SUMMARY
The Gm phenotype Gm f,b or Gm f,n,b was found in all forty patients with Graves' disease studied, contrasted with thirty‐five out of forty controls and twenty out of thirty‐one patients with thyroiditis. The difference between the two groups with autoimmune thyroid disease was significant. These results suggest that thyroid stimulating antibodies may be allotypically restricted.
An increased frequency of HL-A 1 and HL-A 8 was found in patients with Graves’ disease and Hashimoto’s thyroiditis, when compared to a control group from the same geographic area, and drawn from a pool of subjects attending one diagnostic centre. Furthermore, an increased incidence of W15 and W17 was found in Hashimoto’s thyroiditis; however, these were not detected in any patient with Graves’ disease.
We found the rare properdin factor B(Bf) variant F1 to be present in 11% of 72 patients suffering from insulin-dependent diabetes (IDDM) compared with 2% among 150 normal controls. BfF1 thus confers a relative risk for IDDM of 5.55. All eight patients and three controls who were BfF1 positive were also HLA-B18 positive, reflecting the strong linkage disequilibrium between these two factors. We suggest that BfF1 marks a 'diabetogenic' B18-bearing HLA haplotype. Studies of unselected families with one or more affected members suggest that the B18, BfF1 does not necessarily segregate with IDDM phenotype. This study provides further evidence for the genetic heterogeneity of IDDM.
In view of the reported variation in the association between HLA antigens and Juvenile Diabetes Mellitus (J.D.M.) among different Caucasian populations, we have undertaken a study of these antigens among 44 Caucasian Newfoundlanders and 135 matched controls. We have also studied the allotypic markers for Immunoglobulin G (Gm) and variants of C3 among 36 of these patients. We found that both HLA--B8 and B15 were increased among the patient group, resulting in a relative risk of 3.9 and 4.4 respectively. While these values are the highest to be described for J.D.M. among Caucasians, and fell outside the 95% confidence intervals for the combined relative risk calculated from published series, it is still possible that they can be accounted for by sampling. The combination of the two antigens increased the relative risk for J.D.M. in an additive fashion. Additionally, we also found that the combination of HLA B8 and B18, but not B15 and B18, also appear to act in an additive manner. The incidence of Gm allotypes and variants of C3 were not different in the J.D.M. group from those observed among controls.
Summary
The hyperthyroidism of Graves' disease is thought to be related to antithyrotropin receptor (TSH‐R) antibodies. In order to study the degree of immunogenetic homogeneity of these antibodies, we carried out Gm typing of ‘receptor‐purified’ IgG from patients with active Graves' disease and controls. The results were compared to those of serum, total IgG and IgG which failed to attach to TSH‐R. We found that in five out of seven Gm heterozygote patients studied the receptor‐purified antibodies were restricted to the products of one haplotype compared to three out of five similar controls. Such eluted antibodies were biologically active. Similar results in terms of immunogenetic restriction and activity were obtained when F(ab)2 preparations were used. An unexpected finding was that sera and IgG from normal persons attached to thyroid membranes and that the attachment occurred via F(ab)2. Normal whole serum and ‘receptor‐purified’ IgG and F(2 inhibited TSH binding in the receptor assay; however, this inhibition showed no specificity for TSH‐R.
We have studied 25 patients with polyglandular autoimmune disease with respect to HLA antigens. Whereas the combination of insulin dependent diabetes with Graves’disease or atrophic thyroiditis was associated with an increase in HLA–B8, this was not found to be the case for patients with I.D.D.M. and goitrous thyroiditis. However 4/7 of these patients were DRw3 positive in contrast to previously established normal distribution of HLA–B8 in patients with goitrous thyroiditis alone. These data suggest that patients with polyglandular failure may be highly selected for HLA‐B8/DRw3 positivity.
We also report on two families with polyglandular autoimmune disease; the results suggest that these disorders are not necessarily transmitted with B8/DRw3 bearing haplotypes. In one family both the affected mother and non‐affected father were B8 positive. The mother's B8, which was associated with DRw7, BfF and Rga did not appear to be involved in the transmission of disease susceptibility to two affected offspring. The search for complete haplotypic arrangement should be pursued to see whether this uncommon haplotype arrangement is peculiar to autoimmune diseases.
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