Polymorphism of HLA class II genes in various diseases.
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Biomedical subjects
Publications and source records attributed to J Wallin.
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Ten adult patients referred to the Department of Dermatology and Venereology at Akademiska Hospital, Uppsala, from different surgical units due to recurrent herpes simplex virus (HSV) infections in the hand, were investigated. At recurrence, virus isolation and typing revealed genital HSV type 2 virus in nine out of ten patients indicating that recurrent HSV infections located in the hand should be looked upon as a part of a venereal disease.
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Through the analysis of RFLP (restriction fragment length polymorphism) of the HLA-DR beta, -DQ alpha, and -DQ beta genes from 70 serologically well-characterized individuals, we have established unique HLA-DR-DQ RFLP haplotypes correlating to all of the DR1-w14 specificities. The RFLP of DR beta, DQ alpha, and DQ beta genes is very high using the restriction enzyme TaqI and 21 DR-DQ RFLP haplotypes were defined with this restriction enzyme. Our analysis confirms the strong linkage disequilibrium between alleles in the DR and DQ loci. DR beta RFLP indicates a common ancestor for the DR alleles within either of the supertypic DRw52 and DRw53 specificities. The DQ beta gene shows a high degree of RFLP, and the RFLP alleles partly reflect the serologic DQw1-w3 specificities. The results presented here also demonstrate the heterogeneity of DRw6 (DRw13 and DRw14) associated haplotypes, and the DRw13 related Dw18 and Dw19 specificities were found to have distinct DR-DQ haplotypes. The DQw1 positive haplotypes DR1, 2, w10, w13, and w14 are related with regard to DQ alpha and DQ beta RFLPs and the DRw52 positive haplotypes DR3, w11, and w12, as well as the DRw53 positive haplotypes DR4, 7, and w9, are related with regard to DR beta and DQ alpha RFLPs. These findings indicate that polymorphic sequences around the DQ alpha gene are associated with DR beta and DQ beta polymorphism, which suggests a location of the DQ alpha gene between DR beta and DQ beta.
Eighteen MS patients were HLA-typed by RFLP-analysis using DR beta and DQ beta cDNA probes. A closer association to the DQ than to the DR locus was not found in this small material, not even within DR-specificities.
Thirty-five patients with psoriasis vulgaris were HLA-typed by RFLP-analysis using DR beta and DQ beta cDNA probes. A closer association to the DQ than to the DR locus was not found in this small material.
Removal of genital warts by thermocautery was performed in 108 patients (57 men and 51 women) under topical anaesthesia with a local anaesthetic cream, lidocaine and prilocaine (EMLA). Most men had warts in the preputial cavity, most women had warts situated on the mucous membranes of the vulva, and warts at multiple sites were common. About 1 ml of cream per lesion was applied to the warts for 20 to 105 minutes before the operation. Plastic film (Glad, Union Carbide) was applied over the cream when natural occlusion, such as under the prepuce or on the introitus, was not present. Local pallor was seen in 30% of the patients, redness in 53%, and oedema in 15%, but did not cause any discomfort and were clinically insignificant. Analgesia was sufficient in 96% of the men and in 40% of the women. Additional local infiltration was given to 60% of the women, but was not as painful as injections generally are in the genital area. The analgesic efficacy on women may be further improved by optimising the application time on the genital mucosa.
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Insulin-dependent diabetes is generally associated with the serologic HLA-DR specificities 3 and 4, in particular with DR-3,4 heterozygosity. The disease is negatively associated with DR-2. To investigate these associations further at the genomic level, DNA from 13 families with a proband having insulin-dependent diabetes, from 11 other individuals with the same disease, and from HLA-DR-matched control individuals was subjected to restriction fragment analysis. Three different enzymes (Bam HI, Eco RI, and Pvu II) and cDNA clones for three HLA-D region class II antigen alpha- and beta-chains (DR-beta, DQ-beta, and DQ-alpha) were used. In six families, a total of 11 siblings HLA-DR-identical to the proband were examined. There was no discrepancy between the hybridization patterns of the proband and those of the DR-identical siblings. Two different DQ-B fragment patterns were detected with each one of the serologic specificities DR-2 and DR-4. In both cases, only one of the patterns correlated significantly with diabetes. Thus, DQ-beta genomic hybridization may be used in conjunction with HLA-DR typing to identify individuals with higher relative risk to acquire insulin-dependent diabetes. These results may suggest that insulin-dependent diabetes is associated with the DQ rather than with the DR locus.
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13 men with a history of recurrent genital herpes simplex virus type 2 (HSV-2) infection were followed daily for 4 weeks with samples taken from the urethra for virus isolation. Asymptomatic virus shedding occurred in 5 men who had 1 single positive isolation each. Four of these urethral isolates were typed as HSV-1 and 1 as HSV-2.
We have used DNA-DNA hybridization methods to study the relationship of genetic polymorphisms to the established HLA-D region determinants as detected with serological reagents. The supertypic determinants DRw52 and 53 are closely associated with a particular RFLP detected with the DR beta probe, but are seemingly encoded by a distinct beta gene compared to the "conventional" DR antigens. DQw1 is closely associated with a DQ alpha chain polymorphism, whereas the DQw2 and 3 specificities have correlations to RFLP using the DQ beta probe. Additional DQ polymorphism, in linkage disequilibrium with DR but yet without a serological counterpart is also described. Considering the finding that there exist a varying number of DR beta genes in different DR haplotypes (Böhme et al. 1985), from 1 in DRw8 to 3 (or 4) in DR4- and DR7-positive cells, we have made a tentative re-evaluation of the genetic basis for the conventional DR specificities. The combination of cell surface antigens encoded by DR and DQ loci are believed to form the basis for MLC stimulating determinants. We have speculated that a combination of determinants encoded by distinct DR beta genes and in certain instances additional DQ polymorphism is responsible for the DR types. Thus, only a limited variability is observed after DNA-DNA hybridization using DR beta probes. Only DR1-, 2- and 4-positive cells have distinct bands not detected in any other haplotypes, whereas DR3, 5, w6, and w8 can be characterized by a combination of bands, which is the result of hybridization with several DR beta genes. Furthermore, we have suggested that the difference between the DR3 and DRw6 specificities is due to variability with regard to 1 DQ beta gene, and have also made the assumption that DRw6 cells may express a lower concentration of DR locus encoded products compared to DR3-positive cells (Haziot et al. 1985). In addition, we have discussed the genetic basis for so-called DR blanks, implying that an unorthodox combination of DR and DQ determinants forms the basis for difficulties in assigning DR types to such cells in some cases and that "blanks" can be associated with low expression at the cell surface of well-known DR determinants. The use of cDNA and genomic probes for distinct class II genes to elucidate the mechanisms of HLA and disease association has been documented and discussed.
Coronary sinus flow (CSF) was measured in seven patients with normal coronary arteries (group A) during intracoronary injections of 6 ml arterial blood, 6 ml blood from the coronary sinus, 3 and 6 ml isotonic saline, 3 and 6 ml hypertonic glucose, and 6 ml of a contrast agent (sodium metrizoate). In 10 patients with coronary artery disease (group B), CSF was measured after administration of 6 ml isotonic saline, 6 ml sodium metrizoate, and 6 ml of another contrast medium (iohexol). In group A, arterial blood did not affect CSF, while coronary sinus blood induced a 33% increase. After 6 ml isotonic saline, there was a 35% increase in flow and after hypertonic glucose an increase of 70%. Metrizoate induced a rise in flow of 109%. In group B, the increase in CSF after intracoronary injection of saline, metrizoate, and iohexol was 30%, 83%, and 67%, respectively. Blood from the coronary sinus, in contrast to arterial blood, induced a marked rise in peak flow, suggesting a role for reactive hyperemia secondary to myocardial hypoxia in this response. A similar mechanism might have been operative after injection of isotonic saline, as well as after the hyperosmolar contrast agents. However, additional mechanisms mediated by the high osmotic pressure of these substances, such as induction of the Bezold-Jarisch reflex, which will induce coronary vasodilation, may have played a role. Finally, when hyperosmolar agents are used, the possibility of some direct vasodilating properties of the agents cannot be excluded.
In a double-blind study 86 patients with a total of 129 episodes of recurrent genital herpes were treated topically with 0.3% foscarnet or placebo cream. All patients considered, healing time was significantly shortened in the foscarnet group as compared to the placebo group (p less than 0.01). Subgrouped by sex, the healing time among men treated with foscarnet was significantly shortened as compared to those treated with placebo (p less than 0.002), whereas no statistical significant difference was observed among women. Foscarnet treated men with subpreputial lesions had a shorter period of ulcers (1.7 days) than placebo (3.4 days) treated men (p less than 0.02). Overall, foscarnet treatment reduced the period of redness, swelling, blisters and ulcers. Foscarnet was well tolerated, only in 1/57 patients treated was a moderate local adverse reaction recorded.
Sixty-six donors with selective IgA deficiency and one patient with selective IgA2 deficiency were investigated for immunoglobulin gene defects using restriction enzyme digestions and Southern blot analysis. All patients carried alpha 1 and alpha 2 genes in their genome, suggesting that large deletions are uncommon causes for IgA deficiency. Digestion with Bam HI, Pst I and Pvu II, did not reveal any polymorphism in the studied samples.
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The occurrence of motile anaerobic curved rods in vaginal discharge was studied in 94 samples from women attending an STD clinic. Almost all wet smear preparations of discharge contained motile rods. Anaerobic curved rods were isolated from 46% of the samples. Of 28 specimens studied by culture and immunofluorescence, 21 were confirmed to harbour motile anaerobic curved rods. Culture was performed with a dilution and sampling technique that is too time-consuming for diagnostic routines, but it enhanced the precision of information on motile anaerobic curved rods in vaginal secretion. More selective and rapid methods for identification of these bacteria are desirable.
Motile anaerobic curved rods were cultured from vaginal discharge of 19 of 262 women attending an STD clinic. In 26 women, motile rods were observed by examination of wet smears. In all 5 specimens culture-positive for motile anaerobic curved rods of the long type, motile rods were observed in the wet smears, while in only 6 of the 14 specimens culture-positive for motile anaerobic curved rods of the short type, were motile rods seen in wet smears.