[The theoretical and practical importance of the association between HLA and disease].
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Biomedical subjects
Publications and source records attributed to J Dausset.
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The HLA system includes several genes and each of them is polymorphic. Several associations between some HLA alleles and the susceptibility to various diseases are already described. Three kinds of associations are reported: [1] a constant association between an HLA allele and a disease whatever the tested population, [2] an association between the HLA allele and a disease varying according to the tested populations, [3] an association probably due to a mutation of metabolic gene closely linked to HLA. These three kinds of associations probably correspond to three different mechanisms.
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The study of a hundred and fifteen unrelated insulin-dependent diabetes and eight families with at least two insulin-dependent diabetes members made it possible to confirm the higher frequency of HLA-B8 and B18 (p less than 0.001) among patients, producing a RR of 2.24 and 2.47 respectively. The increased B15 frequency did not achieve statistical significance. B18 whose gametic association (delta = 0.0438) was significant only in diabetic patients was often related to Aw19-2 (Aw30 + Aw31). The B8/B18 genotype gave a relative risk (RR = 4.98) which was significantly higher than that of B8, B18 and B15 heterozygotes (1.50, 1.24 and 1.39 respectively). Pairs of diabetic siblings were more frequently HLA identical than would be expected by chance, and distribution of the pairs of affected sibs into the three categories, identical, semi-identical and different, was closer to the recessive model than to the dominant one. The fact that the B8/B18 individuals had a RR slightly higher than the B8 and B18 homozygotes and distinctly higher than the heterozygotes for only one of these genes, favours the hypothesis of two dominant genes, giving the appearance of recessivity. The gene associated with B18 in Southern Europe seems to play the same part as that of the gene associated with B15 in Northern Europe.
Serum VE reacting with 29.8% of French individuals seemed to define the seventh allele of the HLA-C series as shown by serologic and genetic investigations. The gene frequency of Cve is 0.163.
Two sets of differentiation antigens are demonstrated on human T cells by using 11 heterologous anti-human antisera raised against various normal and malignant T cells. The two antigenic determinants from the first set of differentiation antigens are expressed only on thymus cells and on T lymphoblasts, whereas the two antigenic determinants from the second set are expressed on blood T cells, Sezary cells, T.CLL cells, and thymus cells. Four T cell phenotypes are thus defined; two phenotypes are expressed only by T lymphoblasts, whereas the other two phenotypes are expressed both by normal and malignant T cells. Moreover, a clear-cut relationship exists between the four T cell antigenic phenotypes and two other markers of T cell differentiation: terminal deoxynucleotidyl transferase and peanut agglutinin. Two phenotypes are linked with the presence of TdT, one phenotype is linked with the affinity for PNA, and the fourth phenotype is correlated with the absence of both markers.
We studied the lymphomatous cells of 39 children presenting with the classical features of malignant lymphoma. Twenty-two had T lymphoblasts. We could classify these patients into three subsets: The T lymphoblasts from children group 1 displayed antigen(s) shared by a thymocyte subpopulation, had terminal deoxynucleotidyl transferase (TDT), but no affinity for peanut agglutinin (PNA). The T lymphoblasts from children group 2 lacked the thymocyte antigen(s), had no TDT, but showed affinity for PNA. The T lymphoblasts from children group 3 displayed mature T-cell antigens, had no TDT, and no affinity for PNA. Children from the three groups were similar in terms of clinical presentation, age and sex distribution, and cell morphology; however patients from the three groups might have a different prognosis. Fourteen children had B lymphoblasts that, in half of the cases, had affinity for Helix pomatia agglutinin. Three patients had lymphoblasts lacking specific marker. Two of them had cells displaying an antigen found on common acute lymphoblastic leukemia cells and had TDT.
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The genetic study of 11 lymphocyte factors previously described in sheep was continued. 9 factors are the products of alleles at two closely linked loci OLA-A and B. The last two factors are the products of two genes at two distinct loci OL-X and OL-Z. Recombinations between the two closely linked loci are very rare (0.6%); but they are frequent between these two loci and OL-X (26%). The OL-Z locus seems to be independent of the two linked loci OLA-A and B. The allele frequencies at the four loci are given.
One set of antigens is common to some chronic lymphocytic leukemia (CLL) cells bearing surface immunoglobulins (Ig) and normal T cells. Proliferating cells from thirty-eight patients were studied with four antisera recognizing normal human T but not B cells. These antisera were raised in rabbits against (a) Sezary cells, (b) blood lymphocytes from a patient with sex-linked agammaglobulinemia, (c) T lymphoblasts and (d) thymus cells. In four CLL cases, the cells expressed the receptor for sheep erythrocytes and lacked surface Ig. Cells from thirty-four CLL cases bore monoclonal surface Ig and did not bind sheep erythrocytes. Twelve out of these thirty-four cases of CLL had cells which were lysed by one or, more frequently, by the four anti-human T cell xenoantisera. By absorption experiments, one set of at least three antigens common to the cells of some of these CLL and T cells was defined. Depending on the patient, the cells can either carry one, some or all of the antigens of this set. However, it was also demonstrated by absorption that these cells lacked antigens particular to the T cell lineage, while the cells from T CLL cases carried both sets of antigens.
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Spleen cells of (C57BL/6 X C3H/He)F1 mice were assayed for natural killer (NK) cell activity against YAC-1 and FBL-3 lymphoma targets at several intervals after total-body exposure to a high sublethal dose of 137Cs or 60Co gamma-rays. NK cell activity did not decline for the first 12 days but decreased sharply thereafter and remained low until day 24. The recovery of splenic NK cell activity was delayed. Beginning on day 28, the activity was slowly increased, reaching near-normal levels (80% of controls) 41-59 days after irradiation. Suppressor cells detectable during the period of lowest NK cell activity, i.e., on days 17 and 19, may have been responsible for the delayed and slow recovery. These studies indicated that a) mature effectors of natural cytotoxicity are relatively radioresistant renewable cells with a lifespan of about 2 weeks whose progenitors are radiosensitive cells b) the kinetics of decline and especially of recovery of NK cell activity may be influenced by suppressor cells. Should NK cell activity confer resistance to autochthonous lymphomas in vivo, it may be a significant consideration for strategies of tumor therapy by cytotoxic agents that reconstitution of the NK cell pool is a slow process and that suppressor cell function must be overcome for full recovery.
Serial serum samples from 47 renal allotransplant recipients were screened for antiperipheral blood lymphocyte, anti-B cell, and anti-Daudi cell line antibodies. Various associations of these antibodies were observed in 28 patients. Anti-Daudi did not correlate with graft survival, whereas anti-B, although they were often associated with anti-peripheral blood lymphocyte antibodies, showed the strongest correlation with chronic rejection (P = 0.00002). However anti-B cytotoxicity preceded or was concurrent with the onset of chronic rejection in only 53% of the cases. Antibodies were absent in six of nine patients with irreversible acute rejection, but they usually appeared after transplant nephrectomy. These findings suggest that anti-B cell antibodies may play a role in the rejection process. In 15 of 17 recipients (88%), anti-B cell antibodies occurred during the first trimester after transplantation. These patients showed 20% 1-year graft survival compared with 68% in those without antibodies at that time (P less than 0.005).
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In a series of 30 bone marrow grafts (in 29 recipients) from HLA-identical siblings for aplastic anemia, no correlation was demonstrated between rejection and pregraft HLA antibodies (P greater than 0.50). However, after grafting, HLA antibodies persisted in nine cases and graft rejection occurred, whereas in all but one of the remaining eight cases the HLA antibodies disappeared and a permanent engraftment was observed (P = 0.0008). These results suggest a relationship between engraftment and persistence or disappearance of HLA antibodies as an indication of the level of immunosuppression obtained with the conditioning regimen.
Forty-eight unrelated patients with idiopathic hemochromatosis were found to have a significantly higher frequency of three HLA antigens (A3, B7 and B14) than 591 healthy controls. A significant association between HLA haplotypes and disease segregations was demonstrated in 14 family studies. A recessive inheritance of a strongly A3-linked disease gene responsible for abnormal iron stores in the heterozygote state is postulated. The lod score value (4.415 for theta = 0.025) is compatible with this hypothesis. However, the excess of HLA-identical pairs of affected sibs does not exclude the possibility of a pseudo-recessiveness due to two codominant genes both HLA-linked. For the first time, a means of screening for high risk subjects is available and therefore offers the possibility of a preventive approach.