The significance of the anti-class I response. II. Clinical and pathologic features of renal transplants with anti-class I-like antibody.

Although the ability of preformed anti-class I antibodies to mediate hyperacute rejection is well established, their pathogenic role in acute rejection remains ill-defined. We set out to identify patients with anti-class I against donor cells and to define the clinical and pathological features of such patients. We collected sera pretransplant and in the first 3 months posttransplant from 64 renal transplant recipients (59 cadaver donors and 5 one-haplotype matched living-related donors). We assayed the sera for class I-like antibody against donor T cells in complement-dependent microcytotoxicity, with crossmatches against autologous T cells to exclude auto-antibodies. All pretransplant sera were negative against donor T cells. Of the 797 sera tested posttransplant, 131/195 sera from 13 patients were positive, and 602 sera from 51 patients were negative. All patients who formed anti-class I underwent rejections compared with only 41% of patients with no anti-class I detected (P less than 0.0005). More rejections in patients with anti-class I were classed as severe (12/15 [80%] compared with 9/28 [32%] P less than 0.005), and graft loss was significantly higher (5/13 vs. 2/51; P less than 0.002). Rejections associated with anti-class I occurred earlier; more frequently developed oliguria (35% versus 10%) and required dialysis (40% versus 10%) and biopsies (10/13 vs. 6/28); and had a higher rate of rise in serum creatinine (249 versus 79 microns/L in the first 48 hr). Biopsies during anti-class I positive rejections more frequently displayed endothelial injury in the microcirculation, neutrophils in the glomeruli and/or peritubular capillaries, and fibrin deposition in glomeruli or blood vessels. The biopsies in anti-class I negative rejection episodes tended to have tubulitis, interstitial infiltration, and blasts, suggesting that these lesions reflect T-cell-mediated mechanisms. We conclude that patients with antibody against donor class I had more severe rejection, probably because anti-class I injuries the endothelium of small blood vessels of the graft, leading to rapid functional deterioration. We believe that anti-class I may be a major factor in some severe rejection episodes.

Genetic conditions among Canadian Mennonites: evidence for a founder effect among the old colony (Chortitza) Mennonites.

Distinctive disease patterns exist among Canadian Old Colony (Chortitza) Mennonites. This religious and genetic isolate is of 16th century Dutch/German ancestry. The group originated in the Netherlands, then settled in the Vistula delta area of western Prussia for 200 years. A small number of founding families later migrated to Chortitza, the "Old Colony", in the Ukraine in the late 18th/early 19th century, where they remained a distinct genetic isolate. This group has come to Canada over the past 100 years. The more conservative Canadian Mennonites of Chortitza descent practice strict endogamy, have a large family size and live predominantly in rural public health subdistricts in the four western provinces, and in southern Ontario. The world's largest reported familial aggregations of insulin-dependent diabetes mellitus, of autoimmune diseases and of Tourette syndrome were initially ascertained in a small northern Alberta public health subdistrict. Clusterings of malformations, inborn errors of metabolism, and other conditions were also found in the subdistrict, and in group descendents living in other provinces. A founder effect, or genetic drift, accounts for the familial aggregations of autosomal recessive and dominant conditions, some diseases of multifactorial determination, and other inherited conditions in Canadian kinships descending from this ancestral group. The medical literature on genetic conditions among Canadian Mennonites is reviewed and re-evaluated in the light of this information. There is biochemical, serologic, and molecular biologic evidence in favour of genetic homogeneity amongst patients with certain inherited conditions in this special population group. This genetic isolate offers potential for the study of the genetic epidemiology and molecular biology of inherited diseases. A computerized genealogic data base on about 1400 group members, as well as a cryopreserved lymphocyte/DNA bank on over 100 individuals with genetic conditions has been established in this special population group.

Inherited diseases in North American Mennonites: focus on Old Colony (Chortitza) Mennonites.

The patterns of migration and the genetic disorders occurring among North American Mennonites are reviewed, and inherited conditions recently recognized in a religious and genetic isolate, the Old Colony (Chortitza) Mennonites, are described. Old Colony Mennonites are of Dutch/German origin and descend from approximately 400 founding families who settled in the Old Colony, Chortitza (the Ukraine, USSR) in the late 1700s, and then migrated to Canada and Central and South America in the past century. We investigated over 6 generations of a Canadian Old Colony kindred in which there was extensive intermarriage, and in whom 28 individuals developed diabetes mellitus. Insulin-dependent diabetes mellitus (IDDM) occurred in 14 affected individuals in 10 closely related sibships; the 11 living IDDM patients were all concordant for the immunogenetic marker HLA-DR4. Fourteen close relatives had other disorders of carbohydrate metabolism, including gestational diabetes and non-insulin-dependent diabetes mellitus. Other close relatives had autoimmune diseases, including rheumatoid arthritis, hyper- and hypothyroidism, multiple sclerosis, and red cell aplasia. Other inherited diseases, including Alport syndrome, congenital defects, and inborn errors of metabolism were also found in the kindred. In the almost exclusively (99%) Old Colony Mennonite public health district in which the kindred was ascertained, there were multiple cases of Tourette syndrome, of malformations (including congenital heart defects and cleft lip +/- palate), and familial clusters of inborn errors of metabolism. We report this Old Colony (Chortitza) Mennonite isolate because 1) there are large familial aggregations of tissue-specific autoimmune diseases, malformations, inborn errors of metabolism, and of some other conditions whose genetic basis is still unknown; 2) there are multiple cases of rare genetic conditions, 3) we have established a computerized genealogic data base on over 1,000 kindred members as well as a cryopreserved lymphocyte/DNA bank on over 100 closely related individuals with various genetic conditions; and 4) this religious isolate, which extends across North, Central, and South America, offers an excellent opportunity for studying the epidemiology and molecular genetics of both common and rare inherited diseases.

Unusual clustering of diseases in a Canadian Old Colony (Chortitza) Mennonite kindred and community.

We investigated a large Old Colony (Chortitza) Mennonite kindred with branches across Canada. Six generations of the kindred were traced. There was intermarriage among numerous family members. Insulin-dependent diabetes mellitus (IDDM) was identified in 10 members; all 7 living patients were found to carry the immunogenetic marker HLA-DR4. Nine other close relatives had disorders of carbohydrate metabolism, including gestational diabetes mellitus and non-insulin-dependent diabetes mellitus progressing to insulin use. Ten other relatives had autoimmune diseases, including rheumatoid arthritis, hyperthyroidism, hypothyroidism and multiple sclerosis. Cases of Alport's syndrome, congenital malformations, inborn errors of metabolism and unusual malignant diseases were also found in the kindred. In the small Alberta community in which the kindred was ascertained there were people of Old Colony Mennonite descent with genetic conditions such as Gilles de la Tourette's syndrome and congenital malformations, including congenital heart disease. This kindred represents the largest reported familial aggregation of IDDM. This disease and other disorders of carbohydrate metabolism occur in the context of a strong familial predisposition to autoimmune disease. Study of this family may permit empiric testing of proposed models of inheritance of diseases of complex origin such as IDDM. We report this Old Colony (Chortitza) Mennonite community because it is one of the settlements populated by this religious and genetic isolate, which extends across Canada and Central and South America and affords opportunities for the study of both common and rare inherited diseases.

Elevated natural killer cytotoxicity in HLA-B8 and HLA-DR3-positive individuals.

Increased natural killer cytotoxicity in persons positive for HLA-B8 and HLA-DR3 has been found. It is suggested that linkage disequilibrium between the genes coding for HLA-B8 and HLA-DR3 may have evolved as a result of strengthened immunological surveillance in individuals bearing them, as decrease in the frequency of both these antigens has recently been reported in patients with tumours.

Anti-IgM antibodies may regulate the humoral response to paternal HLA antigens in pregnant women.

Anti-IgM antibodies were detected in sera of pregnant women but not in non-pregnant women and men. Anti-IgM activity was associated negatively with presence of anti-HLA antibodies. This finding suggests possible immunoregulatory influence of anti-IgM on humoral response against major histocompatibility antigens in pregnancy. The possibility of a similar mechanism being responsible for enhancement of kidney graft survival due to blood transfusions is discussed.

Antibody-mediated cellular cytotoxicity against Raji cells ADCC(Raji): evaluation of false positives in the detection of circulating immune complexes by Raji-cell assay.

Raji-cell radioimmunoassay is a very sensitive and reproducible method for the detection of circulating immune complexes. Using a complement-independent, antibody-dependent cellular cytotoxicity assay against 51Cr-labeled Raji cells, there is no correlation between activity against Raji cells and positivity in Raji-cell radioimmunoassay for circulating immune complexes in three sets of sera (from renal transplantation patients, multiparous women, and patients suffering from systemic lupus erythematosus). We conclude that IgG antibodies to Raji membranes are not a significant cause of false-positive results in circulating immune complexes as detected by Raji-cell radioimmunoassay.

Genetic variability of HLA in the Dariusleut Hutterites. A comparative genetic analysis of the Hutterities, the Amish, and other selected Caucasian populations.

There are three endogamous subdivisions of the Hutterite population, a North American religious isolate. These individuals live on communal farms, and residence is strictly patrilocal. We report on the distributions of HLA-A and B alleles and haplotypes in 203 married women from one subdivision--the Dariusleut--in Alberta, Canada. We demonstrate that there is significant linkage disequilbrium among a large fraction of the distinct haplotypes in the Dariusleut Hutterite data; there is a restriction in the number of distinct haplotypes present in the Dariusleut; the Hutterites and the Old Order Amish (Lancaster County, Pennsylvania) are the most genetically distant pair of populations in an ensemble of 11 Caucasian populations; and, finally, the Old Order Amish and the Hutterites are approximately as distant from the Indiana Amish as they are from the eight other Caucasian populations, which are tightly clustered in the space of gene frequencies. These results are consistent with the fact that the Amish and the Hutterites are genetic isolates with small numbers of founders. Certain haplotypes show significant linkage disequilibrium in these as well as in other Caucasian samples. Thus, some of the linkage disequilibrium antedates the formation of these Anabaptist sects.