Study of HL-A Genotypes in a Case of Familial Chronic Lymphocytic Leukaemia (CLL)

Blood groups and HL-A antigens were determined in 12 members of a family in which chronic lymphocytic leukaemia (CLL) occurs in four siblings. The same HL-A haplotype [Da25 (W30 + W31), HL-A13] was observed in the three diseased siblings tested.
This case, together with that of a similar family studied by Schweitzer et al. (1973), in which three out of five diseased siblings shared two antigens - HL-A2 and W5 - suggests a possible linkage between HL-A and susceptibility to CLL.     

HL-A8: a genetic link with thyrotoxicosis.

The incidence of HL-A8 was significantly increased in 64 Caucasian patients with thyrotoxicosis compared with 700 Australian blood donors (42% versus 24%). No significant correlation was observed between HL-A8 and autoantibodies to thyroid components in thyrotoxic patients; thus the association of HL-A8 must be either with the disease itself, or possibly with immune responses not tested for this study.     

HL-A Antigens in a Chinese Population

The HL-A antigens of a Chinese population now living on the island of Taiwan have been investigated with reagents obtained from and characterized in Caucasian populations and with antisera obtained from Chinese multiparous women. Both HL-A2, the most frequent specificity found, and HL-A9 appear highly heterogeneous in this Chinese population since groups of antisera used to define HL-A2 or 9 in Caucasians gave discordant reactions. Moreover, new associations were found using chi-square and cluster analyses, further demonstrating the complexity of HL-A in this Taiwanese population. Fourteen % of 1183 Chinese multipara sera and 237 sera from multiple tranfused individuals were lymphocytotoxic and could be placed by cluster analysis into three major groups.     

Observations on the cytotoxicity of lymphocytes to a target cell system

It is known that after mixed culture lymphocytes exhibit an increase in cytotoxicity to a target cell. The present study was undertaken to see if the degree of cytotoxicity was also related to HL-A differences.

A cytotoxic effect was found where there was antigenic disparity. The degree was unrelated to the number of different antigens at the HL-A locus but cytotoxic effect was absent in cultures where there was complete HL-A identity using lymphocytes from twins, siblings and unrelated persons.

     

MLC Between Two HL-A Identical Siblings and a Recombinant

The genotype of an Austrian family tissue typed in Vienna in 1970 is given in Table 1 - one sibling inherited a recombinant chromosome from his father and differed with respect to the FOUR end of the HL-A chromosome from two HL-A identical siblings. More recently, the whole family was reinvestigated with a view to 1) confirming the HL-A genotypes, 2) undertaking mixed lymphocyte cultures between the recombinant and the two HL-A identical siblings, 3) performing a variety of serological and biochemical tests to facilitate the investigation of linkage studies. We report the results of the first two investigations.     

Further Evidence for a Separate MLC-Locus

MLC and HL-A data are given for a family in which one sibling shows definite stimulation with three HL-A identical siblings and conversely, a clear non-stimulation with a sister who differs by one haplotype. All other MLC-reactions between members of the family correlated well with the HL-A typing. This lends support to the suggestion that there is separate MLC-locus which is closely linked to the second (FOUR) HL-A locus.     

Serologic Specificity and Crossreactivity of Soluble HL-A Alloantigens

The serologic activity of soluble human histocompatibility (HL-A) antigens extracted from four human cultured lymphoid cell lines by the 3M KCI method has been evaluated by their ability to inhibit specifically the cytotoxicity of 38 operationally monospecific alloantisera recognizing 18 HL-A specificities. Several HL-A alloantisera directed against the same HL-A specificity, although used at functionally comparable levels of activity, varied in their susceptibility to inhibition by the same soluble HL-A alloantigen preparation. Similarly, lymphocytes from a number of subjects, when used as target cells for the same alloantiserum, detected quantitatively different activities of a given soluble HL-A alloantigen preparations in the inhibition test. Soluble HL-A alloantigens can block the cytotoxicity of antisera directed against HL-A specificities either crossreacting with or present on the cultured lymphoid cells used as source for extraction of soluble HL-A alloantigens. Crossreactivity was exhibited only by some of the soluble alloantigens and alloantisera with a given HL-A specificity tested. Quantitative studies indicate that the amount of soluble HL-A antigens necessary to inhibit the cytotoxicity of operationally monospecific alloantisera (used at the highest dilution producing 95% lysis) directed against crossreacting specificities is significantly greater than that necessary to inhibit alloantisera directed against HL-A determinants present on the soluble HL-A antigens. Since the alloantisera are used at relatively high dilutions, these data suggest that the crossreactivity in the HL-A system is not caused by contamination of operationally monospecific alloantisera with antibodies of low avidity. On the contrary, these data substantiate the hypothesis that crossreactivity is caused by structural similarities among different HL-A antigenic determinants.     

The HL-A System in Reiter's Syndrome

The HL-A phenotypes were determined in 50 patients with Reiter's syndrome. HL-A27 was found in 34 (68%) compared to 7.7% of controls. There was an association between the presence of HL-A27 and sacro-iliitis, uveitis and keratoderma blenorrhagica. Reiter's syndrome was found to have occurred in HL-A27 positive identical twins. In four sibships a brother, sharing a haplotype with the proband, was found to have spondylitis. There was evidence that in some HL-A27 positive individuals spondylitis had developed prior to the first attack of Reiter's syndrome, suggesting that spondylitis and Reiter's syndrome may be separate disease processes in the one genetically predisposed individual. When Reiter's syndrome was associated with severe keratoderma blenorrhagica and widespread psoriasiform lesions, sometimes with persisting psoriasis or recurrent uveitis, HL-A27 was present and HL-A17 absent.
There is some evidence that the HL-A phenotype itself does not determine susceptibility to disease in HL-A27 positive individuals but that linked immune response genes may be present.     

An Association of HL-A3 and HL-A7 with Paralytic Poliomyelitis

The frequency of 22 HL-A antigens in 111 patients who had had paralytic poliomyelitis in past epidemics was compared to the frequency of the same antigens in 395 blood donors. There was a significant increase of HL-A3 and HL-A7 in the polio patients ( P < 0.02, P < 0.002, respectively, after the application of a correction factor for the number of comparisons). It is suggested that this association might represent an association between HL-A and an immune response gene determining an immune response to the virus or a product of viral infection of the central nervous system. As the frequency of HL-A3 and HL-A7 has been found to be increased in studies of multiple sclerosis, a similar aetiological mechanism might be responsible for both diseases.     

HL-A Types in Danish Eskimos from Greenland

HL-A typing of 110 Danish Eskimos has shown a marked difference in the frequencies of some HL-A antigens as compared to Danish Caucasians.
The most striking finding was a high frequency of HL-A9, Ba*(W28), HL-A5, BB (W10), and FJH(W27). There was a low frequency of HL-A1, Li(相似文献   

Studies of human alloantigens on man-mouse hybrids: possible syntheny between hl-a and p systems

The expression of HL-A, P and H (ABO) systems has been studied on man-mouse hybrid clones and their subclones. Using the microcomplement fixation technique, we detected antigens of the HL-A, P and H systems in some clones corresponding to the phenotype of the human cell donor. Absorption tests were used to provide the specificity of the alloantisera. We also found a positive correlation between the presence of HL-A and P1/P antigens in these clones, but no correlation was found between HL-A and P^k specificities and between HL-A and H specificities. It was thought that the positive correlation might be due to a syntheny between HL-A and P loci or to the presence of HL-A and P specificities on a unique molecule. Therefore, preliminary experiments were made using antibody-induced redistribution phenomena (capping) to study the relationships between P and HL-A antigens at the cell surface. They indicated that the two molecules are independent of one another.     

Antigenic Expression and Cross Reactions in HL-A Variants of Lymphoid Cell Lines

Immunogenetic studies were carried out on an HL-A2/HL-A3 heterozygous lymphoid cell line, 8866, and on two HL-A2 negative variant sublines of 8866 which had arisen independently of one another. The parent 8866 line reacted positively with some W28 sera: these cross reactions were absent in both HL-A2 "loss" variant sublines. Other serum reactions, apparently characteristic of lymphoid cell lines, were present in 8866 and were retained in the variants. HL-A3 was expressed in hemizygous rather than homozygous dosage in the variants, ruling out mitotic crossing over as the mechanism producing HL-A2 loss. HL-A2 was undetectable either in the disrupted membranes or in the cytosol of the variant cells.     

HL-A Antigens and Some Immunological Parameters in Psoriasis

HL-A typing was performed on 110 psoriatics and confirmed the highly increased frequencies of W17, HL-A13 and HL-A1-W17 haplotype previously reported in two American works. Psoriasis was found twice as frequently among close relatives of W17 patients as in other groups. Yet, psoriasis and W17, when associated in individuals, were not always transmitted together genetically. Articular signs did not seem to have any relation to HL-A antigens. The comparison of our results with those of two previous investigations showed probable modifications in the distribution of several HL-A antigens: increased HL-A1 and HL-A2, decreased HL-A9, W28, HL-A7 and HL-A12.
Some immunologic disturbances appeared particularly frequently in psoriasis, namely, an elevated IgE titer in serum and an anti-IgG activity demonstrated on peripheral blood lymphocytes and in serum. It has been noted that numerous diseases related to HL-A are accompanied by immune perturbations.
The mechanisms of association between HL-A, immunity disorders and some diseases are discussed, including the following possibilities: indirect action of HL-A through an epistasis phenomenon; direct action of HL-A by antigenic cross-reactions favouring the penetration of an aetiologic agent; no action of HL-A which would thus only be a genetic marker linked with a locus governing some immune reactions.     

Serologic Specificity and Crossreactivity of Soluble HL-A Alloantigens

The serologic activity of soluble human histocompatibility (HL-A) antigens extracted from four human cultured lymphoid cell lines by the 3M KCI method has been evaluated by their ability to inhibit specifically the cytotoxicity of 38 operationally monospecific alloantisera recognizing 18 HL-A specificities. Several HL-A alloantisera directed against the same HL-A specificity, although used at functionally comparable levels of activity, varied in their susceptibility to inhibition by the same soluble HL-A alloantigen preparation. Similarly, lymphocytes from a number of subjects, when used as target cells for the same alloantiserum, detected quantitatively different activities of a given soluble HL-A alloantigen preparations in the inhibition test. Soluble HL-A alloantigens can block the cytotoxicity of antisera directed against HL-A specificities either crossreacting with or present on the cultured lymphoid cells used as source for extraction of soluble HL-A alloantigens. Crossreactivity was exhibited only by some of the soluble alloantigens and alloantisera with a given HL-A specificity tested. Quantitative studies indicate that the amount of soluble HL-A antigens necessary to inhibit the cytotoxicity of operationally monospecific alloantisera (used at the highest dilution producing 95% lysis) directed against crossreacting specificities is significantly greater than that necessary to inhibit alloantisera directed against HL-A determinants present on the soluble HL-A antigens. Since the alloantisera are used at relatively high dilutions, these data suggest that the crossreactivity in the HL-A system is not caused by contamination of operationally monospecific alloantisera with antibodies of low avidity. On the contrary, these data substantiate the hypothesis that crossreactivity is caused by structural similarities among different HL-A antigenic determinants.     

A Study on HL—A System in Japanese

Two hundred unrelated Japanese individuals were HL-A typed with UCLA Research Tray T3 (Terasaki's Tray), which contains specificities added after the Fifth International Workshop. Phenotype, gene and haplotype frequencies were calculated with standard errors and delta values. HL-A9, HL-A5 and W10 had a higher frequency and HL-A1, 3 and 8 had a lower frequency in Japanese than in Caucasians. The frequent haplotypes were HL-A9-HL-A5, HL-A9-HL-A7 and HL-A2W10. HL-A9-HL-A5 showed very positive high linkage disequilibrium parameter (delta value) and HL-A9-W10 showed negative high value. The sera designated as anti-HL-A, W5 and W15 in the T3 Tray which react identically in Caucasians showed different patterns of reaction when tested in the Japanese population. Five hundred Japanese parous women's sera were tested for cytotoxic antibodies. Some Japanese antisera showed high correlation coefficient values on HL-A2, HL-A9, HL-A10, HL-A11 and HL-A12. The women providing the anti-HL-5 complex sera and their immunizing persons were HL-A typed. These complex sera reactions were compared with the antisera in the T3 Tray. A new group of sera (SN-1), "operationally monospecific" and cross-reacting with W22, was found in the present study. Population and family studies suggested that the sera SN-1 are third in frequency within the second series (phenotypic frequency 17-22%) and show high delta values with HL-A11 in the Japanese population.     

The value of a genetic expression of leucocyte typing in renal transplantation

The HL-A haplotypes of donor and recipients were identified by leucocyte typing in fifty-two cases of renal transplantation with related donors. When only the presence or absence of antigenic differences between donor and recipient was considered (conventional typing) no significant correlation was found with the percentage of surviving transplants at 1 year, nor with the creatinine clearance of the grafted kidney 1 year after transplantation. On the contrary when the HL-A genetic situation was considered (haplotyping) and when donor–recipient pairs with both HL-A haplotypes in common were compared with the other pairs, a positive and significant correlation was found, using the same clinical criteria (P < 0·05).

When donor and recipient have only one HL-A haplotype (semi-identical donor), the clinical course is not statistically better in our series than when both haplotypes are different.

Among donors offering the same haplotype situation with regards to the recipient semi-identical siblings are probably better than parents.

     

THE INHERITANCE OF HL-A ANTIGENS IN MYASTHENIA GRAVIS

Thirty-one patients with myasthenia gravis were studied for their HL-A antigen expression. Eighteen patients had family members available for HL-A typing, and full genotyping for HL-A antigens was possible. The inheritance of HL-A8 was studied in detail, and it was noted that this did not correlate exactly with the development of myasthenia gravis. The multifactorial nature of the genetic component of this disease was confirmed by these studies.     

Increased Frequency of HL-A8 in Sjogren's Syndrome

The histocompatibility antigen, HL-A8, was found to be elevated in patients with Sjogren's syndrome. Among 24 patients, the frequency of HL-A8 was 58% compared to 21% among controls (P < 0.001 after correction). With the addition of this disorder to the list of other autoimmune diseases associated with HL-A8, it now seems possible to postulate a single basis autoimmune defect gene in high linkage disequilibrium with HL-A8.     

The Distribution of the HL-A Antigens and Genes in a German Population

The frequency of HL-A antigens and genes was determined in a population of 600 unrelated German people. The results confirmed the two loci concept for the HL-A system, and showed that the gene frequencies, the phenotype distributions and the haplotype frequencies are very similar to those observed in other Caucasian populations.     

HL-A8 and LD-8a in Patients with Myasthenia Gravis

The frequency of HL-A8 in myasthenia gravis is markedly increased in women (60-80%) but not in men. The MLC determinant, LD-8a, is frequently associated with HL-A8. Of the 37 female MS patients, 15 were LD-8a positive (41%), whereas of the males only one of seven was LD-8a positive. The frequency of HL-A8 was 68% in women and 29% in men with the disease. We therefore conclude that the gene which is responsible for the increased susceptibility to myasthenia gravis in women and which is present in the MHS region, is more closely linked to the SD-2 than to the LD-1 locus.