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PubMed1998

The frequency and avidity of committed cytotoxic T lymphocytes (cCTL) for donor HLA class I and class II antigens and their relation with graft vascular disease.

Cellular immune processes may trigger the development of graft vascular disease (GVD). CD4 and CD8 cytotoxic T lymphocytes that infiltrate the allograft could play a role in the development of GVD. We studied the presence of in vivo primed or committed CTL (cCTL) and their avidity for donor HLA class I and class II antigens in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies derived from patients with and without signs of GVD. The fraction of cCTL with high avidity for HLA class I or class II antigens was estimated by the addition of anti-CD8 or anti-CD4 MoAbs to the cytotoxic phase of the limiting dilution analysis. In the first year after transplantation no difference in the frequency of donor-specific class I cCTL between patients with and without GVD was found. Addition of anti-CD8 MoAb revealed that most cultures predominantly consisted of cCTL with low avidity for donor HLA class I antigens, irrespective of the development of GVD at 1 year after transplantation. However, in patients who did not develop GVD, the frequency of cCTL with donor HLA class II specificity was significantly higher than in patients who did develop GVD. The avidity for donor HLA class II antigens was comparable in both groups. A high frequency of donor-specific cCTL for HLA class II antigens seems to be a protective factor against the development of GVD. These cCTL might be cytotoxic for cells involved in GVD development, e.g. activated endothelium and smooth muscle cells of donor origin.

Antibodies, Monoclonal↗

PubMed1993

De novo expression of MHC class I and class II antigens on endomyocardial biopsies from patients with inflammatory heart disease and rejection following heart transplantation.

Inflammation of the heart muscle is caused either by infection (i.e. coxsackie virus) resulting in myocarditis or by rejection following heart transplantation. These processes induce activation of the immune system. We examined endomyocardial biopsies from patients with myocarditis, perimyocarditis and rejection following heart transplantation and compared these to biopsies from patients with coronary artery disease. The biopsies were examined immunohistologically with specific monoclonal antibodies against class I and class II molecules of the major histocompatibility complex (MHC). MHC class I antigens on the normally negative myocytes were evident in myocarditis (38%) and in rejection after heart transplantation (68%). In the interstitium there was an increase of both MHC class I and class II antigens. MHC class II antigens, however, were never seen on myocytes. MHC class I antigens are required for the action of CD 8 positive cytotoxic T cells. Therefore myocytes which express MHC class I antigens are susceptible to cytotoxic effects of the immune system. MHC class II antigens are essential to T helper cells. By cytokine release, activated T helper cells play a central role in the initiation, regulation and mediation of an immune response in myocarditis and rejection following heart transplantation.

Biopsy↗

PubMed1994

A segment of the MHC class II beta chain plays a critical role in targeting class II molecules to the endocytic pathway.

The ability of MHC class II molecules to sort into the endocytic pathway has generally been attributed to the invariant chain glycoprotein. In this paper, we present evidence suggesting that lumenal sequences in the MHC class II molecule itself control the post-Golgi entry of class II into endosomes. Single amino acid changes have been introduced into a highly conserved region of the class II beta chain (amino acids 80-83). Mutant class II beta chain genes and wild-type alpha chain genes have been transfected into cells that lack both class II and invariant chain expression. Immunofluorescent staining of transfected cells indicates that single amino acid changes in this region of beta can positively or negatively modulate expression of class II in endocytic vesicles independently of invariant chain. Mutation at residue 80 leads to prominent localization in vesicular structures typical of late endocytic compartments, while a change at position 82 leads to arrest in the Golgi. These data argue in favor of the possibility that MHC class II molecules bear a sorting signal that allows access to MHC class II molecules into the endocytic pathway of antigen presenting cells.

Animals↗

PubMed1999

Analysis of MHC class II and class IV restriction fragment length polymorphism in chicken lines divergently selected for multitrait immune response.

In the present study, chickens of four lines divergently selected for high (H) and low (L) immunocompetence in replicate were analyzed to investigate polymorphisms of MHC class II and MHC class IV on the molecular level associated with selection. The long-term selection experiment for multitrait immunocompetence was carried out in replicates and allows, therefore, the opportunity to distinguish effects of selection from other genetic factors. The SacI-digested DNA was hybridized individually with MHC class II and MHC class IV gene probes. The MHC class II RFLP analysis revealed four polymorphic bands and only one of them showed a significant difference between the selection directions H and L pooled between replicates. The small frequency differences of this band relative to the long-term selection suggest that this MHC class II fragment may contain genetic elements that are only slightly associated with the immune response traits used for selection. The hybridization with the MHC class IV probe displayed 26 scorable bands, of which 18 were polymorphic. In most instances, the differences between the lines were likely caused by the influence of genetic factors other than selection for multitrait immunocompetence. Only one band displayed a consistency in difference between selection directions in both replicates and no frequency difference between replicates. This band was almost completely absent in both H sublines, but at a frequency of about 50% in both L sublines. The general results of this study did not reveal major differences in band frequencies that indicate a close association of MHC class II and MHC class IV polymorphic markers to the divergent selection for multitrait immune response. Although the MHC makes a crucial contribution in immune response, it may have been difficult to detect single-gene associations with the selection criteria of this study, because of the myriad of components contributing to general immune responses measured in vivo.

Animals↗

PubMed1998

Cytomegalovirus infection enhances the neointima formation in rat aortic allografts: effect of major histocompatibility complex class I and class II antigen differences.

BACKGROUND: The development of chronic rejection has emerged as a major cause of long-term graft failure. Previous studies have demonstrated that cytomegalovirus (CMV) infection is associated with an increased incidence of chronic allograft rejection in renal, cardiac, and aortic allografts. This study was designed to investigate the effects of the major histocompatibility complex (MHC) class I or class II mismatches on CMV-enhanced chronic rejection. METHODS: Aortic transplantation was performed between different inbred rat strain combinations; the Lewis to RP combination was class I-mismatched and Wag/Rij to RP class II-mismatched. At 7, 28, and 90 days after transplantation, the intensity of chronic rejection in mismatched grafts with or without CMV infection was evaluated using histological and immunohistological analysis. RESULTS: The results of this study demonstrated that CMV infection led to an increased influx of monocytes/ macrophages in class I-mismatched grafts at 1 week after transplantation and enhanced infiltration of T lymphocytes in class II-mismatched grafts at 4 weeks. Although more vascular lesions were observed in the class II-mismatched combinations, an intensified neointima formation by CMV infection was observed only in the MHC class I-mismatched allografts. CONCLUSIONS: CMV infection may increase neointima formation of allografts when an MHC class I disparity between donor and recipient is present. This may be associated with the increased perivascular influx of monocytes/macrophages observed in CMV-infected animals early after transplantation.

Animals↗

PubMed1990

Studies on the bovine major histocompatibility class I and class II antigens using homozygous typing cells and antigen-specific BoT4+ blast cells.

Animals were identified from two sire lines as being homozygous for the class I bovine lymphocyte antigen (BoLA-A) w23. These animals were also shown to be homozygous for class II antigens (BoLA-D) which, however, differed between the two sire lines. Lymphocytes from these animals were then used either as stimulator cells in one-way mixed lymphocyte reactions (MLR) with all animals in the herd carrying the w23 antigen or as antigen presenting cells to bovine T4+ cell blasts. It was shown that, within each sire line, the genes encoding the MHC class I and class II antigens were closely linked. There were no detected recombinations between the MHC class I and class II regions nor within the BoLA-D region responsible for mixed lymphocyte reactivity. MLR typing of MHC class II antigens correlated with the results from T-lymphocyte proliferation studies. Cells from these cattle, which are homozygous at the class I and II MHC loci but differ in the class II antigen expressed, could be used to type the BoLA-D of other cattle.

Animals↗

PubMed1991

Production of alloantisera against class II bovine lymphocyte antigens (BoLA) by cross-immunization between class I matched cattle.

This paper describes the production of alloantisera directed against bovine major histocompatibility complex (MHC) (BoLA) class II antigens in animals whose MHC phenotypes had been defined by one dimensional isoelectric focusing. Animals of closely matched BoLA class I types were selected by serology and subsequently typed for class I and class II by 1D-IEF of immunoprecipitated antigens. Those with similar class I type by both methods, but differing at the class II locus, were chosen for reciprocal immunization. Cross-immunization was by two skin implantations 6 weeks apart. The resulting antisera showed low titre after the first immunization and elevated titre 3 weeks after the second immunization. The sera reacted strongly with cells expressing specific BoLA class II antigens. The pattern of reactivity correlated well with IEF class II typing on a panel of animals representing all of the class II IEF types present in the Friesian population.

Animals↗

PubMed2005

Midfacial and mandibular morphometry of children with Class II and Class III malocclusions.

There is insufficient evidence in conventional cephalometric analysis of the actual sites of putative maxillofacial change in Class II and Class III malocclusions. The purpose of this study was to provide more information about the morphological characteristics of the midfacial complex and mandible in children with Class II or III malocclusions. Seventy children with Class II, division 1 malocclusion and 70 children with Class III malocclusion were compared with 70 children with normal occlusion. This study was conducted to carry out geometric morphometric assessments to localize alterations using Procrustes analysis and thin-plate spline analysis. Procrustes analysis indicated the midfacial and mandibular morphologies differed between normal occlusion subjects and subjects with Class II or Class III malocclusion (P<0.0001). The deformations in subjects with Class II malocclusion may represent a developmental elongation of the palatomaxillary complex and a shortening of the mandible anteroposteriorly, which leads to the appearance of a protruding midface and retruding mandibular profile. In contrast, the deformations in subjects with Class III malocclusion may represent a developmental shortening of the palatomaxillary complex and elongation of the mandible anteroposteriorly, which leads to the appearance of a retrognathic midface and prognathic mandibular profile.

Cephalometry↗

PubMed1994

Strain-specific variation in constitutive and inducible expression of MHC class II, class I and ICAM-1 on rat cerebral endothelium.

Strain variation in levels of inducible major histocompatibility complex (MHC) class II expression by rat cerebral endothelium has previously been reported. Using primary cell cultures of rat cerebral endothelium from PVG (RT1c), LEW (RT1l), PVG.LEW (RT1l) and PVG.AGUS (RT1lv?) strains it was determined that variation in levels of inducible MHC class II expression between strains can be accounted for by both cis-acting elements within the MHC region and by trans-acting elements outside the MHC. In addition it was determined that levels of constitutive MHC class I expression varied between PVG (RT1c) and LEW (RT1l) strains which can be attributed to cis-acting elements within the MHC region. Furthermore, while levels of constitutive class I expression vary between PVG (RT1c) and LEW (RT1l) endothelium we could find no difference in the interferon-gamma (IFN-gamma) inducible expression of class I between these two strains. In contrast the inducibility of intercellular adhesion molecule-1 (ICAM-1) in response to IFN-gamma was found to differ between PVG and LEW endothelium. Significant levels of ICAM-1 are induced on LEW cerebral endothelium after 24 hr exposure to 50 U/ml IFN-gamma. However, no significant induction of ICAM-1 could be demonstrated on PVG, or BN cerebral endothelium after the same exposure to IFN-gamma. Induction of ICAM-1 by IFN-gamma precedes MHC class II by at least 24 hr and its persistence is proportional to the concentration of IFN-gamma used. We suggest that the rat MHC region (RT1) contains elements which control the levels of constitutive class I expression and inducible class II expression in response to IFN-gamma, but that other non-RT1 genes influence the inducibility of MHC class II on rat cerebral endothelial cells. This observation, together with the finding that ICAM-1 expression is not significantly increased in response to IFN-gamma on PVG or BN endothelium, suggests that IFN-gamma responsiveness by these strains differs from LEW.

Animals↗

PubMed1996

The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates.

Homologues of the human HLA-A and -B MHC class I loci have been found in great apes and Old World primates suggesting that these two loci have existed for at least 30 million years. The C locus, however, shows some sequence similarity to the B locus and has been found only in gorillas, chimpanzees, and humans. To determine the age of the MHC class I C locus and to examine the evolution of the A and B loci we have cloned, sequenced, and in vitro translated 16 MHC class I cDNAs from two unrelated rhesus monkeys (Macaca mulatta) using both cDNA library screening and PCR amplification. Analyses of these sequences suggest that the C locus is not present in the rhesus monkey, indicating that this locus may be of recent origin in gorillas, chimpanzees, and humans. The rhesus monkey's complement of MHC class I genes includes the products of at least one expressed A locus and at least two expressed B loci, indicating that a duplication of the B locus has taken place in the lineage leading to these Old World primates. Comparison of rhesus monkey MHC class I cDNAs to their primate counterparts reveals fundamental differences between MHC class I and class II evolution in primates. Although MHC class II allelic lineages are shared between humans and Old World primates, no such trans-species sharing of allelic lineages is seen at the MHC class I loci.

Animals↗

PubMed1990

The biosynthetic pathway of MHC class II but not class I molecules intersects the endocytic route.

We studied the intracellular traffic and subcellular distribution of MHC class I and class II antigens in comparison with a recycling surface glycoprotein, the transferrin receptor (Tfr), in the human lymphoblastoid cell line JY. No internalization was detectable for class I molecules. Class II molecules were internalized but did not recycle. In contrast, Tfr was found to internalize and recycle. The biosynthetic pathway of class II molecules differ from that of class I molecules in that it shows a delay (1-3 hr) in transport from trans-Golgi to cell surface: here it intersects the endocytic route. Immunoelectron microscopy using anti-MHC antibodies revealed the existence of vesicular structures that were intensely labeled for class II molecules. It is proposed that at this site combination of class II molecules with processed antigen could occur.

B-Lymphocytes↗

PubMed2002

Cellular, serological, and molecular polymorphism of the class I and class II loci of the canine Major Histocompatibility Complex.

This study was undertaken to determine the relationships between canine cellular and serological determinants and more recently described genes. Such relationships might reveal information about immunological reactivity or function of various proteins. To do this we studied the haplotypic associations of dog leukocyte antigen (DLA) class I and class II alleles determined from a panel of 14 DLA-D homozygous dogs. This panel of dogs was typed for the serological determinants DLA-A, DLA-B and DLA-C. Polymorphisms for DLA-DQA1, DLA-DQB1, DLA-DRB1 and DLA-88 were also determined. The number of alleles (one or two) for two microsatellite markers in the DLA region were also determined. Analyses of the nucleotide sequences and of the serological and cellular typing data revealed that phenotypic homozygosity, as defined by the DLA-D type in mixed leukocyte culture (MLC), tended to correlate with homozygosity at the DLA-DRB1 locus but not necessarily at the DLA-DQB1 locus. Furthermore, MLC specificity was determined by other loci besides DLA-DRB1 and DLA-DQB1. The amino acid at position 63 of the DR beta chain could contribute to the DLA-B serological specificity. DLA-88, the most polymorphic class I gene characterized to date, did not have an easily identifiable association with either the DLA-A or DLA-C class I serological specificities. Homozygosity or heterozygosity of each of two microsatellite markers, FH 2200 and FH 2202, located in the class I or class II region, respectively, did not correlate with homozygosity or heterozygosity of the most polymorphic known class I (DLA-88) or class II (DLA-DRB1) genes.

Animals↗

PubMed1990

HLA class I and class II antigen expression on squamous cell carcinoma of the head and neck.

We compared human major histocompatibility (HLA) class I and class II antigen expression on squamous cell carcinoma of the head and neck with that on normal mucosa. Frozen sections of a consecutive series of 30 squamous cell carcinomas were stained with the monoclonal antibodies W6/32 (class I) and anti-DR (class II) using an immunoperoxidase technique. Normal mucosa showed class I and class II expression in the basal layers only. Class I expression on tumors was diffuse in 87%, patchy in 10%, and scattered in 3%. Class II expression on tumors was diffuse in 20%, patchy in 53%, scattered in 20%, and absent in 7%. Patterns of expression did not correlate significantly with clinical parameters, including survival, except that class II diffuse and patchy patterns were found to correlate with more poorly differentiated tumors.

Adult↗

PubMed1999

Class II transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10.

Microglia are the resident macrophages of the brain, and when activated, have functions including cytokine production, phagocytosis and antigen presentation. The class II MHC genes encode proteins that present antigenic peptides to helper T cells, leading to T cell activation and the development of an antigen-specific immune response. Class II MHC gene expression is strictly regulated by the class II transactivator (CIITA) transcription factor. In this study, we investigated the effects of various immunomodulatory cytokines on IFN-gamma induction of class II MHC and CIITA gene expression in microglia, both primary microglia and a murine microglial cell line, EOC 20. By flow cytometry analysis we show that IFN-gamma-induced surface expression of class II MHC molecules on EOC 20 cells can be inhibited by the cytokines TGF-beta1, IL-4 and IL-10, but not IL-13. Using a ribonuclease protection assay, we have found that TGF-beta1, IL-4 and IL-10 act by inhibiting the expression of IFN-gamma-induced CIITA mRNA and, in turn, class II MHC mRNA. TGF-beta1, IL-4, and IL-10 inhibition of IFN-gamma-induced CIITA mRNA accumulation was not due to destabilization of CIITA mRNA, suggesting an effect at the level of transcription. In primary murine microglia, IL-10 and TGF-beta1 inhibited IFN-gamma-induced CIITA and class II MHC expression. However, a discordant effect of IL-4 was noted in that IL-4 enhanced IFN-gamma-induced CIITA and class II MHC expression in primary microglia. Although some differences are observed between EOC 20 cells and primary microglia in terms of responsiveness to TGF-beta, IL-4 and IL-10, CIITA and class II MHC gene expression are coordinately modulated.

Animals↗

PubMed1993

Allogeneic recognition of class I molecules: anti-H-2Ld repertoire of H-2b mice includes T cells recognizing mutant class II H-2b (Abm12) molecules.

Two major histocompatibility complex (MHC) class I-reactive T cell clones derived from H-2b mice, generated against the allogeneic Ld molecule, were found to recognize the H-2b class II mutant Abm12 molecule as well. In addition, these clones also recognize the class II A(s) molecule, and display a class II-dependent reactivity to staphylococcal enterotoxin B. Neither the class I nor the class II alloreactivities of the clones were found to be dependent on other MHC molecules. Both clones express CD4+CD8- phenotypes. The CD4 molecule appears to be involved in their class II reactivity, while little or no role for CD4 could be detected in the class I reactivity. This is the first report of a class I/class II cross-reactivity being mediated by CD4+ T cells. The structural basis for this cross-reactivity is discussed.

Animals↗

PubMed1996

Active suppression of the class II transactivator-encoding AIR-1 locus is responsible for the lack of major histocompatibility complex class II gene expression observed during differentiation from B cells to plasma cells.

In this study the genetic control of major histocompatibility complex (MHC) class II gene expression during the transition from B cell to plasma cell has been analyzed. Class II molecules are not expressed in plasma cells because of an active suppression resulting in the abrogation of class II gene transcription. We show here that the plasma cell-specific repressor function, designated SIR (suppressor of immune response genes), does not act directly on the transcription of class II genes, but instead on the transcription of the AIR-1 gene, whose product, the class II transactivator (CIITA), is fundamental for the regulation of the constitutive and inducible expression of MHC class II genes. This was unambiguously demonstrated by the fact that plasmacytoma x B cell hybrids carrying an AIR-1 locus derived from CIITA-expressing cells do not express CIITA-specific transcripts. Transfection of a cDNA containing the human CIITA coding sequence under the control of an heterologous promoter restores expression of human MHC class II genes in the hybrids and is responsible for de novo expression of mouse MHC class II genes in both the mouse plasmacytoma cell line and the hybrids. These results confirm and extend the notion of the functional conservation of the AIR-1 gene product across species barriers. Interestingly, in CIITA-transfected cell hybrids, cell surface expression of the human HLA-DQ heterodimer was not observed. This result was not attributable to lack of HLA-DQ alpha or -DQ beta transcription, because both transcripts were present in the CIITA-transfected hybrids, although at reduced levels. These findings further support our previous observations on the distinct regulation of expression of the human HLA-DQ class II subset, which may be thus controlled at the posttranscriptional level by a CIITA-independent mechanism.

Animals↗

PubMed1993

Carcinogen-treated skin allografts rejected by T lymphocytes specific for class I but not class II MHC antigens.

Treatment of skin with the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), which reduces the density of epidermal class II MHC-expressing Langerhans cells (LC), enhances its survival when transplanted onto histoincompatible hosts. We have examined the ability of T lymphocytes which reject DMBA-treated skin to lyse P388D1 cells expressing either only class I or class I and II antigens. Lymphocytes isolated from solvent-treated grafts showed greater cytotoxicity for the targets expressing both antigens, indicating that some of these lymphocytes were specific for class II MHC antigens. In contrast, lymphocytes isolated from carcinogen-treated grafts lysed both targets similarly and hence did not contain any cells specific for class II MHC antigens. Anti-class I MHC antibody blocked cytotoxicity by both leukocyte populations to similar extents, but anti-class II MHC antibodies preferentially blocked T cells isolated from the solvent-treated grafts. There was no difference in the phenotype of the cytotoxic cells isolated from solvent- and carcinogen-treated grafts. Thus, whereas solvent-treated skin grafts are rejected by T cells specific for class I and II MHC antigens, DMBA-treated skin grafts are only rejected by class I MHC-specific T cells which may account for the enhanced survival of the carcinogen-treated grafts.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

The MHC class II-associated invariant chain-derived peptide clip binds to the peptide-binding groove of class II molecules.

Major Histocompatibility Complex (MHC) class II proteins bind to peptides derived from processed foreign antigens, and display them on the cell surface of antigen presenting cells for recognition by CD4+ regulatory T lymphocytes. Prior to their binding to antigenic peptides in endosomal compartments, class II molecules are associated with a nested set of peptides CLIP derived from amino acids 80 to 107 of the invariant chain (Ii). Currently the interaction between the CLIP peptide and class II molecules is not clear. Using an FITC-labeled CLIP peptide and soluble empty class II molecules synthesized in insect cells, we have investigated the direct binding of the CLIP peptide to class II molecules, and the influence of localized polymorphic residues in the peptide-binding groove on the binding. We found that the human class II HLA-DR1 molecule contains a single-binding site for the CLIP peptide as well as the antigenic peptide MP19-31, as analysed by Scatchard analysis. Further studies also showed that occupancy of the peptide-binding groove by antigenic peptides inhibited the binding of CLIP to DR1 molecules and vice versa. Most importantly, the polymorphic residues beta 85 and 86, which define the major peptide-binding pocket, strikingly influence the CLIP-DR1 interaction, as assayed by the SDS-stability of class II-peptide complexes and the affinity of class II-peptide interactions. These data indicate that the peptide-binding pocket and thus the peptide-binding groove of the class II molecule are directly involved in the association with the CLIP peptide.

Antigens, Differentiation, B-Lymphocyte↗