R. L. Dawkins

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.

POLYMYOSITIS AND MYASTHENIA GRAVIS: IMMUNODEFICIENCY DISORDERS INVOLVING SKELETAL MUSCLE

Human polymyositis and aspects of myasthenia gravis may be consequences of subtle immunodeficiency states. Autoimmune processes leading to inflammatory muscle disease and the presence of associated tumours may reflect the partial loss of antibody-mediated homoeostatic mechanisms.

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.

Increased binding of d-penicillamine to monocytes in rheumatoid arthritis

Long-term therapy of D-penicillamine (D-Pen) for rheumatoid arthritis (RA) is associated with a fall in rheumatoid factor, but many patients develop autoantibodies. In vitro binding of D-Pen to human peripheral blood monocytes was examined in 37 patients with RA and 75 healthy subjects. Mononuclear cells were reacted with D-Pen coupled to a fluorescein isothiocyanate-bovine serum albumin (BSA) conjugate in the presence of sodium azide and BSA, and analyzed by flow cytometry. Patients showed significantly higher D-Pen binding to monocytes than did healthy subjects. The proportion of monocytes binding D-Pen increased with age in the patients but not in healthy subjects. None of 6 patients who had D-Pen-induced autoimmune side effects was associated with increased D-Pen binding though patients with therapeutic responses showed high D-Pen binding. These results suggest that D-Pen binding to monocytes may be important in mediating therapy and inducing autoimmune side effects.

MYASTHENIA GRAVIS: THE ROLE OF IMMUNOLOGICAL DEFICIENCY

To evaluate further the association between myasthenia gravis and humoral immune deficiency, 92 sera from myasthenic patients were tested so as to determine titers against commensal E. coli, isohemagglutinin titers, and IgG and IgM concentrations. Results were compared with those obtained from normals, disease controls, and W27 positive arthropathy. On the basis of these three investigations it is concluded that subtle immunodeficiency is common in myasthenia gravis, and it is suggested that an immune defect might explain such diverse associations as thymic disease, HL-A antigens, and various autoimmune phenomena.

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.

An immunogenetic study of juvenile chronic arthritis.

Abstract Ninety‐seven patients from Western Australia and Victoria suffering from juvenile chronic arthritis (JCA) for longer than 1 year were studied with particular reference to immunogenetic markers in the sub‐groups of the disease. In the pauci‐articular group, the antigens DR5, DR8 and BW35 were increased in frequency. The phenotypes within the sub‐groups appeared distinctive despite the absence of any increase in the frequency of single antigens. Complement allotyping did not prove to be different from controls or within the sub‐groups for JCA.