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.     

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.     

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—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.     

Founder Effects for ATM Gene Mutations in Italian Ataxia Telangiectasia Families

We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of 'mild' hot spots of mutation located along the sequence of the ATM gene.     

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—DR specificities among Japanese with several autoimmune diseases

HLA—A,—B,—C, and—DR antigens were determined in order to study the association of HLA in Japanese patients with several autoimmune diseases, hypertrophic cardiomyopathy, and Hodgkin's disease.
The frequency of HLA—DR4 was significantly increased in the patients with rheumatoid arthritis, juvenile-onset insulin-dependent diabetes mellitus (IDDM) and hypertrophic obstructive cardiomyopathy. In this study, no significant associations with A, B, or C specificities were observed except BW22 in IDDM. In contrast, the negative association with HLA—DR2 was observed in Hashimoto's thyroiditis, pemphigus vulgaris and hypertrophic non-obstructuve cardiomyopathy.     

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.     

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—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.     

Segregation of HLA—D Specificities with the HLA-B12 Allotype

In a search for bone marrow donors and HLA-D homozygous cells, MLC family studies were performed. Results of the experiments, in which the Seventh Workshop cells 7W569-KR and 7W568-WE were found, are presented here. Within the KR and the WE families two identified and two non-identified HLA-B12 allotype that both families carry.     

A Simulation of HLA—DR Matching in Kidney Transplantation

A simulation of the matching for HLA-DR, B, A loci was achieved by taking into account the practical situation of kidney transplants for 89 donors and 322 potential recipients. A complete HLA-DR identical graft was theoretically possible in 52% of the cases. Conversely, if the identity for B or particularly the identities for both B and A were sought, the necessary pool of recipients would have to be much larger, requiring intense international cooperation.     

A DFNA5 Mutation Identified in Japanese Families with Autosomal Dominant Hereditary Hearing Loss

Mutations in DFNA5 lead to autosomal dominant nonsyndromic hereditary hearing loss (NSHHL). To date, four different mutations in DFNA5 have been reported to cause hearing loss. A 3 bp deletion mutation (c.991‐15_991‐13del) was identified in Chinese and Korean families with autosomal dominant NSHHL, which suggested that the 3 bp deletion mutation was derived from a single origin. In the present study, we performed genetic screening of mutations in the interval between intron 6 and exon 9 of DFNA5 in 65 Japanese patients with autosomal dominant NSHHL and identified the c.991‐15_991‐13del mutation in two patients. Furthermore, we compared the DFNA5‐linked haplotypes consisting of intragenic SNPs between the reported Chinese and Korean families and found that the Japanese patients showed a shared region spanning 41,874 bp. This is the first report of DFNA5 mutations in Japanese patients with autosomal dominant NSHHL, supporting the suggestion that the 3 bp deletion mutation occurred in their ancestors.     

Human umbilical cord blood-derived mononuclear cell transplantation: case series of 30 subjects with Hereditary Ataxia

Background

Cancer is one of the most difficult current health challenges, being responsible for millions of deaths yearly. Systemic chemotherapy is the most common therapeutic approach, and the prevailing orientation calls for the administration of the maximum tolerated dose; however, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Electrochemotherapy (ECT) is a tumor treatment that combines the systemic or local delivery of anticancer drugs with the application of permeabilizing electric pulses. In this article we evaluate the capability of ECT to allow the use of cisplatin despite its high toxicity in a spontaneous feline model of soft tissue sarcoma.

Methods

A cohort of sixty-four cats with incompletely excised sarcomas were treated with cisplatin-based adjuvant ECT and monitored for side effects. Their response was compared to that of fourteen cats treated with surgery alone.

Results

The toxicities were minimal and mostly treated symptomatically. ECT resulted in increased local control (median not reached at the time of writing) with a mean time to recurrence of 666 days versus 180 of controls.

Conclusions

We conclude that ECT is a safe and efficacious therapy for solid tumors; its use may be considered as part of strategies for the reintroduction of drugs with a narrow therapeutic index in the clinical protocols.