Birth of the major histocompatibility complex

Recursive partitioning is a nonparametric technique that produces a classification tree in which subjects are assigned to mutually exclusive subsets according to a set of predictor variables. We examined the utility of recursive partitioning as a supplement to logistic regression for the multivariable analysis of data from case-control studies, demonstrating the technique using data from women enrolled in a population-based study of subarachnoid hemorrhage. The classification tree produced by recursive partitioning consisted of three main risk subgroups: (1) elderly women who had long-standing hypertension and who were not smokers, (2) middle-aged women who were cigarette smokers and frequent binge drinkers, and (3) women in whom risk variables indicate relative estrogen deficiency (i.e., postmenopausal status, no recent exposure to hormone replacement therapy, cigarette smoking). As a supplemental method, recursive partitioning not only identifies subgroups with varying risks, but also may uncover interactions between variables that may be overlooked in the traditional application of logistic regression to case-control data.     

Alu elements of the primate major histocompatibility complex

The chromosomal region constituting the major histocompatibility complex (MHC) has undergone complex evolution that is often difficult to decipher. An important aid in the elucidation of the MHC evolution is the presence of Alu elements (repeats) which serve as markers for tracing chromosomal rearrangements. As the first step toward the establishment of sets of evolutionary markers for the MHC, Alu elements present in selected MHC haplotypes of the human species, the gorilla, and the chimpanzee were identified. Restriction fragments of cosmid clones from the libraries of the three species were hybridized with Alu-specific probes, Alu elements were amplified by the polymerase chain reaction, and the amplification products were sequenced. In some cases, sequences of the regions flanking the Alu elements were also obtained. Altogether, 31 new Alu elements were identified, representing six Alu subfamilies. The average density of Alu elements in the MHC is one element per four kilobases (kb) of sequence. Alu elements have apparently been inserted steadily into the MHC over the last 65 million years (my). On average, one Alu element is inserted into the primate MHC every 4 my. Analysis of the human DR3 haplotype supports its origin by duplication from an ancestral haplotype consisting of DRB1 and DRB2 genes. The sharing of an old Alu element by the DRB1 and DRB2 genes, in turn, supports their divergence from a common ancestor more than 55 my ago.     

Human major histocompatibility complex: the HLA system

The transmission of Plasmodium berghei-infected mice to Anopheles stephensi mosquitoes showed a peak number of oocysts early in the infection prior to the peak of gametocytaemia. This was followed by a precipitous decline on Days 4 and 5 (see also Dearsley et al., Parasitology, 100, 359-368, 1990). By measuring percentage relative infectivity (using membrane feeds with viable gametocytes), we have shown that serum collected daily during the course of a blood-induced infection blocked infectivity from Day 6 postinfection onward. Although there was a correlation between anti-blood stage antibody levels and the loss of infectivity, a comparison of the infectivity pattern of P. berghei-infected BALB/c and SCID mice (the latter being incapable of antibody production) revealed the same pattern of inhibition in both mouse strains, suggesting that antibody alone is not responsible for this suppression. Sera taken from SCID mice late in the infection tested in vitro demonstrated a decline in infectivity similar to that observed in vivo, suggesting that a non-antibody serum factor(s) is responsible for the sustained decline in infectivity of P. berghei to A. stephensi mosquitoes.     

Assembly of an abundant endogenous major histocompatibility complex class II/peptide complex in class II compartments

To identify the intracellular site(s) of formation of an endogenous class II/peptide complex in a human B cell line, we employed kinetic pulse-chase labeling experiments followed by subcellular fractionation by Percoll density gradient centrifugation and immunogold labeling on ultrathin cryosections. For direct demonstration of assembly of such complexes, we used the monoclonal antibody YAe, which detects an endogenous complex of the mouse class II molecule I-Ab with a 17-amino acid peptide derived from the alpha chain of HLA-DR (DR alpha52-68). We show that in human B lymphocytes, these class II/peptide complexes assemble and transiently accumulate in major histocompatibility complex class II-enriched compartments before reaching the cell surface.     

Association of high-altitude pulmonary edema with the major histocompatibility complex

BACKGROUND: A constitutional susceptibility has been suggested in the development of high-altitude pulmonary edema (HAPE) because HAPE generally affects healthy young people, some of whom suffer recurrent episodes. We examined whether immunogenetic susceptibility is present in HAPE-susceptible subjects. METHODS AND RESULTS: The frequencies of human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE were compared with those in 100 healthy volunteers. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. The pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia were retrospectively examined in 10 of the HAPE-susceptible subjects. HLA-DR6 was positive in 14 (46.7%) of the subjects with HAPE but only 16.0% of the control subjects (P=.0005), and HLA-DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (P=.0001). HLA-DR6 or HLA-DQ4 was positive in 8 (100%) of the subjects with recurrent HAPE. The pulmonary arterial pressure on admission of the HLA-DR6-positive subjects with HAPE was significantly higher than that of the HLA-DR6-negative subjects with HAPE. CONCLUSIONS: There were significant associations of HAPE with HLA-DR6 and HLA-DQ4 and of pulmonary hypertension with HLA-DR6. An immunogenetic susceptibility, which is associated with HLA class II alleles located within the major histocompatibility complex, may underlie the development of HAPE, at least in some of its forms.     

Presentation of antigenic peptides by products of the major histocompatibility complex

Molecules encoded by the major histocompatibility complex (MHC) are polymorphic integral membrane proteins adapted to the presentation of peptide fragments of foreign antigens to antigen-specific T-cells. The diversity of infectious agents to which an immune response must be mounted poses a unique problem for receptor-ligand interactions; how can proteins whose polymorphism is necessarily limited bind an array of peptides almost infinite in its complexity? Both MHC class I and class II determinants have achieved this goal by harnessing a limited number of peptide side chains to anchor the epitope in place while exploiting conserved features of peptide structure, independent of their primary sequence. While class I molecules interact predominantly with the N- and C-termini of peptides, class II determinants form an extensive hydrogen bonding network along the length of the peptide backbone. Such a strategy ensures high-affinity binding, while selectively exposing the unique features of each ligand for recognition by the T-cell receptor.     

Molecular docking of superantigens with class II major histocompatibility complex proteins

The molecular recognition of two superantigens with class II major histocompatibility complex molecules was simulated by using protein-protein docking. Superantigens studied were staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1) in their crystallographic assemblies with HLA-DR1. Rigid-body docking was performed sampling configurational space of the interfacial surfaces by employing a strategy of partitioning the contact regions on HLA-DR1 into separate molecular recognition units. Scoring of docked conformations was based on an electrostatic continuum model evaluated with the finite-difference Poisson-Boltzmann method. Estimates of nonpolar contributions were derived from the buried molecular surface areas. We found for both superantigens that docking the HLA-DR1 surface complementary with the SEB and TSST-1 contact regions containing a homologous hydrophobic surface loop provided sufficient recognition for the reconstitution of native-like conformers exhibiting the highest-scoring free energies. For the SEB complex, the calculations were successful in reproducing the total association free energy. A comparison of the free-energy determinants of the conserved hydrophobic contact residue indicates functional similarity between the two proteins for this interface. Though both superantigens share a common global association mode, differences in binding topology distinguish the conformational specificities underlying recognition.     

Effect of major histocompatibility complex expression on murine intestinal graft survival

BACKGROUND: Clinical intestinal transplantation has been plagued by frequent and severe graft rejection. It has been proposed that the major histocompatibility complex (MHC) antigens might play a critical role in this process owing to their extensive expression on enterocytes and mucosa-associated immune cells. METHODS: The present study examined the role of MHC antigens in intestinal graft rejection using MHC class I-deficient and MHC class II-deficient donors. RESULTS: Grafts with normal MHC expression were rejected by 9 days, whereas survival was prolonged to 14 days in the MHC class II-deficient grafts (P=NS) and to 20 days in the MHC I-deficient grafts (P<0.002). In all groups, early rejection was characterized by (1) increased crypt cell apoptosis, as detected by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) technique of in situ labeling; and (2) the increased expression of perforin and a CD8 phenotype in the graft-infiltrating cells. CONCLUSIONS: These data suggest that MHC antigens, CD8-positive T cells, and perforin-expressing cells contribute to intestinal graft rejection. Apoptosis of the progenitor epithelial crypt cells during early intestinal rejection may impair the gut's ability to regenerate and repair mucosal damage.     

A highly conserved major histocompatibility complex class I-related gene in mammals

We report here a cDNA sequence of a murine homolog of the human major histocompatibility complex (MHC) class I-related gene, MR1. The analyses revealed unprecedentedly high conservation of MR1 in the alpha1 and alpha2 domains (corresponding to the peptide-binding domains in the classical MHC class I molecules) between human and mouse (predicted amino acid identity: 90 and 89% for the alpha1 and alpha2 domain, respectively), compared to MHC class I and other class I molecules. On the other hand, conservation in the alpha3 domain (73%) is comparable to those of others, suggesting domain-specific conservation of MR1. The localization of the mouse MR1 gene was determined to be chromosome 1H1, which corresponds to the human chromosomal region where the human MR1 gene is located (chromosome 1q25). High conservation of MR1 among mammals suggests that MR1 may be involved in critical conserved biological function(s).     

Characterization of a class Ib gene of the rat major histocompatibility complex

Moyamoya disease is characterized occlusion of Willis' artery ring and abnormal "moyamoya" vessels. By supplying sufficient blood flow to the distal area of the stenosis or occlusion, ischemic symptom could be improved and the risk of the hemorrhage are lessen. Encephalo-Myo-Synangiosis (EMS) can increase the blood supply from external carotid artery to the ischemic area just put the temporal muscle on the brain surface. A kind of growth factor are thought to be exist around the brain of the Moyamoya disease patient. Basic fibroblast growth factor (bFGF) contribute angiogenesis in vitro and in vivo. This effect is considered to grow tumors and many experiments are done to use it for therapy by blocking this effect. Few trials are done to utilize the angiogenetic effect for therapy. We studied the effect of the bFGF on angiogenesis after EMS by using rats. We operated EMS on 10 male SDrats. 0.1 microgram of the bFGF was poured on 5 rats between the brain and muscle. On the other 5 rats just saline was poured. One week after rats were sacrificed, new vessels were observed with light microscope and scanning electron microscope. Molding models were also observed. bFGF group grew larger new vessels between the brain and muscle than non bFGF group. On the surface of brain, bFGF had more larger vessels (diameter is over 6 um) and non bFGF group had more small vessels (less than 6 um). Total area of vessel of bFGF group was twice as large as that of non bFGF group. On molding models many closed end of vessels were seen and they were thought to be the growing vessels. In molding models, bFGF group also has larger vessels than non bFGF group. We could prove that bFGF promotes angiogenesis on EMS of the rats, and we also expect that bFGF help the supplying blood flow of the Moyamoya patient.     

Possible conformation of major histocompatibility antigens: implication of amino acid sequence data

Possible conformation of major histocompatibility antigens was proposed on the basis of homology between domains of major histocompatibility antigen polypeptide chains and domains of immunoglobulins, characterized by a beta-pleated structure. In the hypothetical three-dimensional structure, domains alpha 3 and alpha 2 interact along the chain similarly to the CH2 and CH3 domains of IgG. beta 2-Microglobulin together with domain alpha 2 forms a structure analogous to the CH3--CH3 or CH1--CL dimers in IgG. Domains alpha 2 ans alpha 1 interact in such a manner that the beta-pleated sheet of domain alpha 2 is directly joined to the beta-pleated sheet of domain alpha 1. Hypervariable regions in domains alpha 1 and alpha 2, which most likely take part in the formation of the alloantigen determinants, represent the loops joining the regions of the beta-pleated structure. Domains alpha 1 and alpha 2 may be packed in such a way that their hypervariable regions would become adjacent and would be located on their surface turned aside from the surface of the cell membrane.     

Molecular mechanisms of class I major histocompatibility complex antigen processing and presentation

The presentation of antigenic peptides by class I major histocompatibility complex molecules plays a central role in the cellular immune response, since immune surveillance for detection of viral infections or malignant transformations is achieved by CD8+ T lymphocytes which inspect peptides, derived from intracellular proteins, bind to class I molecules on the surface of most cells. The transporter associated with antigen processing selectively translocates cytoplasmically derived peptides of appropriate sequence and length into the lumen of the endoplasmic reticulum where they associate with newly synthesized class I molecules. The translocated peptides are generated by multicatalytic and multisubunit proteasomes which degrade cytoplasmic proteins in a ATP-ubiquitin-dependent manner. This review discusses our current molecular understanding of class I antigen processing and presentation.     

Ancestral major histocompatibility complex DRB genes beget conserved patterns of localized polymorphisms

Genes within the major histocompatibility complex (MHC) are characterized by extensive polymorphism within species and also by a remarkable conservation of contemporary human allelic sequences in evolutionarily distant primates. Mechanisms proposed to account for strict nucleotide conservation in the context of highly variable genes include the suggestion that intergenic exchange generates repeated sets of MHC DRB polymorphisms [Gyllensten, U. B., Sundvall, M. & Erlich, H. A. (1991) Proc. Natl. Acad. Sci. USA 88, 3686-3690; Lundberg, A. S. & McDevitt, H. 0. (1992) Proc. Natl. Acad. Sci. USA 89, 6545-6549]. We analyzed over 50 primate MHC DRB sequences, and identified nucleotide elements within macaque and baboon DRB6-like sequences with deletions corresponding to specific exon 2 hypervariable regions, which encode a discrete alpha helical segment of the MHC antigen combining site. This precisely localized deletion provides direct evidence implicating segmental exchange of MHC-encoded DRB gene fragments as one of the evolutionary mechanisms both generating and maintaining MHC diversity. Intergenic exchange at this site may be fundamental to the diversification of immune protection in populations by permitting alteration in the specificity of the MHC that determines the repertoire of antigens bound.