Genetics of the spondyloarthropathies.

Following three decades of study of the genetics of the spondyloarthropathies by segregation analysis of families, research has increasingly made use of new methods of molecular genetics and immunology. In the past year, most attention has been given to the structure and function of HLA-B27, which, with its various subtypes, is the major phenotype contributing to susceptibility to this group of disorders. Structural studies have revealed which structures are responsible for the common antigenic properties and which are responsible for subtype specificities. Application of increasing understanding of the function of class I HLA antigens is permitting the development of various models of disease. Successful production of HLA-B27 transgenic animals holds promise for testing these models.

Carcinoma of breast and scleroderma: four further cases and a literature review.

Four patients are described in whom scleroderma developed within 18 months of detection of breast carcinoma. Previously reported cases of this association and the relevant literature are reviewed. The available evidence suggests that in some women there may be a causal relationship between breast cancer and scleroderma or progressive systemic sclerosis.

Genetics of the spondarthropathies.

Recent investigation of the possible role of bacteria in the pathogenesis of AS has provided very interesting data. What is at present lacking is a clear demonstration that the findings point to the actual mechanisms involved in the initiation of the disorder. Rapid progress in three related areas of research gives hope that, in the relatively near future, the genetic basis for susceptibility to AS will be elucidated. These are the demonstration of the detailed structure of an HLA class I molecule, of the primary amino acid structure of B27 heavy chain with its subtypes, and of the nature of the interaction between foreign proteins and MHC molecules which leads to antibody and cytotoxic cell responses. It is just possible that the B27 molecules have a disease-promoting capability because of some structural characteristic independent of their antigen binding site. However, it may perhaps be considered more likely that it is the propensity of the specific antigen-binding site itself to bind to a particular group of antigenic peptides that will explain the susceptibility of B27-positive individuals to several clinical disorders. The ability to study the properties of antigenic epitopes which preferentially bind to the very variable binding site of different MHC molecules raises the possibility of revealing the antigenic structures which bind to B27 molecules in patients with AS. This could in turn lead to the source of these antigens in the environment. There has been a tendency to assume that one simple model will explain all the B27-associated disorders but it may be preferable to keep an open mind about the possibility that the mechanisms involved in AS, in the bacteria-induced acute arthropathies and in acute anterior uveitis may not be identical. At the same time, there is a need to continue further direct investigation of the role of microbiological agents in AS both in vitro and in vivo, as ultimately it is most likely that, by blocking the effects of such agents as may be shown to be involved, progress in our ability to influence the progress of the disease in a fundamental way will be achieved. There is still little information as to how the tissues involved in AS come to be the particular targets of the pathological process and currently proposed theories of pathogenesis have not yet provided very satisfactory answers to this problem.

HLA type, islet cell antibodies, and glucose intolerance in cystic fibrosis.

Impaired glucose tolerance, assessed by a raised glycated haemoglobin (HbA1) concentration, was found in 24 (39%) out of 61 patients with cystic fibrosis with an age range of 1-23 years. No correlation between age and HbA1 concentration was found indicating that factors other than progressive pancreatic fibrosis may be important in the aetiology. HLA typing, islet cell antibodies, and autoantibody screen were completed. Eighteen (75%) out of 24 patients with cystic fibrosis who had an impaired glucose tolerance had HLA-DR3 or HLA-DR4 antigens compared with 23 (62%) out of 37 patients with normal glucose tolerance. Islet cell antibodies were present in seven (15%) out of 46 patients with cystic fibrosis; the prevalence in a normal population is 0.5%. Five (25%) of the 20 patients with a raised HbA1 concentration were positive for islet cell antibodies compared with two (8%) out of the 26 with normal glucose tolerance. Six (86%) out of seven patients who were positive for islet cell antibodies had HLA-DR3 or HLA-DR4 antigens. There was no general autoantibody production. Islet cell antibodies may play a part in the development of glucose intolerance in some patients with cystic fibrosis by being produced in those who are genetically predisposed as part of an immune response to damaged pancreatic tissue.

Immunological and immunogenetic investigation of recurrent spontaneous abortion.

Investigations have been performed in 80 couples with unexplained recurrent spontaneous abortions and no live birth (1 degree RSA), as well as in 33 couples with unexplained RSA following one live birth (2 degrees RSA), compared with control couples with no history of repeated early pregnancy failure. A significant bias towards a family history was given for 1 degree RSA women. Elevated total serum IgE levels and tissue-reactive autoantibodies were not significantly more prevalent in the RSA groups, and both 1 degrees and 2 degrees RSA patients had a similar incidence of serum lymphocytotoxic antibody. HLA typing indicated a trend towards parental HLA sharing which did not achieve clear significance at any locus, whereas there was significant apparent HLA-B locus homozygosity for 1 degree RSA women. An elevated prevalence of HLA-A2, B12 haplotypes was also noted for 2 degrees RSA, which may indicate some form of linkage disequilibrium in this population. These results, overall, did not provide evidence to identify a major subgroup of unexplained RSA patients.

Investigation of the associations of a number of HLA antigens with psoriasis and psoriatic arthritis.

A method, using the GLIM computer package, for determining primary and secondary HLA associations with disease is described and is applied to data from patients with psoriasis and psoriatic arthritis.

HLA and immunoglobulin allotypes in mixed connective tissue disease.

A group of patients with mixed connective tissue disease (MCTD) were HLA and immunoglobulin allotyped. We found that the incidence of DR4 in the patient group was increased compared with that in the normal controls, but the increase was restricted to the subgroup of patients with arthritis. The age at onset of MCTD was lower in patients with DR4 and higher in patients with DR2 compared with patients who did not have these antigens. A1, B8, and DR3 were more frequent, but not significantly so, in the MCTD patient group. We also found that there was a significant perturbation of the Gm allotype frequencies in patients with MCTD.

Linkage disequilibrium involving three loci.

A formula for the estimation of "three-locus interaction delta" given by Nijenhuis & D'Amaro (1985) is considered and found to be unsatisfactory. An alternative symmetrical formula is given. Other features of the analysis of Nijenhuis & D'Amaro are criticized and it is emphasized that a more suitable method of analysis of interactions of different orders is given by the use of the empirical logistic method (Green et al. 1983).

Analysis of the HLA association with rheumatoid arthritis.

Definitive determination of the HLA linked gene or genes for susceptibility to RA will be achieved (1) by the accumulation of an adequate body of data on the haplotype frequencies in a random set of RA patients and controls and (2) by further study of other loci in the DR region, involving the use of DNA probes as well as conventional techniques. Indirect evidence is here put forward to suggest that it may turn out that some part of DR4 specificity itself may be directly involved in increasing susceptibility and that DR1 epitopes may be involved in a similar way.

Ankylosing spondylitis, HLA-B27, and Klebsiella: a study of lymphocyte reactivity of anti-Klebsiella sera.

Twenty three anti-Klebsiella antisera were tested for their cytotoxic activity and four for their binding capacity for peripheral blood lymphocytes (PBL) from patients with HLA-B27 positive ankylosing spondylitis (AS+B27+) and from B27 positive (AS-B27+) and B27 negative (AS-B27-) healthy individuals. None of the antisera showed specific activity against PBL from any particular group. The antisera tested included two anti-Klebsiella K43 sera provided by an Australian group, who have reported them to be specifically cytotoxic for AS+B27+ PBL, four antisera raised against a Klebsiella K43 strain provided by this group, and an antiserum from another group, who have reported it as having increased binding capacity for AS+B27+ and AS-B27+ PBL compared with AS-B27- PBL. The results of other workers who have attempted to reproduce the results of either group are reviewed and the possible reasons for the repeated failure to confirm the reported findings are discussed.