Eugene R. Heise

Nomenclature for the major histocompatibility complexes of different species: a proposal.

The major histocompatibility complex (MHC) has been given different names in different species (Klein 1986). It is designatedH-2 in the mouse, HLA in humans, B in the domestic fowl, RT1 in the rat, and Smh in the mole rat. In most other species that have been studied, the MHC is referred to by the LA symbol (for lymphocyte or leukocyte antigen), prefixed by an abbreviation of the species’ common name. Thus, it is called ChLa in the chimpanzee, GoLA in the gorilla, RhLA in the rhesus macaque, RLA in the rabbit, BoLA in the domestic cattle, SLA in the pig, and so on. This practice has two problems associated with it. First, MHC products are expressed on many other tissues in addition to lymphocyte or leukocyte (and lymphocytes express many other antigens in addition to those controlled by the MHC) and their antigenicity is secondary to their biological function. Second, the use of common names to identify a species is a potential source of confusion. Common names are notoriously vague and imprecise. The designation “lemur”, for example, can refer to any of the genera Lemur, Hapalemur, Varecia, Lepilemur; Avahi, Propithecus, and Indri, of which only the first four belong to the family Lemuridae; the last three are members of the family Indriidae. A “bushbaby” can be a Galago, Otolemur, or Euoticus. A “mouse” could be a Notomys, ylcomys, Uranomys, Pogomys, Chiruromys, Chiropodomys, Neohydromys, and so on. Obviously, common names not only fail to identify the species appropriately, they often do not even identify the genes or the family. If the trend in choosing common names for MHC symbols were to continue, chaos would soon ensue because we can expect MHCs in many different species to be identified in the future.

CHRONIC SOCIAL STRESS, SOCIAL STATUS, AND SUSCEPTIBILITY TO UPPER RESPIRATORY INFECTIONS IN NONHUMAN PRIMATES

Objective The objective of the study was to assess the roles of social stress and social status in susceptibility to upper respiratory infection. Method: Sixty male cynomolgus monkeys were randomly assigned to stable or unstable social conditions for 15 months. Two markers of social status, social rank and percent of behaviors that were submissive, were assessed at independent observation periods. Endocrine, immune, and behavioral responses were each assessed (at 3-month intervals) during the 9th through 14th months of the study. At the beginning of the 15th month, all animals were exposed to a virus (adenovirus) that causes a common-cold-like illness. The primary outcome was whether or not an animal developed an infection (shed virus) after viral exposure. Results: Although the social instability manipulation was associated with increased agonistic behavior as indicated by minor injuries and elevated norepinephrine responses to social reorganizations, the manipulation did not influence the probability of being infected by the virus. However, low social status (as assessed by either marker) was associated with a substantially greater probability of being infected. It was also associated with less body weight, greater elevated cortisol responses to social reorganizations, and less aggressive behavior. However, none of these characteristics could account for the relation between social status and infection. Conclusions: Social stress was not associated with susceptibility to infection. However, animals with lower social status were at higher risk than high social status animals.

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 < 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.

HLA associations in IgA nephropathy and focal and segmental glomerulosclerosis.

Twenty percent of patients initiating Medicare-supported end-stage renal disease (ESRD) therapy in the United States have chronic glomerulonephritis-induced ESRD. IgA nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS) likely account for many of these incident dialysis cases, although patients presenting with advanced renal insufficiency may not receive renal biopsies. To determine whether HLA phenotype associations existed in the subset of IgAN and FSGS patients who develop ESRD, we analyzed HLA frequencies by race in patients with these etiologies of ESRD entered in the South Eastern Organ Procurement Foundation (SEOPF) database. Serologically determined HLA frequencies from 605 renal transplant recipients with ESRD due to FSGS and 196 renal transplant recipients with ESRD due to IgAN were compared with those of 4,506 race-matched cadaveric kidney-donor controls. Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between the HLA system and ESRD due to IgAN and FSGS. Values reported were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-B27 and HLA-DR1 frequencies were increased and HLA-DR2 frequency was decreased in African-American and white IgAN-induced ESRD cases compared with race-matched controls (race-combined OR of 2.10, 1.89, and 0.57, respectively; all P < or = 0.004). HLA frequency differences were not observed in FSGS-induced ESRD patients compared with controls. The results of this study indicate that HLA-B27 and HLA-DR1 are positively associated and HLA-DR2 is negatively associated with IgAN-induced ESRD in patients of both races.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

A Race-Controlled Human Leukocyte Antigen Frequency Analysis in Lupus Nephritis

Systemic lupus erythematosus (SLE) has higher incidence and mortality rates in addition to a greater risk for nephropathy in African Americans (blacks), compared with whites. We analyzed the South-Eastern Organ Procurement Foundation (SEOPF) database from 1982 through 1986 to determine if variation in human leukocyte antigen (HLA) frequencies, beyond those normally present between the races, were associated with lupus nephritis (LN). HLA antigen frequencies in 271 black and 230 white renal transplant recipients with LN as the cause of end-stage renal disease (ESRD) were compared with 4,506 race-matched cadaveric kidney donor controls. Odds ratios (ORs) and chi-square values were computed to assess the prevalence of each HLA phenotype among the cases versus the controls separately for blacks and whites. HLA-B8 and -DR2 frequencies were increased, and HLA-DR4 frequency was decreased in cases of both races compared with race-matched controls (race-combined ORs, 1.68, 1.46, and 0.49, respectively; all P < 0.01). Race-specific analyses showed that HLA-DR6 was decreased in black cases versus black controls (OR, 0.48; P < 0.001) and HLA-DR3 was increased in white cases versus white controls (OR, 1.88; P < 0.001). HLA-B8 and DR2 are positively associated and HLA-DR4 is negatively associated with LN in patients of both races. HLA-DR3 and -DR6 demonstrate race-specificity in LN and place whites at a disadvantage relative to blacks. It is likely that non-HLA-mediated genetic factors and/or environmental factors contribute to the increased risk of nephritis observed in black patients with SLE.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA Associations in End-Stage Renal Disease Due to Membranous Glomerulonephritis: HLA-DR3 Associations With Progressive Renal Injury

Membranous glomerulonephritis (MGN) is the most common cause of idiopathic glomerulonephritis in American adults. African-Americans develop end-stage renal disease (ESRD) due to chronic glomerulonephritis four times more often than whites. To determine whether HLA phenotype associations existed in the subset of MGN patients with ESRD we analyzed HLA frequencies, by race, in patients with MGN entered in the Southeastern Organ Procurement Foundation registry between 1982 and 1992. HLA frequencies from 250 renal transplant patients with MGN (190 whites and 60 African-Americans) were compared with 4,506 race-matched cadaveric kidney donor controls (4,039 whites and 467 African-Americans). Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between MGN and HLA frequencies. The reported values were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-DR3 and HLA-DR5 frequencies were increased in cases of both races compared with race-matched controls (race-combined ORs, 2.22 and 1.61, respectively; all P < 0.02). Interracial analyses revealed that HLA-DR7 frequency was decreased solely in whites with MGN (OR, 0.53; P < 0.04). The results of this study indicate that HLA-DR3 and HLA-DR5 are positively associated with ESRD due to MGN in patients of both races and that HLA-DR7 is negatively associated with MGN in whites. These analyses confirm the published reports of HLA-DR3 association with MGN in Chinese, French, British, Chilean, and American white populations. The novel association of HLA-DR5 may reflect the fact that the MGN cases in this study all had ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Lymphocyte Subpopulations in Normal and Preeclampsia Pregnancies

ABSTRACT: We have made an effort to determine whether or not there is any change in subpopulations of lymphocytes in normally pregnant and preeclamptic pregnancies using monoclonal antibody markers. Eleven normally pregnant and ten women with preeclampsia were studied, both during the third trimester and again two months postpartum, and compared to eleven age‐matched nonpregnant women. Mononuclear cells were isolated from heparinized venous blood. One million cells were treated with each appropriate antibody (Ortho‐mune OKM1, OKT3, OKT4, OKT8, OKT11, OKIa), and then reacted with FITC‐antimouse IgG and examined by flow cytometry and/or fluorescence microscopy. No significant differences between these three groups were noted in the OKT3, OKT4, OKT8, OKT11, or OKIa cellular populations. The OKM1 population was significantly decreased in the third trimester of normal pregnancies but not in the preeclamptic pregnancies. No significant differences were found 2 months postpartum.

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.