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Background: Female gender, human leukocyte antigen (HLA) DR2, tobacco smoking and Epstein-Barr virus (EBV) are established risk factors for multiple sclerosis (MS). Their possible interaction however, has been sparsely studied., Objectives: To investigate possible associations between EBV antibody levels and a range of other recognized MS risk factors. DESIGN, SETTING AND STUDY POPULATION: Cross-sectional study undertaken in Denmark based on 517 healthy individuals selected from the Danish population., Methods: We measured change in mean log (anti-Epstein-Barr viral capsid antigen (VCA) immune globulin G) using linear regression., Results: Anti-Epstein-Barr VCA immune globulin G levels were positively correlated with female gender and HLA DR2. Furthermore, current smoking and cumulative tobacco consumption were positively associated with EBV antibody levels., Conclusion: The association between Epstein-Barr VCA antibody levels and non-viral MS risk factors support the view that EBV is critically involved in the etiology of MS. These non-viral MS risk factors may be linked with MS risk through EBV-specific immune responses.

In a previous case-control study of women with unexplained recurrent miscarriages we reported that the frequency of women positive for each of the two histocompatibility (HLA) types HLA-DR1, Br and HLA-DR3 was increased in a subset of patients with a history of four or more miscarriages. In the present study we examined whether the increased frequency of the two HLA types in this subset of patients indicated that they would result in a poor pregnancy prognosis. We related pregnancy outcomes to the mothers' HLA-DR type in a prospective study of a well-defined, closely supervised group of 94 women with unexplained recurrent miscarriages who had achieved intra-uterine pregnancy in the course of one of two prospective placebo-controlled trials concerning the efficacy of immunotherapy. Of the patients who were HLA-DR1, Br and/or HLA-DR3 positive 62% miscarried their next pregnancy compared with 29% of the patients negative for the two HLA types [relative risk of miscarriage in the former group = 2.2 (P < 0.002) unadjusted, and 1.8 (P = 0.025) when adjusted for the number of previous miscarriages]. The results suggest that Danish women with unexplained recurrent miscarriages who are positive for HLA-DR1, Br and/or -DR3 display a poorer pregnancy outcome than patients negative for these types.

We investigated the DNA restriction polymorphism (RFLP) of the Major Histocompatibility Complex (MHC) class II genes: HLA-DQA, -DQB, -DPA, and -DPB in 20 Danish patients with alopecia areata (AA) and in healthy Danes. The frequency in AA of the DQB1*0301 and DQw7 associated DQB Bgl/II 4.2 kb fragment was increased to 65.0 per cent compared to 23.2 per cent in controls (RR = 6.1; p less than 10(-3)) suggesting that the previously reported associations between AA and both DR4 and DR5 is secondary to an association between AA and DQB1*0301, which codes for the beta-chain of the HLA-DQ molecule of the serologically defined HLA-DQw7 specificity. Individuals who carried both DQA1*0501 and DQB1*0301 seemed to have a further increased risk of developing AA compared to individuals carrying only one of these HLA class II genes. Analysis of the combined presence of DQB1*0301 and DPA1*0103 in AA suggests that an additive risk effect (synergism or interaction) exists between the DQB1*0301 and DPA1*0103 alleles which are situated at different HLA class II loci.

A total of 317 unrelated Danish patients with insulin-dependent diabetes mellitus (IDDM) have been HLA-DR typed and the antigen and phenotype frequencies compared with those in 1177 unrelated Danish controls. The strong positive associations with DR3 and 4 and the strong negative one with DR2 were confirmed, and the remaining antigens showed a hierarchy from weakly positive to strongly negative associations: DRw9, w8, 1, 5, w6, 7. The study population included various special groups of patients selected in order to study heterogeneity: very early (less than 5 years) and very late (greater than 40 years) onset IDDM, pregnancy-induced IDDM, IDDM nephropathy, and long-term (greater than 40 years) survivors without complications. When comparing these groups, the following minor differences were seen: the DR3,4 phenotype is significantly (p = .02) more frequent in IDDM with onset before age 20 (35%) than in other cases (24%), and in familial IDDM (48%) than in other cases (28%); the frequency of the DR4 antigen was significantly (p = .008) more frequent in long-term survivors (86%) than in other patients (69%), while it was significantly (p = .02) less frequent in IDDM nephropathy (63%) than in long-term survivors. However, apart from the age-at-onset heterogeneity, which was suspected a priori, these differences may be due to chance, and the main conclusion of this study is that the HLA-DR associations in IDDM are indeed extraordinarily homogeneous irrespective of the clinical characteristics at onset and course of the disease.

The restriction fragment length polymorphism of the human tumour necrosis factor (TNF alpha) region was investigated by means of 20 different restriction enzymes and a human TNF alpha cDNA probe. Only one of the enzymes, NcoI, revealed a polymorphic pattern consisting of fragments of 10.5 and 5.5 kb, which behaved as alleles. In a panel of 108 random, healthy, unrelated Danes, the phenotype frequencies of the 10.5 and 5.5 kb bands were 0.94 and 0.53 and the gene frequencies were 0.71 and 0.29, respectively. The test for Hardy-Weinberg equilibrium showed no significant deviation from the expected values. The 5.5 kb band was strongly positively associated with HLA-DR3, HLA-B8, and HLA-A1. In 22 patients with primary biliary cirrhosis a significantly (corrected P = 0.024) decreased frequency of the 10.5 kb fragment was found. Additional studies are in progress to substantiate this association.

HLA-A, -B, -C and -DR antigens were determined in 70 unrelated Danish patients with idiopathic haemochromatosis. The frequencies of HLA-A and -B antigens compared to 1967 normal control subjects and the relative risk values (RR) were: A3, 80.0% vs. 26.9% (P less than 0.0001), RR = 10.9; B7, 60.0% vs. 26.8% (P less than 0.0001), RR = 4.1; B14, 10.0% vs. 4.5% (P = 0.03), RR = 2.4; B47, 4.3% vs. 0.5% (P less than 0.0001), RR = 9.7; A3, B7, 51.4% vs. 12.2% (P less than 0.0001), RR = 7.6; A3, B14, 10.0% vs. 1.4% (P less than 0.0001), RR = 7.7; A3, B47, 4.3% vs. 0.5% (P less than 0.0001), RR = 9.7. Six patients (8.6%) possessed none of these four typical antigens. There was no association between disease and the frequencies of HLA-C and HLA-DR antigens. The pattern of HLA-antigens associated with haemochromatosis in Denmark shows similarities to those reported both in Germany, being HLA-A3, B7 dominated, and in Brittany, Great Britain and Central Sweden, being HLA-A3, B14 dominated.

Thirty-six unrelated Danish patients with pauciarticular Juvenile Chronic Arthritis (PJCA) and 120 controls were typed for HLA-DPw1-w6 and the local specificity CDPHEI with bulk-expanded Primed Lymphocyte Typing (PLT) cells. The frequency of HLA-DPw2 was 52.8% in PJCA patients and 16.7% in controls (relative risk, RR = 4.5; P less than 0.001). The antigens HLA-Dw5 and/or Dw8 were present in 50% of the patients and in 21.3% of the controls (RR = 4.2; p less than 10(-3)). DPw2 was not associated (in linkage disequilibrium) with Dw5/w8 in patients or in controls, and the DP and D associations with PJCA were independent of each other. However, the combined presence of DPw2 and Dw5 and/or Dw8 gave a significantly higher risk of PJCA than each antigen alone indicating interaction of DP and DR gene products. PJCA is the first disease definitely found to be associated with a DP antigen.