Diabetes and glucose tolerance in New South Wales coastal Aborigines: possible effects of non-Aboriginal genetic admixture.

A survey of adults living in two predominantly Aboriginal communities in eastern New South Wales revealed a crude prevalence of clinically diagnosed diabetes of 6.7% in Aboriginals. 1.4% of Aboriginal subjects investigated with 75 g oral glucose tolerance tests were found to have previously undiagnosed diabetes, and 2.8% had impaired glucose tolerance. 53% of women and 27% of men were obese as judged by body mass index. The age-sex standardised prevalence of diabetes in Aboriginals (previously diagnosed and newly detected) was 7.8%, which is substantially lower than the 15.6% prevalence found in the Aboriginal population of Bourke (central New South Wales). HLA antigen studies on these same individuals suggest approximately 60% genetic admixture from non-Aboriginal sources. Insulin response to oral glucose and mean body mass index were both related to non-Aboriginal genetic admixture with higher values in Aboriginal subjects than in their non-Aboriginal neighbours, and highest values were found in those with no detectable non-Aboriginal HLA haplotypes. The extent of genetic admixture in these communities may partly explain the lower prevalence of diabetes when compared with that found in the Aboriginal population of Bourke.

Significance of non-pathogenic cross reactive bowel flora in patients with ankylosing spondylitis.

We have previously shown that antisera raised in rabbits to certain enteric cross reactive strains of bacteria are capable of specifically lysing the peripheral blood lymphocytes of HLA-B27 positive patients with ankylosing spondylitis (B27+ AS+). We now report that bacteria with cross reactive antigenic determinants are found in the bowel flora of all of 52 B27+ AS+ patients but in only one of 50 HLA-B27 positive normal controls (B27+ AS-). These organisms are functionally similar to the cross reactive enteric bacteria originally reported. They are not confined to a particular genus or species and their cross reactive serological nature appears to be a property shared by all enteric organisms isolated from B27+ AS+ patients. Organisms with these properties have been shown to persist in the bowel flora of 14 B27+ AS+ patients followed up for more than one year.

HLA-B27 associated cross-reactive marker on the cells of New Zealand patients with ankylosing spondylitis.

We have previously shown that antibodies raised in rabbits to certain enteric bacteria will specifically lyse, in a 51Cr release assay, the peripheral blood lymphocytes (PBL) of 80% of HLA-B27 positive patients with ankylosing spondylitis (B27+ AS+) but not the PBL of HLA-B27 positive normal controls (B27+ AS-). Other laboratories have been unable to reproduce these findings. This study was designed to ascertain whether this lack of reproducibility was due to a peculiarity of our B27+ AS+ patients or to technical difficulties in the complement mediated 51Cr release assay. We have shown in this blind study that the PBL of 16 out of 18 B27+ AS+ patients from a New Zealand population were lysed by our antisera but none of the PBL of 20 B27+ AS- normal controls were lysed. The phenomenon of 'cross reactivity' between certain enteric bacteria and B27+ AS+ PBL is not confined to the Sydney AS population.

A prospective randomized trial of matching for HLA-A and B versus HLA-DR in renal transplantation.

A prospective randomized trial was performed comparing survival of cadaveric grafts allocated by HLA-A+B matching and HLA-DR matching. The two allocation methods resulted in very similar graft survivals. HLA-A matching had no significant effect on graft survival. HLA-B and HLA-DR matching were shown to have approximately equal, significant, independent, and additive effects on graft survival. Other factors that were demonstrated to have significant effects were blood transfusion, preformed antibodies, graft number, and recipient sex. The results indicate that neither allocation method alone is optimal, and that matching for HLA-B+DR is necessary. However a large pool size is necessary to obtain a high frequency of good matches.

A factor in the culture filtrate of some Klebsiella isolates specifically modifies the fibroblasts of HLA-B27-positive normal individuals.

Cultured skin fibroblasts of HLA-B27-positive clinically normal individuals specifically bind, and are modified by, a factor in the culture filtrate of some Klebsiella isolates. These modified fibroblasts are serologically similar to the cells (lymphocytes and fibroblasts) of B27-positive patients with ankylosing spondylitis (B27+AS+). By contrast, B27+AS+ cells fail to bind the factor, presumably because a receptor present on B27+AS- cells has already been blocked or modified by a Klebsiella antigen in vivo.

Enteric bacteria and HLA-B27 associated cell surface modification in patients with seronegative spondarthritis.

Cytotoxic studies indicate cross-reactivity between some enteric organisms and cells obtained from the majority of patients with ankylosing spondylitis. Preliminary studies suggest that the factor responsible for cross-reactivity may be generated by a bacterial plasmid. However, the mechanism mediating the interaction between the HLA-B27 positive cell and the bacterial antigen is at present unknown.

Possible role of enteric organisms in the pathogenesis of ankylosing spondylitis and other seronegative arthropathies.

One-hundred eighty-five clinical isolates of Salmonella sp., Shigella sp., Escherichia coli, and Campylobacter sp. were tested for their ability to absorb the lymphocytotoxic activity of an antiserum (anti-Klebsiella sp. K43) directed against a specific HLA-B27-associated cell surface determinant on the lymphocytes of patients with ankylosing spondylitis (AS). Seven of these isolates (three Salmonella sp., two Shigella sp., one E. coli, and one Campylobacter sp.) were found to cross-react with the B27-positive cells of AS patients (B27+ AS+); an E. coli organism isolated from the rectal swab of an HLA-B27-negative clinically normal individual also cross-reacted with B27+ AS+ cells. These cross-reactive enteric organisms elaborate a factor (modifying factor) which specifically modifies the B27-positive lymphocytes of normal individuals; this factor is structurally and antigenically related to a functionally similar factor secreted by certain isolates of Klebsiella sp. These data suggest that certain enteric organisms share a common determinant which cross-reacts with B27+ AS+ cells. It is suggested that this cross-reactivity is somehow related to an early event in the pathogenesis of AS and possibly of other seronegative arthropathies.

A factor shed by lymphoblastoid cell lines of HLA-B27 positive patients with ankylosing spondylitis, specifically modifies the cells of HLA-B27 positive normal individuals.

Epstein-Barr virus transformed lymphoblastoid cell lines from HLA-B27 positive individuals with ankylosing spondylitis (B27+AS+) release, into the culture medium, a factor capable of specifically modifying the HLA-B27 positive lymphocytes of normal individuals (B27+AS-); this modification results in a phenotypic change similar to that seen on B27+AS+ lymphocytes. This lymphoblastoid cell line derived factor appears to be physically and functionally similar to a factor present in the culture filtrate of certain Klebsiella isolates. Biogel P-100 chromatography of the material released from the cell line indicated a mol.wt of 25,000-30,000, similar to that of the Klebsiella derived factor. Chromatofocusing on a PBE 94 column revealed that cell line derived factor had an isoelectric point of 5.5 (cf. pI 5.4 for the Klebsiella derived factor). Immunoadsorption experiments suggest that the factor from the B27+AS+ cell line shares antigenic determinants with a cell surface component present on certain Klebsiella isolates. These results will form the basis for future studies on the nature of the interaction between HLA-B27 and certain enteric organisms and their products. A better understanding of this association should elucidate some of the early events in the pathogenesis of the seronegative arthropathies.

Immunochemical characterization of Klebsiella antigens which specifically modify an HLA-B27-associated cell-surface component.

Culture filtrates of some Klebsiella isolates contain a factor(s) capable of specifically modifying the HLA-B27-positive lymphocytes of normal individuals, resulting in a phenotypic change similar to that seen on lymphocytes from patients with ankylosing spondylitis (AS). To further delineate the nature of the interaction between HLA-B27 and some Klebsiella products we have undertaken a chemical characterization of B27+AS+-cross-reactive Klebsiella antigens from the culture filtrate and the bacterial cell-membrane. Biogel P-100 chromatography of the Klebsiella K43-derived modifying factor from the culture filtrate and from an NP-40-solubilized membrane extract gave a molecular weight of 26,000-30,000. Isoelectric focusing revealed that the modifying factor had an isoelectric point of approximately 5.4. Membrane-associated modifying factor activity was found only in outer-membrane preparations indicating that the cross-reactivity between Klebsiella K43 and B27+AS+ cells is defined, at least in part, by outer-membrane antigens. These studies demonstrate that membrane components of Klebsiella K43 share antigenic determinants with a modifying factor, which is released into the culture medium, and that these components are capable of specifically altering the HLA-B27 antigen or an associated cell-surface structure. Such a modification occurring in vivo following exposure to Klebsiella, or to antigenically related organisms, could explain the triggering of the B27-associated arthropathies such as AS.

Cadaver renal transplantation and HLA matching in Australia from 1971 to 1980. A report of the Australian and New Zealand Combined Dialysis and Transplant Registry.

The influence of HLA matching on the survival of 2648 cadaver renal grafts carried out in Australian transplant units from January 1971 to October 1980 was analyzed. Survival of grafts well matched for the HLA-A and B antigens was significantly better than that of poorly matched grafts from 1 to 5 years after transplant. The improvement in survival was predominantly attributable to matching for the HLA-B locus antigens, matching for antigens of the HLA-A series contributing only marginally. Although survival of secondary grafts was slightly poorer than that of primary grafts, their survival was improved by HLA matching. No difference in survival on the basis of sex, blood group, or demonstrable presensitization to HLA could be shown, but the influence of HLA matching was greater in males than in females, in group A than group O subjects, and in subjects not sensitized to HLA. In all patient groups, HLA matching based on the number of incompatible antigens carried by the donor had greater prognostic value than matching based on the number of antigens shared by donor and recipient.

Idiopathic hemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families.

In five families with idiopathic (hereditary) hemochromatosis, clinical and biochemical expression of the disease occurred in offspring of probands, suggesting an autosomal dominant mode of inheritance. However, HLA typing of subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in four of the five families, resulting in homozygous offspring. Thus, in these families inheritance of the hemochromatosis trait was best explained in terms of an autosomal recessive or intermediate mode of inheritance. This study demonstrates the value of HLA typing in identifying homozygous-heterozygous matings in hemochromatosis families.

HLA family studies and multiple sclerosis: A common gene, dominantly expressed.

All available Australian families with more than one member suffering multiple sclerosis (MS) were HLA typed. As with all other individual published studies, convincing evidence for linkage between the HLA system and disease was not obtained. An analysis of 100 published affected sib-pairs and 17 cousin-pairs, however, established the existence of an HLA-linked disease susceptibility gene for MS, which is likely to be dominantly expressed. Dominance was also supported by the finding of only three HLA-DR2 (Dw2) homozygous individuals out of 60 unrelated patients which enabled rejection of a recessive gene hypothesis (p less than 0.02). Analysis of the sib-pair data strongly suggested that this MS gene is not rare in the normal population and may be as common as DR2.