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PubMed2005

Growth and behavioral traits in Donaldson rainbow trout (Oncorhynchus mykiss) cosegregate with classical major histocompatibility complex (MHC) class I genotype.

Although polymorphism in major histocompatibility complex (MHC) genes has been thought to confer populations with protection against widespread decimation by pathogens, this hypothesis cannot explain the type of large allelic diversity in classical MHC class I (Ia) in rainbow trout. Based on expression of Onmy-UBA (MHC class Ia) in trout neurons, we hypothesized that polymorphism in trout class Ia may contribute to polymorphism in behavioral traits. The present study examined whether polymorphism in Onmy-UBA was associated with behavioral variation in Donaldson rainbow trout (Oncorhynchus mykiss) using experiments on food competition, lure-catch, fright recovery, diel locomotor activity and activity characterized as dominance or aggression. These behavioral traits were investigated in fish having Onmy-UBA*401/*401 or *4901/*4901 homozygous, or Onmy-UBA*401/*4901 heterozygous genotypes (referred to as BB, FF and BF, respectively). The BB fish exhibited boldness, aggression, faster growth and crepuscular activity, while the FF fish showed little boldness, smaller body size, and diurnal activity with no aggressive behavior. The BF fish displayed traits intermediary to those of the BB and FF fish. These results are consistent with polymorphism in a single MHC class Ia locus driving variation in neural circuits, thereby creating behavioral variation in the trout. This is the first study in any animal to show a potential correlation between polymorphism in MHC class Ia genes with polymorphism of behavioral traits such as aggression.

Aggression↗
PubMed1990

Differential expression of class I and class II major histocompatibility complex antigen in early postnatal rats.

Cells expressing major histocompatibility complex (MHC) antigens are rarely found in normal mature brains, but cells resembling microglia can be induced to express these antigens following the onset of neural degeneration. In young rats, these cells show spontaneous expression of class I MHC antigens, which is further enhanced in the superior colliculus by the degeneration resulting from eye removal. By contrast, class II MHC antigen expression does not occur spontaneously and can only be induced by eye removal when the lesion is performed after the first postnatal week, when the optic tract begins to myelinate. We suggest that different signals are responsible for induction of class I and of class II MHC antigen expression.

Animals↗
PubMed1990

Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer's disease.

Expression of major histocompatibility complex (MHC) class I (HLA-A,B,C) and class II (HLA-DR) antigens was studied in postmortem brain tissue of Alzheimer's disease and age-matched control cases. Monoclonal antibodies to class I antigens stained reactive microglia weakly to moderately and vascular endothelial cells strongly in Alzheimer's gray and white matter. Capillaries were also stained strongly in control brains, but only a few positively stained microglia could be observed in white matter. In Alzheimer cases, HLA-DR positive reactive microglia were more numerous and more strongly staining than MHC class I positive reactive microglia but many cells appeared to express both classes of antigen. Rare large cells of uncertain origin also stained positively for class I. Double immunostaining established that MHC class I positive cells were a separate population from glial fibrillary acidic-protein-positive astrocytes.

Antibodies, Monoclonal↗
PubMedDate not supplied

Production and characterization of a peptide specific, anti-major histocompatibility complex class II, monoclonal antibody.

Monoclonal antibodies to major histocompatibility complex Class II proteins have been useful probes in understanding both the biochemistry and biology of these proteins. Almost all of the monoclonal antibodies previously described have been produced by immunization of mice with living cells. These antibodies react with native Class II proteins, but not usually with denatured material. It has been difficult to obtain specific anti-Class II antibodies which react with denatured proteins. Antibodies reactive with denatured proteins and with well-defined specificities would be useful in studies of Class II assembly and trafficking during the process of antigen presentation. In order to produce such an antibody we have immunized hamsters with a synthetic peptide corresponding to residues 146-177 (beta 1 domain) of the mouse A beta b protein. An antibody has been produced which reacts with the mouse Class II A beta chain from H-2b, H-2d, H-2p, and H-2q mice in immunoblotting assays, but not with the beta chain from H-2f, H-2j, H-2k or H-2s mice. Comparison of the amino acid sequences of these proteins along with the reactivity patterns of the antibody on synthetic peptides corresponding to homologous regions from A beta b, A beta k, A alpha b and Dp suggest that the region of 153 to 155 is critical for the reactivity of this antibody. This antibody does not react with native Class II protein found on the surface of living mouse cells.

Amino Acid Sequence↗
PubMed1988

Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection.

The major histocompatibility complex (MHC) loci are known to be highly polymorphic in humans, mice and certain other mammals, with heterozygosity as high as 80-90% (ref. 1). Four different hypotheses have been proposed to explain this high degree of polymorphism: (1) a high mutation rate, (2) gene conversion or interlocus genetic exchange, (3) over dominant selection and (4) frequency-dependent selection. In an attempt to establish which of these hypotheses is correct, we examined the pattern of nucleotide substitution between polymorphic alleles in the region of the antigen recognition site (ARS) and other regions of human and mouse class I MHC genes. The results indicate that in ARS the rate of nonsynonymous (amino acid altering) substitution is significantly higher than that of synonymous substitution in both humans and mice, whereas in other regions the reverse is true. This observation, together with a theoretical study and other considerations, supports the hypothesis of overdominant selection (heterozygote advantage).

Animals↗
PubMed2005

T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide.

Unusually long major histocompatibility complex (MHC) class I-restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to alphabeta T cell receptor (TCR)-MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B(*)3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR-peptide-MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR-MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.

Amino Acid Sequence↗
PubMed1991

Transmembrane domain length variation in the evolution of major histocompatibility complex class I genes.

The fifth exons of major histocompatibility complex (MHC) class I genes encode a transmembrane domain (TM) that is largely responsible for class I antigen cell-surface expression usually through conventional hydrophobic amino acid-membrane interactions or, less often, through phosphatidylinositol linkage. In this report we show that Peromyscus leucopus, a Cricetidae rodent, has MHC class I genes (Pele-A genes) encoding three distinct sizes of TMs. Increases in TM lengths were due to tandem duplications of sequences similar to human hypervariable minisatellite repeats and the lambda chi site. We discerned remnants of a similar duplication event in comparable rodent and primate MHC class I genes. Furthermore, several duplications and deletions appear to have occurred independently in H-2, RT1, Pele-A, and ChLA genes in near-identical positions. Accumulated data suggests that sequences in the fifth exon of MHC class I genes may, therefore, constitute a mutational or recombinational hot spot that is mediated by minisatellite- and chi-like sequences imbedded within the coding region. The MHC class I genes may thus have recruited "selfish" DNA in their evolution to encode cell surface proteins. Expression of Pele-A genes was examined by the polymerase chain reaction (PCR) using oligonucleotide primers specific for exon 4 and 5 sequences. The PCR product sizes indicated that genes encoding each TM domain length are ubiquitously transcribed.

Animals↗
PubMed1995

A general model of invariant chain association with class II major histocompatibility complex proteins.

The binding of invariant chain to major histocompatibility complex (MHC) proteins is an important step in processing of MHC class II proteins and in antigen presentation. The question of how invariant chain can bind to all MHC class II proteins is central to understanding these processes. We have employed molecular modeling to predict the structure of class II-associated invariant chain peptide (CLIP)-MHC protein complexes and to ask whether the predicted mode of association could be general across all MHC class II proteins. CLIP fits identically into the MHC class II alleles HLA-DR3, I-Ak, I-Au, and I-Ad, with a consistent pattern of hydrogen bonds, contacts, and hydrophobic burial and without bad contacts. Our model predicts the burial of CLIP residues Met-91 and Met-99 in the deep P1 and P9 anchor pockets and other detailed interactions, which we have compared with available data. The predicted pattern of I-A allele-specific effects on CLIP binding is very similar to that observed experimentally by alanine-scanning mutations of CLIP. Together, these results indicate that CLIP may bind in a single, general way across products of MHC class II alleles.

Alleles↗
PubMed1999

A novel element and a TEF-2-like element activate the major histocompatibility complex class II transactivator in B-lymphocytes.

Major histocompatibility complex (MHC) class II molecules play a central role in immune responses, and transcription of this family of genes requires the MHC class II transactivator (CIITA). CIITA has four promoters, which are transcribed in a tissue-specific manner. CIITA promoter III is constitutively active in mature B-lymphocytes. This report now describes the minimal 319-base pair promoter region necessary for maximal transcriptional activity in B-lymphocytes. Ultraviolet light and dimethylsulfate in vivo genomic footprinting analyses reveal five occupied DNA sequence elements present in intact B-lymphocytes. Functional analysis of these elements using promoter deletions and site-specific mutations demonstrates that at least two of the sites occupied in vivo are critical for transcriptional activity. In vitro protein/DNA analysis suggests that one of the sites is a TEF-2-like element and the other is occupied by a novel transcription activator. In addition, nuclear factor-1 associates with the promoter both in vivo and in vitro. In myeloma cell lines, loss of CIITA transcription correlates with a completely unoccupied CIITA promoter III. These findings suggest that CIITA transcription in B-lymphocytes is activated through at least two strong promoter elements, while loss of expression in myeloma cells is mediated through changes in promoter assembly.

B-Lymphocytes↗
PubMed2006

Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket.

Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated the peptide loading rate. The effect was evident only for an allelic subset and strictly correlated with the presence of glycine at the dimorphic position beta86 of the HLA-DR molecule. The residue forms the floor of the conserved pocket P1, located in the peptide binding site of MHC molecule. Apparently, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly(beta86) pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl-susceptible" MHC molecules. As catalysts of antigen loading, compounds targeting P1 may be useful molecular tools to amplify the immune response. The observation, however, that the ligand repertoire can be affected through polymorphic sites form the outside may also imply that environmental factors could induce allergic or autoimmune reactions in an allele-selective manner.

Adamantane↗
PubMed1997

Ii chain controls the transport of major histocompatibility complex class II molecules to and from lysosomes.

Major histocompatibility complex class II molecules are synthesized as a nonameric complex consisting of three alpha beta dimers associated with a trimer of invariant (Ii) chains. After exiting the TGN, a targeting signal in the Ii chain cytoplasmic domain directs the complex to endosomes where Ii chain is proteolytically processed and removed, allowing class II molecules to bind antigenic peptides before reaching the cell surface. Ii chain dissociation and peptide binding are thought to occur in one or more postendosomal sites related either to endosomes (designated CIIV) or to lysosomes (designated MIIC). We now find that in addition to initially targeting alpha beta dimers to endosomes, Ii chain regulates the subsequent transport of class II molecules. Under normal conditions, murine A20 B cells transport all of their newly synthesized class II I-A(b) alpha beta dimers to the plasma membrane with little if any reaching lysosomal compartments. Inhibition of Ii processing by the cysteine/serine protease inhibitor leupeptin, however, blocked transport to the cell surface and caused a dramatic but selective accumulation of I-A(b) class II molecules in lysosomes. In leupeptin, I-A(b) dimers formed stable complexes with a 10-kD NH2-terminal Ii chain fragment (Ii-p10), normally a transient intermediate in Ii chain processing. Upon removal of leupeptin, Ii-p10 was degraded and released, I-A(b) dimers bound antigenic peptides, and the peptide-loaded dimers were transported slowly from lysosomes to the plasma membrane. Our results suggest that alterations in the rate or efficiency of Ii chain processing can alter the postendosomal sorting of class II molecules, resulting in the increased accumulation of alpha beta dimers in lysosome-like MIIC. Thus, simple differences in Ii chain processing may account for the highly variable amounts of class II found in lysosomal compartments of different cell types or at different developmental stages.

Animals↗
PubMed1991

Defective intracellular transport as a common mechanism limiting expression of inappropriately paired class II major histocompatibility complex alpha/beta chains.

Distinct combinations of class II major histocompatibility complex (MHC) alpha and beta chains show widely varying efficiencies of cell surface expression in transfected cells. Previous studies have analyzed the regions of the class II chains that are critically involved in this phenomenon of variable expression and have shown a predominant effect of the NH2-terminal domains comprising the peptide-binding site. The present experiments attempt to identify the post-translational defects responsible for this variation in surface class II molecule expression for both interisotypic alpha/beta combinations failing to give rise to any detectable cell membrane molecules (e.g., E alpha A beta k) and intraisotypic pairs with inefficient surface expression (e.g., A alpha d A beta k). The results of metabolic labeling and immunoprecipitation experiments using L cell transfectants demonstrate that in both of these cases, the alpha and beta chains form substantial amounts of stable intracellular dimers. However, the isotype- and allele-mismatched combinations do not show the typical post-translational increases in molecular weight that accompany maturation of the N-linked glycans of class II MHC molecules. Studies with endoglycosidase H reveal that no or little progression to endoglycosidase H resistance occurs for these mismatched dimers. These data are consistent with active or passive retention of relatively stable and long-lived mismatched dimers in a pre-medial-Golgi compartment, possibly in the endoplasmic reticulum itself. This retention accounts for the absent or poor surface expression of these alpha/beta combinations, and suggests that conformational effects of the mismatching in the NH2-terminal domain results in a failure of class II molecules to undergo efficient intracellular transport.

Alleles↗
PubMed1994

A natural killer cell receptor specific for a major histocompatibility complex class I molecule.

Target cell expression of major histocompatibility complex (MHC) class I molecules correlates with resistance to lysis by natural killer (NK) cells. Prior functional studies of the murine NK cell surface molecule, Ly-49, suggested its role in downregulating NK cell cytotoxicity by specifically interacting with target cell H-2Dd molecules. In support of this hypothesis, we now demonstrate a physical interaction between H-2Dd and Ly-49 in both qualitative and quantitative cell-cell binding assays employing a stable transfected Chinese hamster ovary (CHO) cell line expressing Ly-49 and MHC class I transfected target cells. Binding occurred only when CHO cells expressed Ly-49 at high levels and targets expressed H-2Dd by transfection. Monoclonal antibody blocking experiments confirmed this interaction. These studies indicate that the specificity of natural killing is influenced by NK cell receptors that engage target cell MHC class I molecules.

Animals↗
PubMed2000

Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages.

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) regulates intracellular trafficking and peptide loading of MHC class II molecules. Such loading occurs after endosomal degradation of the invariant chain to a approximately 3-kD peptide termed CLIP (class II-associated invariant chain peptide). Cathepsins L and S have both been implicated in degradation of Ii to CLIP in thymus and peripheral lymphoid organs, respectively. However, macrophages from mice deficient in both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Both processes are blocked by a cysteine protease inhibitor, indicating the involvement of an additional Ii-processing enzyme(s). Comparison of cysteine proteases expressed by macrophages with those found in splenocytes and dendritic cells revealed two enzymes expressed exclusively in macrophages, cathepsins Z and F. Recombinant cathepsin Z did not generate CLIP from Ii-MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S in CLIP generation. Inhibition of cathepsin F activity and MHC class II peptide loading by macrophages exhibited similar specificity and activity profiles. These experiments show that cathepsin F, in a subset of antigen presenting cells (APCs), can efficiently degrade Ii. Different APCs can thus use distinct proteases to mediate MHC class II maturation and peptide loading.

Animals↗
PubMed1998

Infection of cells with varicella-zoster virus down-regulates surface expression of class I major histocompatibility complex antigens.

In vitro assays indicate that both major histocompatibility complex (MHC) class I and II-restricted cytotoxic T lymphocytes are important for recognition of varicella-zoster virus (VZV)-infected cells. This study demonstrates that infection of human fibroblasts with wild-type or recombinant-derived strain Oka VZV results in down-regulation of surface expression of class I MHC heavy chains. Radioactive labeling of infected cells indicated that the amount of newly synthesized class I antigen was similar in uninfected and VZV-infected cells. In addition, immunoblotting showed that the amount of total cellular class I MHC heavy chains was unaffected by VZV infection. These results suggest that the reduction of class I heavy chains on the surface of VZV-infected cells is due to a defect in posttranslational processing. The down-regulation of class I MHC antigens in VZV-infected cells may provide a mechanism for the virus to escape the host immune response.

Cell Line↗
PubMed1992

Two upstream elements activate transcription of a major histocompatibility complex class I gene in vitro.

Expression of major histocompatibility complex (MHC) class I genes exhibits unique tissue and developmental specificity. In an effort to study molecular mechanisms of MHC class I gene regulation, an in vitro transcription system has been established. In B cell nuclear extracts a template DNA containing the mouse H-2Ld promoter sequence accurately directed RNA polymerase II-dependent transcription of a G-free cassette. A conserved class I regulatory complex previously shown to moderately enhance promoter activity in vivo enhanced transcription in vitro by 2-3 fold. Much of this enhancement was accounted for by a 40 bp fragment within the complex, which was capable of activating a basal H-2Ld promoter in either orientation. Farther downstream, another element called site B was identified, which independently activated MHC class I transcription in vitro by 2-4 fold. Site B bound a specific nuclear factor(s) through an NF-1 binding site but not through a neighboring CCAAT site. The functional significance of site B in vivo was demonstrated in transfection experiments in which site B enhanced MHC class I promoter activity to a degree comparable to that seen in vitro. With the identification of the two upstream activators, MHC class I genes may serve as a model to study roles of sequence-specific DNA-binding proteins in transcription in vitro.

Animals↗
PubMed1995

The expressed class II alpha-chain genes of the marsupial major histocompatibility complex belong to eutherian mammal gene families.

The major histocompatibility complex (Mhc) is a multigene family found in vertebrates. Mhc genes code for heterodimeric cell-surface molecules involved in presentation of peptides to T-lymphocytes. There are two classes of Mhc, and in eutherian mammals four main families of class II genes have been recognized; DR, DQ, DP, and DN/DO. Each class II family contains genes that code for one or more alpha and beta chains. Do the class II genes of marsupial mammals belong to any of these eutherian mammal class II families? The results to date are conflicting. The expressed class II beta-chain genes could not be satisfactorily assigned to any eutherian class II gene family and were designated as new gene families, while, conversely, a partial sequence of an expressed alpha-chain gene was clearly very similar to the DNA gene of eutherian mammals. The aim of this study was to conduct a more thorough analysis of the alpha-chain genes in a marsupial by obtaining full-length sequences of all the expressed alpha-chain genes in the red-necked wallaby, Macropus rufogriseus. Two class II alpha-chain genes were isolated from a spleen-derived cDNA library, and both have the potential to code for fully functional MHC molecules. Phylogenetic analysis indicated they belonged to previously identified eutherian class II families and are designated as Maru-DRA and Maru-DNA. Northern blot data indicated processed transcript sizes of approximately 1.6 kb for Maru-DRA and approximately 2.5 kb for Maru-DNA and that the latter was expressed at a lower level than the former. The phylogeny shows that the DR, DQ, DP, and DN/DO gene families diverged prior to the divergence of the marsupial and eutherian mammal lineages.

Animals↗
PubMed1997

Prolongation of murine vascularized heart allograft survival by recipient-specific anti-major histocompatibility complex class II antibody.

BACKGROUND: Antibodies targeting recipient major histocompatibility complex (MHC) class II molecules have been demonstrated to be effective at prolonging allograft survival. However, antigen-presenting cell depletion would explain this effect and has not been definitively excluded as the mechanism of action of such antibodies. We have studied an anti-MHC class II antibody (OX6) proven to be noncytotoxic in the recipient strain used. METHODS: Antibody was administered the day before, 2 hr before, and the day after grafting. RESULTS: Antibody administration on the day before, 2 hr before, and the day after grafting significantly prolonged vascularized cardiac allograft survival. Importantly, treatment recognizing recipient MHC was effective, whereas a similar regimen recognizing donor MHC was not. CONCLUSIONS: Noncytotoxic recipient MHC class II-specific antibodies modify allograft rejection. Possible mechanisms for this therapeutic effect are discussed.

Animals↗