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PubMed1989

Class I and class II regions of the major histocompatibility complex both contribute to individual odors in congenic inbred strains of rats.

The major histocompatibility complex (MHC) of the rat has three regions--A (class I), B/D (class II), and C/E (class I)--and congenic strains are available which differ in each of these regions. We used the habituation-dishabituation procedure to examine the ability of PVG-RT1u male rats to discriminate between the urinary odors of congenic rat strains which differ genetically only at certain individual regions of the MHC. The results of five experiments indicate that discrimination can be made between urine from rats which differ in all three regions of the MHC (PVG vs. PVG-RT1av1 donors), only in the class I A region (PVG vs. PVG.R1 donors), only in the class I C/E region (PVG.R19 vs. PVG-RT1av1 donors), only in the class II B/D region (PVG.R1 vs. PVG.R19 donors), and in all regions except the classical class IA locus (PVG-RT1av1 vs. PVG.R1 donors). These results indicate that all of the MHC regions may contribute to the individual odors of rats.

Animals↗

PubMed2005

Patterns of variability at the major histocompatibility class II alpha locus in Atlantic salmon contrast with those at the class I locus.

In order to investigate the mechanisms creating and maintaining variability at the major histocompatibility (MH) class II alpha (DAA) locus we examined patterns of polymorphism in two isolated Atlantic salmon populations which share a common post-glacial origin. As expected from their common origin, but contrary to the observation at the MH class I locus, these populations shared the majority of DAA alleles: out of 17 sequences observed, 11 were common to both populations. Recombination seems to play a more important role in the origin of new alleles at the class II alpha locus than at the class I locus. A greater than expected proportion of sites inferred to be positively selected (potentially peptide binding residues, PBRs) were found to be involved in recombination events, suggesting a mechanism for increasing MH variability through an interaction between recombination and natural selection. Thus it appears that although selection and recombination are important mechanisms for the evolution of both class II alpha and class I loci in the Atlantic salmon, the pattern of variability differs markedly between these classes of MH loci.

Amino Acid Sequence↗

PubMed2004

Expression of MHC class I, MHC class II, and cancer germline antigens in neuroblastoma.

BACKGROUND: Neuroblastoma is the most common solid extracranial tumor in childhood, still with poor survival rates for metastatic disease. Neuroblastoma cells are of neuroectodermal origin and express a number of cancer germline (CG) antigens. These CG antigens may represent a potential target for immunotherapy such as peptide-based vaccination strategies. OBJECTIVE: The purpose of this study was to analyze the presence of MAGE-A1, MAGE-A3/A6, and NY-ESO-1 on an mRNA and protein level and to determine the expression of MHC class I and MHC class II antigens within the same tumor specimens. METHODS: A total of 68 tumors were available for RT-PCR, and 19/68 tumors were available for immunohistochemical (IHC) analysis of MAGE-A1, MAGE-A3/A6, and NY-ESO-1. In parallel, the same tumors were stained with a panel of antibodies for MHC class I and MHC class II molecules. RESULTS: Screening of 68 tumor specimens by RT-PCR revealed expression of MAGE-A1 in 44%, MAGE-A3/A6 in 21%, and NY-ESO-1 in 28% of cases. Immunohistochemistry for CG antigens of selected tumors showed good agreement between protein and gene expression. However, staining revealed a heterogeneous expression of CG antigens. None of the selected tumors showed MHC class I or MHC class II expression. CONCLUSIONS: mRNA expression of MAGE-A1, MAGE-A3/A6, and NY-ESO-1 is congruent with the protein expression as determined by immunohistochemistry. The heterogeneous CG-antigen expression and the lack of MHC class I and II molecules may have implications for T-cell-mediated immunotherapy in neuroblastoma.

Antigens, Neoplasm↗

PubMed1996

Interferon gamma (IFNgamma) gene transfer of an EMT6 tumor that is poorly responsive to IFNgamma stimulation: increase in tumor immunogenicity is accompanied by induction of a mouse class II transactivator and class II MHC.

Abstract Interferon gamma (IFNgamma) is an important cytokine with immunomodulatory properties that include activation of immune cells and induction of class I and class II major histocompatibility complex antigens. In this study a retroviral vector was used to introduce the IFNgamma gene into EMT6 tumor cells to assess the effect of IFNgamma gene expression on tumor immunogenicity. Transfectants were selected in G418-containing tissue-culture medium and were determined to express the inserted IFNgamma gene by reverse transcriptase/polymerase chain reaction. Flow-cytometric analysis revealed that parental unmodified EMT6 cells constitutively expressed only class I MHC and were poorly responsive to exogenous IFNgamma stimulation, whereas class II MHC was induced in IFNgamma-transfected cells. The induction of class II MHC in IFNgamma-transfected cells correlated with the expression of a mouse class II transactivator gene that was dormant in unmodified or mock-transfected cells. In addition, IFNgamma-gene-transfected tumor cells were found to secrete up to 17 ng IFN (equivalent to 75 units/10(6) cells) by enzyme-linked immunosorbent assay (ELISA). Whereas parental EMT6 cells grew unchecked, the growth of genetically modified tumor cells was significantly inhibited in immunocompetent mice. Rechallenge of animals that rejected an IFNgamma-transfected EMT6 clone (EMT6-B17) with parental EMT6 cells resulted in tumor rejection, suggesting that IFNgamma-transfected EMT6 cells were able to induce long-term immunity. Mixing experiments using gene-transfected and unmodified tumor cells demonstrated that 10% of IFNgamma-transfected cells in the population was sufficient to protect mice against subsequent challenge with tumorigenic EMT6 cells. These studies demonstrate that the immunogenicity of tumor cells that are poorly responsive to exogenous IFNgamma can be enhanced by inserting and expressing the IFNgamma transgene. These findings also suggest a role for class II MHC in reducing tumorigenicity of the EMT6 tumor and inducing long-term tumor immunity.

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↗

PubMed1989

Flavivirus infection up-regulates the expression of class I and class II major histocompatibility antigens on and enhances T cell recognition of astrocytes in vitro.

West Nile virus (WNV) infection of astrocytes can up-regulate their expression of both class I and class II major histocompatibility complex (MHC) antigens as determined by flow cytometry with monoclonal antibodies specific for class I and class II MHC antigens. The up-regulation of class I MHC antigen expression could be partly caused by interferon secreted after WNV infection because the synthetic interferon inducer polyinosinic-polycytidylic acid (poly I:C) has similar effects. In contrast the up-regulation of class II MHC antigen expression was not induced by poly I:C. The increased MHC antigen expression by WNV infection had significant effects on T cell recognition. Thus, WNV and influenza virus A/WSN double-infected astrocytes but not astrocytes infected by A/WSN alone were lysed by influenza virus-immune cytotoxic T cells. Similarly, WNV-infected astrocytes were better stimulators than normal astrocytes for a class II MHC-reactive T cell line, both in terms of T cell proliferation and interleukin release.

Animals↗

PubMed1989

CD8 is involved in both class I- and class II-induced proliferation of a cytolytic T-cell clone with dual specificity for HLA-B27 and HLA-DR2 antigens.

A CD3+ CD4- CD8+ cytolytic T-lymphocyte (CTL) clone, CTL 47, could be induced to proliferate in the presence of exogenous interleukin 2 by either HLA-B27.1+ or HLA-DR2+ cells. B27.1-induced proliferation was strongly and equally inhibited by an anti-B27 and by an anti-CD8 monoclonal antibody (MoAb). DR2-induced proliferation was inhibited by the same anti-CD8 MoAb less efficiently and with a different time course than anti-class II blocking, only being significant when the antibody was added ab initio or very early during the assay. These results indicate that CD8 is essential for class I-induced proliferation but that it also enhances class II-induced stimulation of this CTL clone. It is proposed that the necessary role of CD8 in class I-induced proliferation is related to its interaction with the same class I molecule bound by the T-cell receptor. The accessory role in class II-induced proliferation would be due to an additive effect on the avidity of cell adhesion, resulting from interaction of CD8 with the class I antigens on the stimulator cell, or perhaps to a regulatory role of CD8 as a transducer of early signals for T-cell activation.

Antibodies, Monoclonal↗

PubMed2006

Comparison of second molar eruption patterns in patients with skeletal Class II and skeletal Class I malocclusions.

INTRODUCTION: The eruptive positions of the second molars in Class I and Class II malocclusions were studied. METHODS: Pretreatment records of 221 patients with a mean age of 11.3 years were evaluated. About 19% of them had skeletal Class I, 31% had skeletal maxillary Class II, and 50% had skeletal mandibular Class II malocclusions. RESULTS: The mean values of the dental and chronologic ages of the subjects were similar. The eruptive positions in relation to a reference line, the developmental stages of the patients' second molars and dental ages were recorded from the panoramic roentgenograms. The distribution of the various developmental stages in each malocclusion group was similar, and no association between skeletal malocclusion and dental developmental stage of the second molars was encountered. The eruptive position of the maxillary second molars was more occlusal only in the oldest maxillary Class II group, above 12 years of age (P = .02). CONCLUSIONS: These results support, in part, previous reports suggesting that the maxillary second molars may erupt earlier in patients with skeletal maxillary Class II malocclusions.

Analysis of Variance↗

PubMed2000

Generation of both MHC class I- and class II-restricted antigenic peptides from exogenously added ovalbumin in murine phagosomes.

The phagosome fraction derived from a murine macrophage cell line (J774.1), which had internalized ovalbumin (OVA)-coated latex beads, was isolated. The peptides recovered from the phagosome fraction were separated on reverse phase HPLC and each fraction was analyzed for the content of either major histocompatibility complex (MHC) class I- or class II-restricted OVA-derived peptide. Both peptides were detected in the phagosome fraction after less than 15 min of internalization. It was also indicated that phagosomes degrade OVA protein into both MHC class I- and class II-restricted antigenic peptides by employing the same types of cathepsins. Furthermore, the results suggest that the MHC class I-restricted peptide rapidly exits from the phagosome to the cytosol. These findings illustrate a potential role for phagosomes not only in MHC class II-restricted but also in MHC class I-restricted exogenous antigen presentation pathways. Our results also point to the vital role of phagosomes in non-cytosolic antigen presentation pathway, in which further degradation of antigens by the proteasome is dispensable.

Amino Acid Sequence↗

PubMed1993

Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens.

This study demonstrates that a syngeneic specific cytotoxic T lymphocyte (CTL) response to a class I major histocompatibility complex (MHC) positive tumour requires dual processing and recognition of tumour antigens. One type of antigen is processed and expressed in association with class I MHC at the surface of intact tumour cells. It is recognized by CD8 alpha, beta TCR CTL in vitro and by protective immune T cells in vivo and thus functions as a tumour-associated transplantation antigen (TATA). The other type of antigen is processed and expressed by distinct host APC in association with class II MHC. This is recognized by immune CD4 T cells which function as essential helper cells in the generation of the CD8 CTL response. These conclusions are supported by cell depletion and reconstitution experiments as well as by blocking experiments with monoclonal antibodies using the highly metastatic class II negative murine lymphoma ESb as a model system. The existence of two types of cognate T cell responses in a syngeneic anti-tumour response was directly proved by the establishment of two types of tumour specific T cell lines which required as co-stimulator either MHC class II positive APC or IL-2. In suboptimal mixed lymphocyte tumour cell cultures either of these co-stimulator functions was found to be limiting the overall anti-tumour CTL response. The generation of the tumour specific CTL response could be blocked by monoclonal antibodies against all the molecules involved in the cognate interactions (i.e. class I MHC, CD8, class II MHC, CD4 and TCR) but not by anti-CD2 or anti-IgG. The strict requirement for helper cells and APC could be bypassed by the addition of recombinant IL-2 but optimal triggering of CD8 CTL-precursor required viable tumour stimulator cells. This well characterized in vitro assay may be useful (i) for monitoring the immune status of CD4 and CD8 immune T cells separately, for instance of tumour bearing and/or treated animals and (ii) for the development and testing of potent tumour cell vaccines with T cell stimulatory and/or co-stimulatory activities.

Animals↗

PubMed1991

Islet transplantation in experimental diabetes of the rat. XIII. Cryopreservation reduces MHC class II but not class I antigens of rat pancreatic islets.

Pretreatment of islet allografts prior to transplantation may reduce islet immunogenicity and prolong graft acceptance. We have studied the MHC antigen reducing effect of cryopreservation onto rat pancreatic islets performing indirect immunofluorescence tests and peroxidase-anti-peroxidase staining (PAP). Three different freezing programs were used. Program A: 0.5 degrees C/min to -35 degrees C and 1 degree C/min from -35 to -100 degrees C. Program B: 2 degrees C/min to -35 degrees C and 6 degrees C/min from -35 to -100 degrees C. Program C: 0.25 degrees C/min to -40 degrees C. Cryopreservation clearly reduced the number of class II antigen positive cells per islet in all cases. Program A was most effective with 45.5% of class II antigen negative islets compared to 6.4% of class II antigen negative fresh islets as shown by indirect immunofluorescence. The class II antigen reducing effect of cryopreservation proved to be permanent and not only temporary. Reduced class II antigen expression of cryopreserved islets could not be reestablished by incubation of the islets with rat IFN. A combination of cryopreservation followed by a 10 day culture period proved to be most effective with 85.6% of class II antigen negative islets. In contrast, we could not show any effect of cryopreservation on class I antigen expression. Viability of the cryopreserved rat islets was shown in-vitro by glucose stimulated insulin secretion.

Animals↗

PubMed1992

Hormonal regulation of major histocompatibility complex class I genes in rat thyroid FRTL-5 cells: thyroid-stimulating hormone induces a cAMP-mediated decrease in class I expression.

Thyrocytes normally express major histocompatibility complex (MHC) class I, but not class II, cell surface antigens. A rat thyrocyte cell line, FRTL-5, also expresses MHC class I antigens, in addition to a variety of thyroid-specific genes. Treatment of FRTL-5 thyrocytes with physiological concentrations of thyroid-stimulating hormone (TSH) has been shown to induce increased expressed of thyroglobulin and thyroid peroxidase but to simultaneously decrease expression of the TSH receptor. The reduction in TSH receptor expression by TSH is cAMP mediated. In the present study, it is demonstrated that, in thyrocytes treated with TSH, MHC class I expression decreases concomitant with the decrease in TSH receptor expression. This decreased expression is evidenced by reduced cell surface levels of MHC class I antigens, by reduced steady-state RNA levels, and by reduced transcription of the class I genes. TSH-mediated reduction of MHC class I gene transcription in FRTL-5 cells was mapped to a region within 135 base pairs of the promoter.

Animals↗

PubMed1993

Specific suppression of major histocompatibility complex class I and class II genes in astrocytes by brain-enriched gangliosides.

The effect of brain-enriched gangliosides on constitutive and cytokine-inducible expression of major histocompatibility complex (MHC) class I and II genes in cultured astrocytes was studied. Before treatment with gangliosides, astrocytes expressed constitutive MHC class I but not class II molecules, however, the expression of both MHC class I and II cell surface molecules on astrocytes was induced to high levels by interferon gamma (IFN-gamma). Constitutive and IFN-gamma-inducible expression of MHC class I and II molecules was suppressed by treatment of astrocytes with exogenous bovine brain gangliosides in a dose-dependent manner. Constitutive and induced MHC class I and II mRNA levels were also suppressed by gangliosides, indicating control through transcriptional mechanisms. This was consistent with the ability of gangliosides to suppress the binding activity of transcription factors, especially NF-kappa B-like binding activity, important for the expression of both MHC class I and II genes. These studies may be important for understanding mechanisms of central nervous system (CNS)-specific regulation of major histocompatibility molecules in neuroectodermal cells and the role of gangliosides in regulating MHC-restricted antiviral and autoimmune responses within the CNS.

Animals↗

PubMed1998

Alteration of a single hydrogen bond between class II molecules and peptide results in rapid degradation of class II molecules after invariant chain removal.

To characterize the importance of a highly conserved region of the class II beta chain, we introduced an amino acid substitution that is predicted to eliminate a hydrogen bond formed between the class II molecule and peptide. We expressed the mutated beta chain with a wild-type alpha chain in a murine L cell by gene transfection. The mutant class II molecule (81betaH-) assembles normally in the endoplasmic reticulum and transits the Golgi complex. When invariant chain (Ii) is coexpressed with 81betaH-, the class II-Ii complex is degraded in the endosomes. Expression of 81betaH- in the absence of Ii results in a cell surface expressed molecule that is susceptible to proteolysis, a condition reversed by incubation with a peptide known to associate with 81betaH-. We propose that 81betaH- is protease sensitive because it is unable to productively associate with most peptides, including classII-associated invariant chain peptides. This model is supported by our data demonstrating protease sensitivity of peptide-free wild-type I-Ad molecules. Collectively, our results suggest both that the hydrogen bonds formed between the class II molecule and peptide are important for the integrity and stability of the complex, and that empty class II molecules are protease sensitive and degraded in endosomes. One function of DM may be to insure continuous groove occupancy of the class II molecule.

Amino Acid Substitution↗

PubMed1993

Immunization of mice with human immunodeficiency virus glycoprotein gp160 peptide 315-329 induces both class I- and class II-restricted T cells: not all T cells can respond to whole molecule stimulation.

The V3 loop of human immunodeficiency virus (HIV) glycoprotein gp160 is of interest as a possible site for protective immune responses. This article examines the murine T cell response to peptide 315-329 derived from HIV gp160. Surprisingly, immunization with peptide in complete Freund's adjuvant induced class I-restricted T cells as well as class II-restricted T cells. These data suggest that this peptide may have the unusual ability to enter the class I antigen processing pathway. Strategies that employ V3 loop peptides to induce protective immunity must generate T cells that can recognize epitopes derived from whole molecules in vivo. Therefore, peptide-induced T cells were tested for their ability to respond to naturally processed forms of gp120 and gp160 whole-molecule preparations. Peptide induced class I-restricted cells were capable of recognizing transfectants expressing gp160. However, only one of two class II-restricted T cell lines was capable of recognizing soluble whole molecules. This indicates that peptide immunization induces T cells that recognize a class II-restricted determinant that is not generated during normal processing of whole molecules. We have also examined the response of peptide primed T cells to lipidated peptide antigens. Lipidated peptides are generally considered to have increased antigenicity and immunogenicity as compared to normal peptides. However, lipidation of peptide 315-329 damaged both the class I- and II-restricted determinants, indicating that lipidation is not always desirable. The data presented here highlight a potential serious problem in the use of peptide vaccines, in that peptide immunization may not always induce T cells that can protect against a viral challenge.

Animals↗

PubMed2005

Curative antitumor immune response is optimal with tumor irradiation followed by genetic induction of major histocompatibility complex class I and class II molecules and suppression of Ii protein.

Transfecting genes into tumors, to upregulate major histocompatibility complex (MHC) class I and class II molecules and inhibit MHC class II associated invariant chain (Ii), induces a potent anti-tumor immune response when preceded by tumor irradiation, in murine RM-9 prostate carcinoma. The transfected genes are cDNA plasmids for interferon-gamma (pIFN-gamma), MHC class II transactivator (pCIITA), an Ii reverse gene construct (pIi-RGC), and a subtherapeutic dose of adjuvant IL-2 (pIL-2). Responding mice rejected challenge with parental tumor and demonstrated tumor-specific cytotoxic T lymphocytes (CTLs). We have extended our investigation to determine the relative roles of each one of the four plasmids pIFN-gamma, pCIITA, pIi-RGC, and pIL-2 in conjunction with radiation for the induction of a curative immune response. Upregulation of MHC class I with pIFN-gamma or class II with pCIITA, separately, does not lead to a complete response even if supplemented with pIL-2 or pIi-RGC. An optimal and specific antitumor response is achieved in more than 50% of the mice when, after tumor irradiation, tumor cells are converted in situ to a MHC class I+/class II+/Ii- phenotype with pIFN-gamma, pCIITA, pIi-RGC, and pIL-2. We demonstrate further that both CD4+ helper T cells and CD8+ cytotoxic T cells are essential for induction of an antitumor response because in vivo depletion of either subset abrogates the response. The radiation contributes to the gene therapy by causing tumor debulking and increasing the permeability of tumors to infiltration of inflammatory cells.

Animals↗

PubMed1994

Differences in dental arch morphology among adult females with untreated Class I and Class II malocclusion.

The purpose of the study was to evaluate differences in dental arch morphology among an orthodontic sample of 386 untreated adult females between 17 and 68 years of age, categorized by age group (17-25 years, 26-35 years, or 35+ years) and malocclusion (Class I, Class II division 1, or Class II division 2). The results show that both maxillary and mandibular dental arch size were significantly larger for the younger age group. Arch shape was relatively shorter and wider for the oldest age group. Palatal height was greatest for the youngest age group and least for the oldest group. Subjects with Class II malocclusion had significantly smaller arches, greater maxillary incisor irregularity, and less mandibular incisor irregularity than patients with Class I malocclusion. Subjects with Class II division 1 malocclusion had greater palatal heights and relatively longer/narrower maxillary dental arches than subjects with Class II division 2 malocclusion.

Adolescent↗

PubMed2004

Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer.

Cervical cancer is a multifactorial disease and infection by oncogenic human papilloma viruses represents the main environmental risk factor. Only a subset of infections becomes persistent and develops into cancer, implying that genetic susceptibility factors are needed for malignant progression. Here, we use a population-based cohort of affected sib-pairs (ASPs) to examine the role of the human leukocyte antigen (HLA) class I and class II loci in cervical cancer susceptibility. Analysis of 278 ASPs revealed significant excess genetic sharing for all three HLA class II loci studied, DPB1, DQB1 and DRB1, with the strongest evidence for DQB1 and DRB1. No evidence of excess sharing was observed for the HLA class I HLA-B and HLA-A loci. When the material was stratified on the basis of the DQB1*0602/DRB1*1501 susceptibility haplotype, carriers showed significant sharing for all loci, whereas non-carriers showed no evidence of excess genetic sharing at any of the loci. However, for the DPB1 locus there was no difference in allele frequency between carriers and non-carriers indicating that the effect seen in DPB1 is not simply due to linkage disequilibrium. Our results show that the HLA class II represents a major genetic susceptibility locus to cervical cancer in contrary to the class I that do not appear to have a significant impact on predisposition to the disease. The strongest class II effects are coming from the DQB1 and DRB1 loci, but the DPB1 locus also contributes to the susceptibility to cervical cancer.

Cohort Studies↗