Detection of HTLV-1 gag related sequences in leucocyte DNA from patients with polyendocrinopathies (Basedow-Graves' disease and insulin-dependent diabetes).

Relationships with retroviruses have recently been found in different human pathologies as autoimmune diseases which would be associated with the presence and eventually the expression of retroviral sequences. Detection of the presence of HTLV-1 and HIV-1 homologous sequences and their expression was realised on lymphocytes of 14 patients with polyendrocrinopathies (Basedow-Graves' disease and insulin-dependent diabetes) and four relatives of one index case. No antibodies to HTLV-1 and HIV-1 could be detected by Western blot and Elisa tests. HTLV-1 related sequences were revealed by Southern blot (SB) in 5 out of 18 subjects' DNA. Analyses of all DNA were performed by polymerase chain reaction (PCR). Seven DNA, including the 5 previously positive in SB, and two relatives (father and grandfather), negative in SB, contained HTLV-1-gag related sequences, but neither pol nor pX regions. Concerning HIV-1, all 18 DNA examined were negative by both methods. DNA of ten clinically healthy donors were found to be negative with the same tests.

MHC related genetic susceptibility to Hodgkin's disease.

The present report describes 4 Caucasoid families, HLA genotyped, with at least 2 affected siblings suffering from Hodgkin's disease. The affected sibling pairs were identical (2 shared haplotypes) in 2 families and haploidentical (1 shared haplotype) in the 2 others. These results together with the data already published provide evidence for a distortion of the segregation of HLA haplotypes: from a total of 43 pairs of siblings reported, the observed repartition is 22, 15, 6 (2, 1, 0 shared haplotypes respectively) instead of 10.75, 21.5, 10.75 (mendelian repartition). The excess of identical siblings pairs (51% instead of 25%) (p less than 10(-5) confirms the existence of a genetic linkage between the chromosomal HLA region and the susceptibility to the disease.

MHC classes I, II, III antigens study in 70 insulin-dependent diabetics with associated auto-immune diseases.

Seventy IDDM patients (insulin-dependent diabetics), 48 females and 22 males, most of them adults at the onset of diabetes, and suffering from at least one other associated autoimmune manifestation (AAM) were studied for HLA A,B,C, DR markers and Bf, C4 complement components. Comparisons were made with 108 normal controls and a series of 287 IDDM patients with juvenile onset (under 25 years) and no patent other autoimmune disease. The increase in frequency of HLA-B8 among IDDM patients with AAM was confirmed (36% versus 20% in controls) (p less than 0.04). The frequency of DR4 among diabetics with AAM (33%) was not significantly different from the normal frequency (27%), and the allelic combination DR3/4 was found in only 13% of IDDM with AAM. Corresponding frequencies in patients with IDDM alone were 66% for DR4 and 34% for DR3/4 (p less than 10(-6) and 10(-3) respectively). These results confirm the heterogeneity of IDDM and support, by genetic arguments, the concept of overlapping entities. The hypothesis of a common background of autoimmunity associated with B8 DR3 can be postulated, while the organ specific target process should be associated with various DR alleles.

Study of HLA antigens in a population of Mali (West Africa).

Eighty-two healthy individuals have been typed for HLA-A, B, C, antigens, and 49 of them also for HLA DR alleles. They were a sample representative of 11 of the 14 Malian ethnic groups living in the area of Bamako (Mali). Phenotypic frequencies have been compared to those of other Negroid and Caucasoid reference populations. As expected, in Negroids the increased frequency of HLA A23, A28, A30, and ATh was confirmed in the present series. Additionally, a significantly increased frequency of HLA B5 (B51 and Bw52) was noted--already observed in some but not all Negroid populations. Conversely, a decreased frequency--compared with that usually found in Negroid population--was observed for the alleles Bw42, Bw58, Cw6, and DRw6. Our results underline the originality of the Malian population among Western Africans.

[Endocrine polyadenomatosis of 2a type (MEN 2a). Clinical and genetic study of a family]. / Polyadénomatose endocrinienne de type 2a (MEN 2a). Etude clinique et génétique d'une famille (GETC).

In a large kindred with multiple endocrine neoplasia type 2a (MEN 2a) (137 members, 5 generations), bilateral thyroid medullary carcinoma was found in all affected members. Pheochromocytoma was present in 59% of the cases, and was responsible at least for 4 out the 5 deaths related to MEN 2a. Hyperparathyroidism was less frequent (41%). Family screening leads to a reduction in age for diagnosis and to an improvement in the prevalence of complete healing after surgery. Linkage between HLA loci and a dominant gene for MEN 2a was investigated in this kindred. Lod scores for recombination fraction were all negative (-0.47 for a recombination fraction of 0.05). These results comfort the lack of linkage between MEN 2a and the HLA complex.

HLA antigens in acute measles encephalitis.

The frequency of HLA-A, B, DR antigens was studied in 24 patients with acute measles encephalomyelitis compared to 1926 control subjects. The results demonstrated no association between the susceptibility to the disease and HLA markers. However, DR4 was observed in 6 patients out of 10 who developed intrathecal secretion of specific antimeasles immunoglobulins, while absent in 4 patients, who did not (p less than 0.04). Further studies on a larger series are needed.

HL-A and disease.

Of more than 500 diseases or syndromes studied for HL-A markers, more than 40 are known to be associated with an allele of class I, II, or III. Seven are linked to the HL-A region: six are recessive (idiopathic hemochromatosis, C2, C4A, and C4B deficiencies, congenital and late-onset deficiencies) and one is dominant (spinocerebellar ataxia). In addition, insulin-dependent diabetes mellitus is also linked to HL-A with more than one single locus. HL-A typing is of practical interest for diagnosis of ankylosing spondylitis by B27 antigen determination and for prevention of idiopathic hemochromatosis by genotyping of siblings of the index case. Prenatal diagnosis of 21-OH deficiency by genotyping fetal cells permits genetic counseling. Indeed, the discovery of the relationship between HL-A and disease can be considered a new approach to medical genetics. Extensive use of HL-A technology will probably allow better prediction of risk and may elucidate the mechanisms of certain diseases. For the first time the study of one single immunogenetic system may have a significant effect on public health through the possibility of wide-scale prevention.

HLA and multiple sclerosis: population and families study.

Association between HLA and multiple sclerosis (MS) was investigated at the population level on 100 MS patients genotyped for HLA-A, B, C, DR and Bf, Glo, and on 155 patients phenotyped for the same HLA antigens. Association between MS and DR2 was clearly confirmed, although its strength is rather weak. No other genetic marker could be related to the disease, no haplotype nor any allelic combination could be recognized as MS specific, and antigen genotype frequencies among the diseased could not ascertain the mode of inheritance, although dominance is very likely. Computer analysis between HLA, Bf, Glo and age of the patient, sex, age of onset and evolution of MS, impairment indexes, titres of anti-DNA and anti-measles antibodies in CSF did not show any interaction. Twenty sib pairs and two trios of MS were also studied; they showed no significant distortion with the random distribution of haplotypes. DR2 gene frequency, however, was significantly higher in sib pairs showing one or two haplotypes than in HLA different affected siblings. Three crossing-overs were identified which suggest where the HLA-linked MS susceptibility (MSS) gene could be located within the HLA segment, while other epistatic MSS genes or environmental factors are likely to be important.

A linkage study between HLA and cutaneous malignant melanoma or precursor lesions or both.

In seven pedigrees displaying the familial atypical multiple mole-melanoma (FAMMM) syndrome, three successive linkage analyses were performed between HLA and an assumed dominant gene determining respectively each of the following affected phenotypes: (1) precursor lesions, (2) cutaneous malignant melanoma (CMM), and (3) precursor lesions or CMM or both. Close linkage could be excluded in (1) and (3). However, if the transmission of malignant melanoma itself were assumed to be due to a single gene different from the one responsible for precursor lesions, a maximum lod score of 1.64 was observed at a recombination fraction of 5%, assuming low penetrance values. These different results are discussed in respect to the possible mechanisms causing the familial distribution of these traits. Two alternative hypotheses were proposed. Either the FAMMM syndrome is a rare genetic entity not closely linked to HLA or the association and transmission of precursor lesions and CMM in families are due to several factors among which HLA might play a role.

[Computer analysis of anti-HLA sera: ANASER. Its application in kidney transplantation]. / Un système d'analyse informatique des sérums anti-HLA : ANASER. Son application en transplantation rénale.

ANASER is a system of 3 computer programs for the analysis of sera from multi-transfused patients, multiparous women and dialysed patients awaiting kidney transplantation, which react against one or more HLA antigens. This system permits: 1) the recognition of one or more HLA specificities in each serum using iterative analyses. 2) The calculations of correlation coefficients among several sera. 3) The drawing of positive serological reactions according to either a given sera or to a given antigen. It can be used for two main purposes: 1) to permit selection of the best sera for HLA typing (positive correlations). 2) To study the preimmunization of dialysed patients awaiting kidney graft. Owing to sequential comparison of the consecutive bleedings from the same individual, they allow the definition of a pattern of anti-HLA immunisation, and in the case of large spectrum antibodies, the specification of antigens not concerned by the antibodies produced (negative correlations). ANASER may help in the choice of the best compatible transplant for hyperimmunized patients, who need a precisely matched organ.

HLA markers in patients suffering from aplastic anaemia.

135 patients, suffering from aplastic anaemia (AA) and their families were genotyped for HLA. The antigen and haplotype frequencies were compared to an HLA genotyped control panel composed of 209 normal couples and their healthy offsprings, and to another series of 2286 normal individuals. An excess of HLA-A2 was observed in the patients: 61% versus 42% (pc less than 0.001) (relative risk: 2) and versus 48.5% (p less than 0.01) in two control series, respectively. When considering the HLA-A, B antigens shared in common by the parents of the AA patients, an excess of HLA-A2 was observed: 32% as compared to 17% shared by normal couples (p less than 0.001). An excess of homozygous HLA-A2 was noted in the AA patients (14%) in comparison to the normal controls (4%) (p less than 0.001). The mechanism of this association is discussed as well as the hypothesis of a gene involved in haematopoiesis which might interact within the HLA-A region.

Is the strength of single HLA antigen mismatch variable in kidney transplant survival?

The survival rate among 458 cadaver kidney grafts with "full-house" four HLA-A,B antigens detected in the donor, three being identical to those of the recipient and only one mismatched, was studied specifically in relation to antigen incompatibility. At the A locus, the A3 incompatibility was associated with a lower transplant survival (44% at 2 years) than all of the others, and particularly more than the A11 (80% at 2 years) (P less than 0.003 but without significance after correction multiplying by the number of tested alleles). At the B locus, there was no significant difference in survival rate among the alleles. These results are only preliminary and need confirmation based on longer series permitting possible cross-reactions which exit between donor and recipient antigens to be taken into consideration.

HL-A phenotyping in an Indonesian population.

The frequencies of 30 HL-A antigens were studied in an Indonesian population of 95 individuals from the city of Jakarta. The antigens HL-A9, or more precisely W24, and HL-A11 (first series) and W15 (second series) occurred with high frequencies, whereas HL-A8, W14 and W22 were completely absent. These results are consistent with previous reports of HL-A typing in South East Asian populations.