasian populations, only DRB1*0405-DQA1*0301-DQB1*0302 was significantly increased in the Algerian patients (25% vs. 1% in controls, RR = 30.3, P_c < 10^-3). Accordingly, the highest risk of disease was observed in DRB1*0301-DQA1*0501-DQB1*0201/DRB¹*0405-DQA1*0301-DQB1*0302 heterozygotes (34% in patients vs. 0% in controls; RR = 49; P_c < 10^-3). This observation and its comparison with DR-DQ haplotypes in other ethnic groups suggest that the DRB1*0405 allele which encodes an Asp57-negative β chain may contribute to IDDM susceptibility in a similar way as Asp57-negative DQβ chains.     

The expression and relation of HLA, beta2-microglobulin and receptor for marmoset red blood cells on man/mouse and man/Chinese hamster hybrid cells.

The expression of HLA, human and mouse beta2-microglobulin (beta2m), P red blood cell antigen and a receptor for marmoset red blood cells (MaRBC) were studied on 18 man/mouse and man/Chinese hamster hybrids. A positive correlation was found between the expression of HLA, P, and the receptor for MaRBC, which we interpret as a possible synteny between these different loci. We studied 3 hybrid clones where HLA antigens are still expressed despite the absence of human beta2m and where redistribution experiments demonstrate that HLA is associated with mouse beta2m. Synteny between HLA and the receptor for MaRBC can be a useful tool to select HLA-positive hybrid clones.     

Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility.

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers composed of a DQ alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)