Nomenclature for the major histocompatibility complexes of different species: a proposal.
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Animals↗
Biomedical subjects
E R Heise
Publications and source records attributed to E R Heise.
Restriction fragment polymorphism of the cynomolgus monkey major histocompatibility complex.
Among old world monkeys, the major histocompatibility complex (MHC) is defined only in the rhesus (Macaca mulatta), cynomolgus (Macaca fascicularis) and pigtailed (Macaca nemistrina) species. However, little is known about the organization of class I and class II MHC genes or the extent of polymorphism in macaques. In the present study, human and murine class I and class II gene probes were used to analyze the leukocyte antigen (CyLA) system of unrelated and related cynomolgus monkeys. Restriction fragment length polymorphism (RFLP) analysis with a HLA-B7 cDNA probe supports the serologic evidence indicating the existence of a family of class I loci of which several are highly polymorphic. As in the human MHC, the class II beta genes are more polymorphic than class II alpha genes. In a pedigree study, RFLP patterns correlated with CyLA haplotypes as deduced from CyLA-A,B,C and complement factor B(Bf) phenotypes. The RFLP data are consistent with three expressed class I gene loci as well as nonclassical MHC genes potentially related to Qa/T1a in mice. We conclude that the RFLP analysis with cross-hybridizing DNA probes augments the information obtained by serotyping and sets the stage for gene mapping and structural analysis of the CyLA region.
Animals↗
The impact of different immunosuppressant regimens on recurrent glomerulonephritis.
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Adult↗
Conservation of HLA class I private epitopes in macaques.
Fifty mouse monoclonal antibodies (mAb) specific for HLA class I epitopes were compared for their reactivity against two closely related nonhuman primate species, pigtailed macaques (Macaca nemestrina, Mn) and longtailed macaques (M. fascicularis, Mfl), which diverged from the hominoids 23-40 million years ago. An analysis of Nei's genetic identity (I) and distance (D) based on reactivity of all class I-specific mAb showed, as expected, that the macaques are more closely related to each other (I = 0.959) than to man (I = 0.782 for Mn and 0.859 for Mfl). However, there were clear differences in genetic similarity with respect to certain epitopes. Macaques were most different from each other and from man in expression of heterologous epitopes recognized by the mouse that are not polymorphic among humans. In contrast, the most polymorphic epitopes unique to single HLA alleles, so-called private epitopes, were present in all the species, and neither macaque species could be distinguished from humans, suggesting that certain class I private epitopes may be highly conserved in evolution.
Animals↗
Testicular germ cell tumors in HLA-genotype non-twin brothers.
The diagnosis of metastatic testicular carcinoma in a thirty-three-year-old man and his nineteen-year-old brother is reported. Histologically, the tumor of the older brother consisted predominantly of embryonal carcinoma with minor components of seminoma and adult teratoma; the tumor of the younger brother consisted entirely of embryonal carcinoma. Since previous reports suggest the possibility that the HLA genotype may be a factor in the etiology of testicular cancer, we typed the parents and four children of this family. The two affected brothers shared a paternal HLA-A3, Cw-,B7,DR2 haplotype that had not been transmitted to the two other living siblings. Analysis of the distribution of HLA haplotypes of the affected non-twin brothers of this family and those of three other non-twin pairs of brothers that have been reported showed that the affected pairs in each family shared one HLA haplotype. The differences between the expected and the observed distribution of HLA haplotypes in the four sibling pairs is not statistically significant, perhaps because of the small number of patients typed. Two of the four pairs shared a common haplotype. Additional family studies are required to establish a genetic origin of testicular tumors and to determine whether or not a "testicular carcinoma disease" gene is linked to the HLA complex. A large number of multicase families will be required for linkage analysis.
Adult↗
Increased frequency of HLA-DR2 in patients with autoantibodies to epidermolysis bullosa acquisita antigen: evidence that the expression of autoimmunity to type VII collagen is HLA class II allele associated.
Epidermolysis bullosa acquisita (EBA) is a chronic blistering disease characterized by circulating and tissue bound IgG auto-antibodies to the basement membrane zone (BMZ) of stratified squamous epithelium. Recent studies have shown that antibodies recognize epitopes present in the noncollagenous carboxyl-terminal domain of type VII collagen, a BMZ matrix protein. Antibodies with identical specificity also have been detected in patients with the rare blistering disease, bullous systemic lupus erythematosus (bullous SLE), suggesting EBA and bullous SLE are immunologically related diseases. In this study we determined the major histo-compatibility antigen types of 29 EBA patients and 6 patients with bullous SLE. Analysis of the results showed HLA-DR2 was significantly increased in both black EBA patients, P = 0.013 (corrected, RR = 4.8) and white EBA patients, P = 0.0008 (corrected, RR = 13.1). Five of the six bullous SLE patients also were positive for the DR2 antigen, P = 0.009. These results show the expression of autoimmunity to type VII collagen is HLA class II allele associated and that EBA and bullous SLE are immunogenetically related diseases.
Adolescent↗
The major histocompatibility complex of primates.
The major histocompatibility complex (MHC) encodes cell surface glycoproteins that function in self-nonself recognition and in allograft rejection. Among primates, the MHC has been well defined only in the human; in the chimpanzee and in two species of macaque monkeys the MHC is less well characterized. Serologic, biochemical and genetic evidence indicates that the basic organization of the MHC linkage group has been phylogenetically conserved. However, the number of genes and their linear relationship on the chromosomes differ between species. Class I MHC loci encode molecules that are the most polymorphic genes known. These molecules are ubiquitous in their tissue distribution and typically are recognized together with nominal antigens by cytotoxic lymphocytes. Class II MHC loci constitute a smaller family of serotypes serving as restricting elements for regulatory T lymphocytes. The distribution of class II antigens is limited mainly to cell types serving immune functions, and their expression is subject to up and down modulation. Class III loci code for components C2, C4 and Factor B (Bf) of the complement system. Interspecies differences in the extent of polymorphism occur, but the significance of this finding in relation to fitness and natural selection is unclear. Detailed information on the structure and regulation of MHC gene expression will be required to understand fully the biologic role of the MHC and the evolutionary relationships between species. Meanwhile, MHC testing has numerous applications to biomedical research, especially in preclinical tissue and organ transplantation studies, the study of disease mechanisms, parentage determination and breeding colony management. In this review, the current status of MHC definition in nonhuman primates will be summarized. Special emphasis is placed on the CyLA system of M. fascicularis which is a major focus in our laboratory. A highly polymorphic cynomolgus MHC has been partially characterized and consists of at least 14 A locus, 11 B locus, 7 C locus class I allelic specificities, 9 Ia-like class II antigens and 6 Bf (class III) variants.
Animals↗
Possible association of MN locus haplotypes with essential hypertension.
Five multigenerational kindreds with familial hypertension were typed for human leukocyte antigen (HLA) and blood group antigens to investigate genetic factors that influence variability in blood pressure. Pedigree analysis revealed that children of matings in which both parents were hypertensive had a significantly greater risk of hypertension than children of matings in which one parent or neither parent was hypertensive. Blood types N and MN were abnormally distributed among hypertensive as compared with normotensive members of white but not black families. The distribution of ABO and Rh types was not significantly different between hypertensive and normotensive siblings. When all possible pairings of siblings were examined for HLA haplotype sharing, abnormal distributions were observed among hypertensive sib pairs whereas the expected mendelian segregation was observed among hypertensive-normotensive sib pairs and normotensive-normotensive sib pairs. These results suggest the genetic factors controlling variation in blood pressure may include loci in the region of the MN locus on chromosome 4 and, possibly, the major histocompatibility complex on chromosome 6.
Blood Group Antigens↗
Safe conversion from cyclosporine.
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Azathioprine↗
The major histocompatibility complex of the cynomolgus monkey. II. Polymorphism at three serologically defined loci and correlation of haplotypes with stimulation in MLC and skin graft survival.
The major histocompatibility complex (MHC) of the cynomolgus monkey has been further characterized by testing in population and family studies 50 new alloantisera along with previously characterized sera. This resulted in the redefinition of three of the original 21 CyLA specificities and the identification of 14 additional specificities. Genetic evidence for the existence of a third class I locus, designated CyLa-C, is presented together with evidence for the linkage of a locus-controlling allostimulation of mixed lymphocyte cultures (MLC) to this complex. The number of alleles assigned to the CyLA-A locus was increased from seven to 14, the B locus from six to ten, and the newly defined C locus was assigned six alleles. Haplotype and gene frequencies were counted from the family data and compared with estimates from the population. Several examples of linkage disequilibrium were noted, though this does not appear to be a pronounced feature of the system. One informative family was identified in which a recombination resulted in the segregation of the MLC response with CyLA-A thus, implying that this may be the homologue of the B locus of other primate systems. In addition to the linkage of an MLC locus to CyLA, further evidence that this is the cynomolgus MHC came from the effect of haplotype matching on the survival of skin grafts exchanged within families. An increase in the mean graft survival time was dependent upon the number of haplotypes matched. The organization and degree of polymorphism of the cynomolgus MHC was shown to be homologous to other primate systems, which should allow this species to serve as a substitute for the rhesus macaque as a genetically defined model in transplantation and immunology research.
Alleles↗
The major histocompatibility complex of the cynomolgus monkey: absorption analysis of 24 CyLA antisera.
The major histocompatibility complex (MHC) of the cynomolgus monkey consists of at least 35 serologically defined specificities, 14 of which have been assigned to the CyLA-A locus, 10 to the B locus, and six to the newly identified C locus. Selected specificities and antisera were further studied by the analysis of data obtained from absorptions with single donor platelets of known CyLA type. These data confirmed the existence of four groups of cross-reactive specificities identified by serological typing and revealed that three other well-defined specificities could be divided into two or more subtypes. Seven sera were shown to contain two or more populations of distinct, probably noncross-reactive antibodies that could be readily separated by absorption. Of the 24 sera analyzed, only three could be considered likely to contain antibodies reactive with a single CyLA specificity. At least three antibody specificities, after repeated absorption attempts, could not be readily removed by platelets and may reflect poor expression of the determinants on the platelet membrane. The complexity and degree of polymorphism of the CyLA system approaches that known for the human HLA complex. This homology of genetic organization and serologic features provide additional evidence in yet another species for the important role that these systems of alloantigens play in the organism.
Animals↗
Serologic recognition of a HLA-B44(12) subgroup associated with the 44.2 specificity defined by CML.
Several investigators have reported that subdivisions of HLA-B44, which are not defined by available cytotoxic antisera, can be detected by cytotoxic T lymphocytes. The present study was designed to evaluate two sera which appear to recognize a specificity on some HLA-B44 and B45 positive cells and to determine whether the specificity is correlated with one of the B44 subgroups which are defined by cell-mediated lympholysis. Serum BG1359, eluted from a placenta and serum Cutchember (a gift from Dr. Wilma Bias), were tested on a 23-member B44 positive cell panel. The panel was typed independently with CTLQ1/M3 (specificity 44.1) and CTLM3/Q1 (specificity 44.2). Cells classified as 44.2 usually typed positive with serums 1359 and Cutchember, whereas 44.1 cells usually were negative with these sera in the Amos modified cytotoxicity technique. In the 4th American workshop data, serologic reactivity correlated with B44 (r = 0.87 and 0.75) and B45 (r = 0.32 and 0.34) for serums 1359 and Cutchember, respectively. In a North Carolina population study (N = 155), specificity 1359 was detected in 37 of 53 (70%) of B44 positive individuals and in 5 of 6 B45 positive individuals. In three informative families, the 1359 private specificity segregated with B44 haplotypes. The 44.2 subgroup is in positive linkage disequilibrium with C4 and DR7 and possibly with A23, A26, and A29, whereas the 44.1 subgroup seems to be in disequilibrium with A2, Cw5, DR4, and DRw6.
Cytotoxicity, Immunologic↗
The effect of HLA-A, -B matching on cadaver renal allograft rejection comparing public and private specificities.
Data collected prospectively on 3811 cadaver renal transplants performed between June 1977 and July 1982 by the 42 member institutions of the South-Eastern Organ Procurement Foundation (SEOPF) were analyzed to determine whether donor-recipient compatibility based on public rather than private HLA-A,-B specificities influenced the beneficial effect of HLA matching on outcome. HLA compatibility was calculated considering match and mismatch based on common private or various public (crossreactive group, [CREG]) specificities. Donor-recipient compatibility using certain CREG assignments provided an equivalent means of stratifying graft outcome by the degree of HLA-A,-B match or mismatch, and other CREGs assignments did not. Multivariate Cox regression analysis of donor-recipient compatibility based on certain public antigens showed as high an association (P less than 10(-5) between good matching and decreased graft rejection as did matching for private antigens alone. Patient stratification by HLA match provided a stronger association with graft outcome than by HLA mismatch, irrespective of whether private or public antigens were considered. The likelihood of finding a better match was significantly increased using CREG assignments, and patients with at least one matched private antigen had equivalent or better graft survival when additional public antigens were matched. These findings indicate that with conventional immunosuppressive therapy: (1) matching of private or public HLA-A,-B antigens plays a highly significant role in decreasing renal allograft rejection; (2) matching based on certain public antigens can provide the same or a better association with outcome as private antigens; and (3) the association (crossreactivity) of various HLA specificities can be defined on a functional basis in terms of graft survival.
Cadaver↗
The major histocompatibility complex (CyLA) of the cynomolgus monkey. I. Serologic definition of 21 specificities.
Thirty-seven lymphocytotoxic antisera, 27 of which were raised by immunization with skin grafts and blood from partially matched donors, were tested against cells obtained from 218 unrelated animals and 205 offspring from a colony of cynomolgus monkey (Macaca fascicularis). Evidence was obtained for the presence of at least 21 specificities defined by cluster analysis and segregation within families. Allelic relationships between 16 specificities was suggested by segregation patterns, the absence of triplets and statistical analysis of association in the unrelated population sample. The data support a two-locus model, with tentative assignment of seven specificities to the A locus and six to the B locus. That these lymphocyte alloantigens constitute the major histocompatibility complex (MHC) of the cynomolgus monkey is suggested by analogy with other known MHCs and by the increased survival times of skin grafts between paternally matched half sibs compared to haplodistinct full sibs.
Animals↗
A critical analysis of paternity determination using HLA and five erythrocyte antigen systems.
Five hundred and thirty-seven cases of disputed paternity in North Carolina were tested for five erythrocyte polymorphisms, HLA antigens, or both. The data were analyzed to evaluate the ability of the tests to exclude the alleged father or to include the alleged father as the biological father. Incompatibility between the phenotypes of the alleged father, and those of the mother and child, were found in 40.6% of black males and 30.3% of white males (P less than 0.005). The rates of exclusion appeared to vary between countries in which the cases originated, although the significance of the differences could not be determined because of the small sample size. Using a Bayesian approach and 0.5 as the prior probability of paternity, we calculated the posterior probability of paternity for HLA and five erythrocyte systems combined as well as for HLA and erythrocyte systems separately. The probability of paternity values based on the combined HLA and RBC tests exceeded 95% in 299 of the 345 nonexcluded cases as compared to only 218 cases based on HLA tests alone and 36 cases based on erythrocyte tests alone. We conclude that in approximately 10% of paternity cases in the population served by this laboratory, the information obtained is inconclusive. To resolve these cases, additional polymorphisms and/or a panel of genetic tests systems which can provide greater than 95% probability of exclusion is required.
Bayes Theorem↗
HLA standardization and proficiency testing in the Southeastern organ Procurement Foundation.
Five years of experience with cell exchanges between laboratories comprising the Southeastern Organ Procurement Foundation (SEOPF) were analyzed in order to evaluate progress in HLA typing proficiency. The results of the analysis of 15 cell exchanges involving a total of 60 cells indicate that the average detection rate was 95% or greater for HLA-A1, 2, 3, 9, 10, 11, 28, and 29; B7, 8, 12, 13, 14, 15, 17, 27, and 40. HLA-A locus antigens were detected more often (85.8%) than B locus antigens (80.9%). False negative results were more frequent than false positive antigen assignments. Errors in antigen assignments tended to be nonrandomly distributed for certain antigens belonging to cross-reacting groups but usually were randomly distributed for well defined antigens. During the period of the study, SEOPF laboratories demonstrated improved proficiency in the identification of most HLA-A, B, and C provisional (w) specificities. The results demonstrate the benefits of interlaboratory proficiency testing and indicate that cell exchanges can be carried out successfully on a regional basis.
Cell Survival↗
Diseases associated with immunosuppression.
Impairment of any of the major components of the immune system (T-cells, B-cells phagocytes, complement) may result in clinical immunodeficiency. Immune defects can arise from intrinsic or heritable defects of lymphoid elements, failure of normal cellular differentiation, viral infection or other acquired causes. Clinical impairment of immunity is expressed as a marked susceptibility to opportunistic and pathogenic organisms which are difficult to control and by an increased risk of malignancy, allergy and autoimmune disease. Certain immunodeficiency disorders are associated with aberrant immune regulation. The major types of immune deficiency are characterized by unique patterns of infections depending on the level at which the defect occurs and the pathogenic mechanisms of the parasite. The basic defects of representative primary and secondary immunodeficiencies are discussed in relation to observed immunologic consequences.
Autoimmune Diseases↗
Chemotherapy of advanced ovarian epithelial carcinoma with melphalan and levamisole: a pilot study of the Gynecologic Oncology Group.
Twenty-three patients with Stage III, Stage IV, or recurrent epithelial ovarian cancer were treated with a combination of melphalan and levamisole to determine a tolerable dosage schedule, possible adverse effects, and a general estimate of response rate and duration. In seven patients with measurable disease there were four complete responses (57%) with a median duration of 75 weeks. Two of the complete responders have had negative second-look laparotomies while the other two patients have had subsequent progression. Of 16 patients with nonmeasurable disease two have had negative second-look laparotomies and two remain progression free. Thus 8 of 23 patients (35%) had complete responses or remain progression free whereas 4 of 23 patients (17%) have had negative second-look laparotomies. No serious toxicity was encountered. Immunologic monitoring did not indicate significant immunologic reconstitution in these immunosuppressed patients.
B-Lymphocytes↗