P. H. Kay

Disease Associations with Complotypes, Supratypes and Haplotypes

We have used the term supratype to describe combinations of alleles and have examined associations with disease. In RA and insulin-dependent diabetes one or more supratypes appear to be important but their functional significance remains obscure. In MG and SLE the HLA supratype may contain loci involved in immunoregulation, complement synthesis and hormone metabolism. MG induced by D-Pen is associated with Bw35/DR1 rather than A1, B8, DR3. In contrast there is no evidence of a supratype in AS. We have proposed a model for the pathogenesis of sacroiliitis and AS and have postulated two non-linked genes which act stepwise upon HLA-B27. There are cogent reasons for examining the functional effects of known loci within the MHC and particularly those involved in the expression of complement components.

HLA and complement allotypes in Type 1 (insulin-dependent) diabetes.

SummaryA group of patients with Type 1 (insulin-dependent) diabetes mellitus was investigated for HLA-A, B and DR antigens as well as C4 and factor B polymorphism. A significant excess of DR3/DR4 heterozygotes was observed (27% versus 17% by Hardy-Weinberg expectation). The factor B allele BfF1 was present in 13% of patients with Type 1 diabetes (gene frequency of 0.08 versus 0.01 in control subjects). A rare C4 B allele, C4 B2.9, was found in 18% of patients with Type 1 diabetes (n=63) compared with 1.1% of control subjects (n=176). Total C4 deficiency at the C4A locus (C4AQ0,0) was present in 10% of patients with Type 1 diabetes compared with 0% of control subjects. Examination of HLA, C4 and Bf phenotypes in patients with Type 1 diabetes suggested that three high risk supratypes, HLA-A1 B8 BfS C4AQ0 C4 B1 DR3; HLA-B18 BfF1 C4A3 C4BQ0 DR3; HLA-A2 CW3 BW62 BfS C4A3 C4 B2.9 DR4 are markers for susceptibility alleles.

Autoimmunity in spontaneous myasthenia gravis in dogs

Spontaneous canine myasthenia gravis (MG) mimics the human disease in almost every respect. Both dogs reported here exhibited the autoantibodies characteristic of MG, i.e., anti-acetylcholine receptor (anti-AChR) and antistriational (AStr). Fluctuations in the anti-AChR titer during spontaneous remission and recurrence of MG in one dog provide support for the concept of a symptomatic threshold titer above which anti-AChR must rise before disease signs develop. The increase in the anti-AChR titer and recurrence of disease signs followed vaccination and an infection. Interestingly AStr also reappeared in this dog and serum IgG concentration increased. AStr in the second dog was associated with the presence of a thymoma and had a staining pattern characteristic of human MG.

HLA and complement genetic markers in diabetic retinopathy

Dear Sir, In a recent publication Dornan et al. [1] reported an association between HLA-DR4 and retinopathy in Type I (insulin-dependent) diabetic patients and concluded that genetically determined factors appeared to influence susceptibility to retinopathy. We have also examined the relationship between HLA and retinopathy in a smaller series of patients with Type 1 diabetes with onset before the age of 40years and duration > 10years. Patients were divided into three groups; those with no retinal changes, those with background retinopathy and those with severe retinopathy (proliferative changes or vascular changes requiring laser therapy). HLA antigens, properdin factor B(Bf) and complement C4 allotypes were determined in these patients. Table 1 shows the frequencies of HLA-B8, B15, DR3, DR4 and the complement variant C4B2.9 in the three patient groups examined. Although B 15 and DR4 are more frequent in patients with severe retinopathy, the differences were not statistically significant. The rare factor B allele BfFI was equally prevalent among the patients with and without retinopathy. On the other hand, the C4B allele C4B2.9 was present in 28% with severe retinopathy and only in 10% of patients with no retinopathy (NS). This variant is nearly always found on a DR4 haplotype and is also associated with rheumatoid arthritis.

Heterogeneity of steroid 21-hydroxylase genes in classical congenital adrenal hyperplasia.

Careful genotyping of three families, each having a member with classical salt‐losing steroid 21‐hydroxylase deficiency, has allowed identification of carrier haplotypes. Digestion with TaqI or EcoRI and probing with a cDNA probe for the 21‐hydroxylase genes (pC21/3c) revealed that all six affected haplotypes are abnormal with at least EcoRI. The data suggest that there is extreme polymorphism of the 21‐hydroxylase genes and that dysfunction may result from several different abnormalities.

Thyrogastric autoimmunity and MHC associated alleles at the C4 locus in patients with Type 1 (insulin-dependent) diabetes

SummaryHLA antigens, complement allotypes, insulin antibodies and thyrogastic autoantibodies were determined in 69 patients with Type 1 (insulin-dependent) diabetes defined by a tendency to ketosis, non-obesity and insulin requirement within 2 years of diagnosis. Analysis of HLA and C4 allotypes suggested that Type 1 diabetes was associated with only certain DR3- and DR4-containing supratypes. Low antibody response to insulin was associated with all HLA-DR3, being present in 89% of those with DR3 compared with 48% of those without. Thyrogastric autoantibodies were associated with a null allele at the C4A locus, usually with HLA-B8-C4AQO-C4B1-BfS-DR3. These results indicate that, unlike Type 1 diabetes, low insulin antibody response was associated with all HLA-DR3. Thyrogastric autoantibodies, on the other hand, were associated with a null allele at the C4A locus. It is probable that while interaction between certain HLA-DR3- and -DR4-containing supratypes is important in conferring susceptibility to Type 1 diabetes, other manifestations of autoimmunity are associated with supratypes containing C4AQ0, and in particular the diabetogenic supratype HLA-B8-C4AQ0-C4B1-BfS-DR3.