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An association between Graves' disease and the human leukocyte antigen (HLA) system has previously been reported. The disease was more strongly associated with the HLA D locus antigen Dw3 than with HLA B8. Products of the HLA D locus are determined by the interaction of test cells with standard typing lymphocytes, a technically difficult procedure. Recently, it has been possible to type serologically for D locus related (DRw) specificities on peripheral bone marrow-derived (B) lymphocytes. Blood B lymphocytes from 50 unrelated controls and 41 patients with Graves' disease were typed for seven HLA DRw specificities. 28 patients with Graves' disease (68%) were positive for DRw3, in contrast to 14 controls (28%); whereas only 21 patients (50%) were HLA B8 positive, compared with 13 (26%) controls. Thus, positivity for DRw3 afforded a relative risk for Graves' disease of 5.5, whereas that for HLA B8 amounted to 3.0. Additionally, a family with multiple cases of Graves' disease in which the disease was previously shown to be inherited with the haplotype, was linked to DRw2, which suggests that the susceptibility to the disease was inherited in association with that antigen. Two HLA B/glyoxalase recombination events were observed in this family; in both instances HLA DRw followed HLA B. This study thus demonstrates that the disease susceptibility gene for Graves' disease is in strong linkage disequilibrium with DRw3; however, it may be associated with other DRw specificities and inherited within family units in association with them.

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.

We found the rare properdin factor B(Bf) variant F1 to be present in 11% of 72 patients suffering from insulindependent 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.

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.

Using 800 control sera and 55 from insulin-dependent diabetics we set out to determine if an increase in HLA-B15 in the diabetic population was associated with an increase in C22, the secon

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.

Peripheral leucocytes from healthy controls, patients with Hashimoto's thyroiditis or patients with Graves' disease were assayed for susceptibility to the cytotoxic activity of cold agglutinins. Lymphocytes from patients with thyroiditis were killed as readily as control cells, however, lymphocytes of patients with Graves' disease were clearly less susceptible to lysis by cold agglutinins. Lymphocytes from patients with Graves' disease cultured for 3 days in the presence or absence of PHA, were as susceptible to cold agglutinins as were control lymphocytes and lymphocytes from patients with thyroiditis. We suggest that the amounts of Ii antigens on the surface of Graves' lymphocytes may be modulated by autoantibodies which are present in many of these patients.

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.

Association between Graves' disease and HLA—B8 has been previously documented, as have been associations between 1 gG heavy chain allotype markers (Gm). We found a significant increase in the phenotype fnb/fb (ie. positivity for fb) in patients with Graves' diesase compared to controls, raising the possibility of allotypic restriction of thyroid stimulating antibodies thought to be causally related to the disease. The influence of fb on the susceptibility to Graves' disease was found to be independent of HLA—B8 status suggesting that the immunological network operated by the Histocompatibility-linked genes is independent of that centered around IgG allotypes. It is postulated that, whereas the former genes determine the level of helper T lymphocyte function in the production of thyroid stimulating antibodies in Graves' disease, a person who also happens to carry the Gm marker fb would be assured of the production of IgG antibodies with thyroid stimulatory activity.

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.

A population of lymphocytes is found to stain positively for esterases. The positively staining lymphocytes are more predominant among T than B lymphocytes and are significantly increased on stimulation with PHA. Treatment with cholinestrase inhibitors reduces their number significantly.

The polymorphism of C2 was studied by isoelectric focussing in 60 patients with Graves' disease and compared to 800 control sera. No difference in gene frequencies was observed.

OBSERVATIONS in laboratory animals suggested an association of experimental and spontaneous thyroiditis with histocompatibility genes.1 2 3 However, in contrast to the definite association between Graves' disease and specific human leukocyte (or histocompatibility) antigens (HLA),4 5 6 7 no such relation was shown for Hashimoto's thyroiditis.7 8 9 10 11 In this study 127 patients with thyroiditis were typed for HLA-A and HLA-B antigens; 40 were also tested for HLA-D-related (DRw) specificities. Materials and Methods All 262 subjects (135 controls and 127 patients) studied were referred for investigation of thyroid function. The patients satisfied at least three of five of the criteria for the diagnosis of Hashimoto's thyroiditis.7 The . . .