HLA—Bw52 in Takayasu Disease

Takayasu disease is characterized by a pulseless condition which most often occurs in young females from Asian or South American areas. The cause of this disease remains obscure. Recently we encountered monozygotic, Japanese identical twin sisters, both of whom were diagnosed as having Takayasu disease. A genetically related factor was considered and HLA analysis was carried out. A population study on HLA typing analyses of 65 patients with Takayasu disease revealed a high frequency of HLA-B5 as compared with 128 healthy Japanese (chi2 :17.0, P less than 10(-4)). Subgroups of B5, Bw51 and Bw52 were successively studied in 82 patients with this disease. Bw51 antigen was found in 12.2% of patients with Takayasu disease and in 19.5% of 128 healthy Japanese. Contrarily, Bw52 antigen was confirmed in 43.9% of patients, a statistically significant frequency with the level of 26.5 in the chi2 test (cP less than 3 x 10(-4)) when compared with 12.5% in normal Japanese. Thus a genetically related factor in the pathogenesis of Takayasu disease has to be considered.     

HLA—DR Antigens in Black North-Americans and Their Association with HLA—D

A random population of 108 Black North-Americans, 79 of whom had also been typed for HLA-D in Mixed Leukocyte Culture (MLC), were serologically tested for DRw with Seventh International Histocompatibility Workshop trays. Clusters of B cell alloantisera were identified which defined several DRw antigens. Although the clusters for DRw1, DRw2, DRw3 and DRw7 showed similarities with the clusters derived during the Seventh International Histocompatibility Workshop, distinct differences were observed which should be taken into account for the assignment of the DRw antigens in Blacks. DRw6 was defined by a cluster of sera which also reacted with DRw1 and DRw2 cells. The tails of these sera were used to assign DRw6, but this was only possible with DRw1 and DRw2 negative cells. It was not possible to identify serum clusters specific for DRw4 or WIA8. The associations between DRw and the corresponding Dw specificities were reasonably good for DRw1, DRw2 and DRw7, but weaker for DRw3 and DRw5. The cumulative gene frequencies for DRw1, DRw2, DRw3, DRw5, DRw6 and DRw7 was 0.86. The frequencies of these six DRw antigens fitted into a Hardy-Weinberg distribution, suggesting that DRw in Blacks is controlled by a single gene with multiple alleles.     

Two HLA—D and DR Alleles are Associated with Coeliac Disease

A group of 45 children affected with Coeliac Disease (CD) was typed for HLA-A, B, C, D, and DR specificities. The most significant associations were found with two alleles of the D series, with both cellular and serological typing. It is suggested that the susceptibility to CD is determined by two different genes within the HLA region, the first in common with organ-specific autoimmune diseases and associated with DW3, the second possibly specific for CD and associated with Dw7.     

Association of hypergammaglobulinemia G with HLA—DR3 in Graves' disease

Serum levels of immunoglobulins (Ig) IgA, IgG and IgM were measured in 96 HLA—typed patients with Graves'disease and an equal number of sex and age matched controls.
Patients showed significantly increased serum immunoglobulin levels compared to controls. HLA DR3-positive patients had larger elevations of IgG concentration than their HLA—DR3-negative counterparts. Variation in serum immunoglobulin levels was not associated with sex, treatment or ophthalmopathy. It is suggested that the hypergammaglobulinemia of Graves'disease is related to defective suppressor cells triggered by Ig or Ig-linked genes. HLA-related gene(s) must, in addition, be involved to account for hypergammaglobulinemia G in the HLA—DR3-positive subset of patients.     

HLA—Dw4 and Rheumatoid Arthritis

Forty-seven patients with a "definite" or "classical" rheumatoid arthritis according to the ARA criteria were typed for the serologically detectable HLA--A, --B, and --C antigens and 36 of these patients were typed for the HLA--D antigens, Dw1, 2, 3, 4, 6, 7, and 8 by the MLC technique. The frequency of Dw4 was increased to 44.4% in the patients compared to 17.2% in normal controls (P = 8 X 10(-4)). The frequency of Dw1 and Dw7 was also increased although this was only of borderline significance. The frequency of Dw2 was remarkably low, especially in females, which is of interest, as the same antigen has a low frequency in some other autoimmune diseases. No significant deviations of the frequencies of HLA--A, --B, and --C antigens were found in rheumatoid arthritis patients.     

HLA—D Typing in 72 Psoriasis Vulgaris Patients: Distribution of Seven HLA—D Alleles

The phenotype distribution of seven HLA—D alleles among 72 unrelated Psoriasis vulgaris patients was investigated. Statistically significant deviation from the antigen frequency in healthy donors was found for a new HLA—D allele, locally designated EI, with a relative risk value of 5.97. This observation indicates that Psoriasis vulgaris belongs to the group of diseases with associations to HLA—B as well as HLA—D alleles.     

HLA-linked susceptibility gene of Takayasu Disease

The HLA-A, B, DR and MB antigens were investigated in patients suffering from Takayasu disease (Aortitis syndrome). Out of twenty-one HLA-A and B antigens tested, only HLA-Bw52 was significantly deviated (30147, PF = 63.8%, RR = 7.8) from the controls (14/76, PF = 18.4%). Since in the Japanese, HLA-Bw52 is in positive linkage disequilibria with HLA-DR2 and MB1, the association of the DR2 and MB1 antigens with Takayasu disease was studied. The HLA-DR2 antigen was significantly increased (23/30, PF = 76.7%,, RR = 6.0) in patients compared with the control (18/51, PF = 35.3%). Moreover, an almost perfect association of MBI (29/30, PF = 96.7%, RR = 12.6) with Takayasu disease was demonstrated. This finding supports the hypothesis that the genes in the HLA-D region play a major role in determining the susceptibility to Takayasu disease.     

Association of HLA—B8, DRw3, and Anti-Acetylcholine Receptor Antibodies in Myasthenia Gravis

Twenty-eight patients with myasthenia gravis (MG), five with and 23 without thymoma, and 47 normal controls were typed for serologically defined HLA-A, B, C, and DRw antigens. Sera from all patients were titered for antibodies to acetylcholine receptors (AChR). The frequency of HLA-B8 and DRw3 in the non-thymoma MG patients was significantly higher than in the normal population. Most of the non-thymoma patients with AChR titers higher than the average level were positive for HLA-B8 and/or DRw3, while the majority of the HLA-B8(-) and/or DRw3(-) non-thymoma patients demonstrated AChR titers below average. These findings support the possibility of the existence of immune response genes in the HLA-B, DRw segment of the major histocompatibility complex which are concerned in the response to or recognition of autoantigens.     

Increased HLA—B Heterozygosity with Age

427 healthy individuals ranging in age from 16 to 101 years were tested for HLA-A and -B antigens. No significant differences were found for any particular antigen according to the age of the individual. However, a significant trend of increasing frequency with age was found for individuals possessing two detectable HLA-B antigens. An apparent trend of increasing frequencies for individuals possessing four HLA-A and -B antigens was not significant. These results concur with those of some previously published studies.     

The inclusion of HLA—Bw42, Bw54 and Bw55 within the HLA—B14 cross-reactive group

Six out of 24 broad HLA antisera containing antibody activity directed towards HLA—B14 were found to include Bw42, Bw54 and Bw55 within their reaction range. The inclusion of these Bw22 related antigens within the HLA—B14 crossreactive group was confirmed using the techniques of "specific resistance to lysis", sequential absorption and elution.     

HLA—DR Typing of Frozen B Lymphocytes

In the complement dependent lymphocytotoxic microtechnique it was found that antibody-killed frozen B lymphocytes are sufficiently stained for reliable reading after 30 min of incubation with trypan blue, while the background of staining is only about 10%. During the next 30 min of incubation, however, the background of staining increases to about 30%, whereafter it remains constant for at least 24 h. Formaldehyde is able to stop the trypan blue uptake by killed or damaged lymphocytes completely. Consequently, if formaldehyde is added to the reactions 30 min after the trypan blue addition, the otherwise rapidly increasing background of staining is kept at an acceptable level of 10%, thus making HLA-DR typing of frozen stored B lymphocytes possible. The trypan blue staining seems rather independent of incubation conditions before the addition of the dye. Similar results were obtained with T lymphocytes.     

HLA—A, B, Bf Three Point Association of 1,072 Haplotypes in a German Population

Altogether 1,072 HLA-A, B, Bf haplotypes in 536 parents of 268 German families were analyzed by gene and haplotype counting in order to investigate the two and three point association of HLA-A and B antigens with Bf alleles. In agreement with previously published data (Albert et al. 1975, Bender et al. 1977) significant positive linkage disequilibria were found for HLA-A3 and BfF, B7 and BfS, B8 and BfS, Bw35 and BfF, whereas significant negative Delta values appeared to exist for HLA-A3 and BfS, B7 and BfF, B8 and BfF, B12 and BfS, as well as Bw35 and BfS. Significant positive three point Delta values were found for the following haplotypes: HLA-A11, Bw35, BfS, HLA-Aw23, Bw35, BfS, HLA-A28, B12, BfS, HLA-A2, B17, BF, HLA-A3, Bw35, BfF, HLA-Aw24, b12, BfF and HLA-A29, B12, BfF. According to the large number of comparisons performed calculating the level of significance of the three point associations, these data have to be corroborated by further investigation. The three point Delta values, obtained by calculation from the patients' phenotypes differed markedly from those results obtained by haplotype counting.     

New HLA—D Specificity Included in Dw7

An HLA--D homozygous typing cell -- MS -- was found to induce typing responses with a phenotype frequency of 7% tested in a panel of 202 random individuals. All but two of these were positive for HLA--Dw7, which implies that the MS cell defines a split of Dw7. The new subgroups, MS, is associated with B12. Three individuals positive for MS but lacking Dw7 were found to be B13 positive. The relationship of the MS specificity to HLA--Dw11 has yet to be defined.     

HLA—Determination in Families with Hereditary Ataxia

In three families with hereditary ataxia, where the inheritance pattern was autosomal and dominant, HLA antigens were determined in 25 members. In two of the families, HLA linkage of disease was suggested, whereas in the third family, the data did not directly support this concept, since two recombinational events between the postulated locus for disease and the HLA region had to be assumed. However, with this assumption, our data are compatible with those of one family described recently (Jackson et al. 1977) implying the presence on the sixth chromosome, outside the HLA region, of a locus that determines the development of spino cerebellar ataxia (SCA). Further tests with definition of enzyme markers will have to be performed before conclusions as to HLA linkage of a postulated SCA gene can be made.     

Strong Linkage Disequilibrium between HLA—Dw2 and BfS in Multiple Sclerosis and in the Normal Population

An increased frequency of the S allele of Properdin factor B (BfS) was found amongst 162 patients with multiple sclerosis (MS) compared with 470 normal controls. This increase was shown to be due to a strong linkage disequilibrium (LD) between BfS and HLA-Dw2 in 77 patients typed for both systems (delta = 3.84%, P = .0002). The same LD was demonstrated amongst 100 normal controls (delta = 2.24%, P = .0049) and 31 patients with idiopathic demyelination of the peripheral nervous system (IDPN). A total of 70 haplotypes with HLA-Dw2 were encountered (40 MS, seven IDPN and 23 normal controls) and all contained BfS. In the MS patient group, a much weaker association was noted between BfS and HLA-B7 suggesting either that the Bf locus is musch closer to the HLA-D than the HLA-B locus or (and) that HLA-D and Bf products selectively interact (perhaps on the surface of B lymphocytes) with evolutionary advantage or disadvantage resulting from certain allelic combinations. Strong associations between BfS1 and HLA-Bw21 (P = .0000) and BfF1 and HLA-B18 (P = .0001), both previously reported, were confirmed in the current study. No increase in the frequency of a glyoxalase (GLO) allele was found amongst the MS patients and no LD was encountered between HLA-Dw2 and a GLO allele. The possibility that the HLA-Dw2, BfS disequilibrium has resulted from a selective advantage conferred on the general community but at the expense of increasing susceptibility to MS should be considered.