M.J. Garlepp

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.

Myasthenia gravis and HLA antigens in American blacks and other races

The association of HLA B8 and DR3 with generalised adult onset myasthenia gravis (GMG) in European Caucasoids is now well established. Studies of the HLA association with myasthenia gravis (MG) in other races might help to determine the location of a critical disease locus. Some previous studies in Japanese, Thais, Asian Indians and Filipinos have been reported. In this study HLA A, B, C and DR typing on 28 American blacks with either GMG or ocular myasthenia gravis (OMG) is reported. A significant increase in both HLA A1 and B8 was detected but there was an increase in DR5 rather than DR3. A review of the HLA antigen frequencies in other races and in D-penicillamine (D-Pen) induced MG suggests that prior claims implicating immune response genes marked by DR3 require review. It seems unlikely that any particular HLA allele is involved directly. Other possibly relevant combinations of alleles or supratypes are suggested. These may provide the basis for future studies of the immunogenetic basis for MG.

The diagnostic significance of autoantibodies to the acetylcholine receptor.

The predictive value of the assay for antibodies to the acetylcholine receptor (anti-AChR) is dependent upon the reference range used and the question being asked by the clinician. A reference range has been established after assaying sera from 200 healthy individuals, 314 patients with diseases often considered in the differential diagnosis of myasthenia gravis (MG) or found in association with MG, and 72 patients with active adult onset MG. If the assay is to be used to screen an unselected population for MG a conservative cut off point (2 units) should be used. After establishment of a differential diagnosis more significant may be attributed to a lower result (1 unit or greater). A negative result does not exclude MG. In patients with Systemic Lupus Erythematosus. Graves disease or thymoma anti-AChR has been demonstrated in the absence of signs of MG. Such patients may have latent or subclinical MG. Two such patients subsequently developed clinically evident MG concomitant with a rise in anti AChR titre above their particular biological threshold.

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.

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.

Extractable Nuclear Antigen autoantibodies and their association with other autoantibodies and thymoma in myasthenia gravis

The presence of autoantibodies to Extractable Nuclear Antigens (ENA) in myasthenia gravis (MG) was evaluated. These antibodies represent a subset of antinuclear antibodies (ANA), with ENA consisting of RNA and nucleoprotein. ENA autoantibodies had a prevalence of 44% in MG when tested by an