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PubMed1995

MHC class I-like, class II-like and CD1 molecules: distinct roles in immunity.

Genes encoding MHC class I-like, class II-like and CD1 molecules have evolved to assume specific immunological functions. Some class I-like molecules, including H-2M3 and Qa-2, present formylated bacterial peptides or have distinct peptide-binding motifs. The class II-like DMA and DMB gene products play a role in presentation of peptide antigen by class II molecules. By contrast, CD1 molecules appear to have evolved separately into presenters of nonprotein antigens and into TCR ligands with specialized roles in the immune response. Thus, class I-like, class II-like and CD1 molecules appear either to serve important independent functions or to complement MHC class I and class II. It is expected that future efforts will increasingly reveal the functional ramifications of these molecules.

Animals↗

PubMed1996

Expression of beta 2-microglobulin-free HLA class I alpha-chains on activated T cells requires internalization of HLA class I heterodimers.

HLA class I molecules on activated T cells are expressed as heterodimers associated with beta 2-microglobulin (beta 2-m) and also beta 2-m-free HLA class I alpha-chains. Mechanisms leading to the expression of the activation associated beta 2-m-free HLA class I alpha-chains are poorly defined, however. Upon enzymatical removal of HLA class I alpha-chains on activated T cells, re-expression is observed within minutes upon reculture, reaching half-maximal levels within 1 hr. This process is independent of de novo protein synthesis and of export of newly synthesized proteins. Inhibition of the formation of coated pits by potassium depletion of cells abrogated the re-expression of HLA class I alpha-chains, suggesting that recycling events of HLA class I heterodimers via endosomal compartments are required for the generation of monoclonal antibody LA45-reactive alpha-chains. Furthermore, the rate of alpha-chain generation seems to be governed by the amount of cell surface-expressed HLA class I heterodimers. Taken together these findings suggest that beta 2-m-free HLA class I alpha-chains are generated during the process of class I heterodimer recycling.

Antibodies, Monoclonal↗

PubMed1993

The segment of invariant chain that is critical for association with major histocompatibility complex class II molecules contains the sequence of a peptide eluted from class II polypeptides.

Major histocompatibility complex class II molecules present peptides from an extracellular source of antigens to CD4+ T lymphocytes. The class II-associated invariant chain affects this role of alpha and beta polypeptides by restriction of peptide loading to endocytic vesicles. Up to now no specific portion of the invariant chain has been defined as the class II binding site. We constructed recombinant invariant chain genes and inspected association of the mutant invariant chains with class II polypeptides. Here we demonstrate that an extracytoplasmic sequence of the invariant chain (aa 81-109) that is only 23 residues away from the transmembrane region is essential for contact with class II polypeptides, whereas the remaining C-terminal part is dispensable for binding. The sequence of invariant-chain-derived peptides that were eluted from class II molecules is contained in this segment and may define the class II binding site of the invariant chain. The membrane-proximal position of this region suggests that the invariant chain and invariant-chain-derived peptides isolated from class II molecules bind to a domain distinct from the class II pocket.

Amino Acid Sequence↗

PubMed1991

A subpopulation of mouse cytotoxic T lymphocytes recognizes allogeneic H-2 class I antigens in the context of other H-2 class I molecules.

Recently, independent lines of evidence strongly suggested that peptides derived from one foreign major histocompatibility complex (MHC) molecule bound to another MHC molecule can give rise to multiple composite MHC complexes that are able to stimulate allo-(xeno)-reactive T cells. In this study, we describe that in vivo immunization of mice with cells mismatched with the recipient for a single class I antigen results in the induction of CD8+ cytotoxic T lymphocytes (CTL) specific for allogeneic class I locus products (Dd, Kd, Dq) in the context of other class I molecules (Ks, Kd, Kk) present on stimulator cells. Evidently, the target antigen for these class I-restricted alloreactive CTL is not the native class I molecule but peptides derived from endogenous processing of allogeneic class I products presented by class I molecules. Using a combination of limiting dilution and split-well analyses, we estimated for Kk-restricted Dq-specific alloreactive CTL a precursor frequency (CTLpf) that was approximately 10 times lower than the CTLpf for "classical" nonrestricted Dq-specific alloreactive CTL. These data suggest that H-2 class I peptides presented by intact H-2 class I molecules are allostimulatory, supporting the concept that the capacity for presentation of MHC peptides by MHC molecules constitutes a part of the allogeneic immune response.

Animals↗

PubMed1998

Morbidity differences by occupational class among men in seven European countries: an application of the Erikson-Goldthorpe social class scheme.

BACKGROUND: This paper describes morbidity differences according to occupational class among men from France, Switzerland, (West) Germany, Great Britain, the Netherlands, Denmark, and Sweden. METHODS: Data were obtained from national health interview surveys or similar surveys between 1986 and 1992. Four morbidity indicators were included. For each country, individual-level data on occupation were recorded according to one standard occupational class scheme: the Erikson-Goldthorpe social class scheme. To describe the pattern of morbidity by occupational class, odds ratios (OR) were calculated for each class using the average of the population as a reference. The size of morbidity differences was summarized by the OR of two broad hierarchical classes. All OR were age-adjusted. RESULTS: For all countries, a lower than average prevalence of morbidity was found for higher and lower administrators and professionals as well as for routine nonmanual workers, whereas a higher than average prevalence was found for skilled and unskilled manual workers and agricultural workers. Self-employed men were in general healthier than the average population. The relative health of farmers differed between countries. The morbidity difference between manual workers and the class of administrators and professionals was approximately equally large in all countries. Consistently larger inequality estimates, with no or slightly overlapping confidence intervals, were only found for Sweden in comparison with Germany. CONCLUSIONS: Thanks to the use of a common social class scheme in each country, a high degree of comparability was achieved. The results suggest that morbidity differences according to occupational class among men are very similar between different European countries.

Adult↗

PubMed1985

Altered distribution of class I and class II MHC antigens during acute pancreas allograft rejection in the rat.

The expression of MHC class I and class II antigens was investigated in a model of acute pancreas allograft rejection in the rat. Pancreaticoduodenal and duct-ligated DA(RT1a)-to-LEW(RT1(1] and LEW(RT1(1]-to-LEW.1U(RT1u) pancreas grafts were compared with normal organs and with LEW(RT1(1] isografts at daily intervals from day 1 to day 10 after transplantation. The results show profound changes of MHC antigen distribution in allografts during the process of rejection. Exocrine acinar cells, being class-I-antigen-negative in the normal pancreas, strongly express these antigens during rejection. Class II antigens, normally not found in pancreatic endothelia or parenchymal cells, appear in duct epithelia, acinar cells, and endothelia of big vessels. Endocrine islet cells and smooth muscle cells stay Ia-negative throughout the rejection process. Focal class I reactivity is also observed in acinar cells of pancreaticoduodenal isografts; but class II antigens are neither seen in parenchymal cells nor in endothelia of any isograft. Thus, in the rat pancreas allograft model, the induction of class II antigens is an early phenomenon characteristic of an ongoing immune response, and it provides a valuable new diagnostic criterion. Antibodies reactive exclusively with donor-haplotype antigens demonstrate an increase in donor-derived class I and class II antigen-positive interstitial cells in addition to parenchymal antigenic changes. A possible effect of the antigenic alteration described on the course of the rejection process is discussed.

Animals↗

PubMed1986

Expression of class I and class II major histocompatibility antigens in normal and transplanted human heart.

The expression of monomorphic determinants of class I and class II histocompatibility antigens in human heart before and after cardiac transplantation was examined using monoclonal antibodies and an immunoperoxidase technique. Thirty-five biopsy specimens were examined. Seven were from nontransplanted hearts and 28 were from patients who had received orthotopic cardiac transplantation 5-270 days previously. In normal hearts no class I was found on the surface of the myocardium, but intercalated discs were occasionally stained and interstitial structures (blood vessels and discrete mononuclear cells) strongly expressed the antigen. In contrast, of the 28 specimens from transplanted patients, 24 expressed class I antigen strongly on the outer surface and intercalated discs of the myocardium as well as on the interstitial structures. Class II antigen was not found on the myocardium of normal heart. It was present on small capillaries, the endothelia of some large capillaries, and discrete mononuclear cells. In 20 of 25 samples from transplant patients there was increased expression of class II antigen on interstitial structures but not on myocardium. The increased expression of class I antigen on the myocardium following transplantation may make it a potential target for cytotoxic T cells. The relevance of increased expression of class I and class II antigens in response to transplantation is discussed.

Adolescent↗

PubMed1991

Evidence that the fate of class II-disparate corneal grafts is determined by the timing of class II expression.

While the immune privilege nature of the eye affords significant protection to corneal grafts, immunologic rejection is the leading cause of graft failure. Class II antigens are normally absent or expressed at very low levels in normal cornea. The role that class II antigens play in causing graft rejection is particularly interesting. Class II molecules are present on many cells of the immune system, and therefore are important in modulating and mediating immune reactions. The absence of class II bearing cells in the cornea leads to the interesting issue of whether or not those antigens can induce immune rejection of a corneal graft. In the current study we have made use of a pair of congenic rat strains that differ only at class II loci to determine the impact of these antigens on corneal graft survival. Central corneal grafts were not rejected. Recipients preimmunized with skin grafts rejected 100% of the class II disparate corneas with a median survival time (MST) of 15.5 days. When class II disparate Langerhans-cell-containing (LC+) corneas were grafted, the corneas were not rejected, but they immunized the recipients as evidenced by the rejection of a second corneal graft on the contralateral eye. Immunofluorescent stains demonstrated transient expression of class II antigens on graft epithelium after transplantation. This temporary appearance of class II provides a target for rejection in the preimmunized animals but is of insufficient duration to both prime naive animals and provide a target for antigraft effectors.

Animals↗

PubMed1996

Evidence for the in vivo role of class II transactivator in basal and IFN-gamma induced class II expression in mouse tissue.

The class II transactivator (CIITA) is a protein that induces the transcription of MHC class II genes. We studied the expression of CIITA in vivo, comparing steady state levels of CIITA and class II mRNA in various mouse tissues. Many tissues in normal mice contained mRNA for CIITA, correlating with class II mRNA. The basal expression of CIITA and class II mRNA in mice with disrupted IFN-gamma genes (GKO mice) was similar to that in wild-type mice. Injection of rIFN-gamma strongly induced CIITA and class II mRNA: CIITA mRNA increased at 2 hr and declined to baseline by 48 hr, whereas class II mRNA increased at 24 hr and returned to baseline at 7 days. Proinflammatory stimuli that induce IFN-gamma production (allogeneic cells and LPS) induce CIITA and class II expression in wild-type mice, but not in GKO mice. CIITA induction by IFN-gamma was partially sensitive to cycloheximide, suggesting that another protein is required for CIITA induction. The data suggest that CIITA is a major regulator of basal and induced class II expression in vivo.

Animals↗

PubMed1996

Expression of MHC class I and class II antigens in pancreatic adenocarcinomas.

The antigens encoded by the major histocompatibility complex (MHC) are cell surface glycoproteins that play a fundamental role in the regulation of the immune response. Anomalous MHC expression in tumor cells has been viewed as an important feature to escape tumor recognition by immune cells. Low or absent MHC class I expression as well as ectopic MHC class II expression have been often observed to correlate with high grade malignancy and metastatic potential in a variety of human cancers. To date, very little investigation of MHC (HLA in man) class I and class II expression in human pancreatic cancer has been reported. We investigated this aspect on frozen sections of 8 pancreatic adenocarcinomas and 18 established in vitro cell lines. HLA class I was expressed in all but two cancers whereas de novo HLA class II expression was detected in 3 of 8 cancers. Interestingly, a hierarchy in the expression of the various subsets of HLA class II was found with HLA- DR > -DP > -DQ. Results on cell lines strongly resembled the ones obtained in cancer tissues. However, a peculiar feature was observed in certain cell lines. HLA class II antigens were expressed in only a few cell lines and in some of them a mixed population of positive and negative cells was found. Sorting and cloning of the two populations confirmed the existence of tumor cell clones with stable and distinct HLA class II phenotype. Taken together, these results indicate the cellular heterogeneity of pancreatic cancer cells with regard to the qualitative and quantitative expression of major histocompatibility complex genes, and may provide new insights for a better understanding of the tumorhost relationships in this extremely severe form of neoplasia.

Adenocarcinoma↗

PubMed2006

Job control, job demands, or social class? The impact of working conditions on the relation between social class and health.

BACKGROUND: The aim of the study was to investigate (1) how much of the association between health and social class is accounted by psychosocial working conditions, and (2) whether health is related to working conditions after controlling for social class. METHODS: The data derive from the surveys of the Helsinki health study, collected in 2000, 2001, and 2002 from 40-60 year old employees working for the City of Helsinki (n=8970, response rate 67%). The study measured occupation based social class and Karasek's demand-control model. The health outcomes were self rated health as less than good and limiting longstanding illness. Age adjusted prevalence percentages and fitted logistic regression models were calculated. RESULTS: The individual effects of social class and psychosocial working conditions on self rated health and limiting longstanding illness were strong among both men and women. The relation between social class and both health outcomes considerably attenuated when job control was controlled for, but was reinforced when controlling for job demands. Controlling for both job control and job demands attenuated the relation between social class and self rated health and limiting longstanding illness among women, however, was reinforced among men. CONCLUSIONS: A substantial part of the relation between social class and health could be attributed to job control, however, job demands reinforced the relation. Although the effect of social class is mediated by psychosocial working conditions, both social class and working conditions were related to health after mutual adjustments.

Adult↗

PubMed2003

MHC class I+ and class I- HPV16-associated tumours expressing the E7 oncoprotein do not cross-react in immunization/challenge experiments.

It has been demonstrated repeatedly that a high proportion of tumours derived from MHC class I+ precursors are MHC class I-. Since a major task in immunotherapy strategies for treatment of malignancies is to develop polyvalent tumour vaccines efficient against a broad spectrum of tumours, we have examined whether MHC class I+ cell-based tumour vaccines can cross-protect against homologous MHC class I- tumour challenge and vice versa. For these purposes, we have used two oncogenic cell lines induced independently by co-transfection of murine H-2b cells with E61E7 HPV16 and activated Ha-ras oncogenes, the tumours TC-1 (MHC class I+, HPV16 E7+) and E7+). Surprisingly, it was found that these two tumours do not cross-react, although both of them contain the crucial HPV16-coded tumour rejection antigen E7. Preimmunization with the MHC class I+ tumour did not protect against a subsequent challenge with the MHC class I- tumour and vice versa; however, immunization with the TC-1 tumour could protect syngeneic mice against the TC-1 tumour challenge and, similarly, immunization with the MK16/1/IIIABC tumour could protect mice against the MK16/1/IIIABC tumour challenge. If this finding can also be confirmed as a more general phenomenon with other MHC class I+ and class 1- tumours, it could have serious implications for design of immunotherapeutic vaccines and protocols.

Animals↗

PubMed2001

Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellular fate of MHC class II molecules.

MHC class II molecules associate with peptides through pocket interactions and the formation of hydrogen bonds. The current paradigm suggests that the interaction of side chains of the peptide with pockets in the class II molecule is responsible for the formation of stable class II-peptide complexes. However, recent evidence has shown that the formation of hydrogen bonds between genetically conserved residues of the class II molecule and the main chain of the peptide contributes profoundly to peptide stability. In this study, we have used I-A(k), a class II molecule known to form strong pocket interactions with bound peptides, to probe the general importance of hydrogen bond integrity in peptide acquisition. Our studies have revealed that abolishing hydrogen bonds contributed by positions 81 or 82 in the beta-chain of I-A(k) results in class II molecules that are internally degraded when trafficked through proteolytic endosomal compartments. The presence of high-affinity peptides derived from either endogenous or exogenous sources protects the hydrogen bond-deficient variant from intracellular degradation. Together, these data indicate that disruption of the potential to form a complete hydrogen bond network between MHC class II molecules and bound peptides greatly diminishes the ability of class II molecules to bind peptides. The subsequent failure to stably acquire peptides leads to protease sensitivity of empty class II molecules, and thus to proteolytic degradation before export to the surface of APCs.

Animals↗

PubMed2002

Proteasome, transporter associated with antigen processing, and class I genes in the nurse shark Ginglymostoma cirratum: evidence for a stable class I region and MHC haplotype lineages.

Cartilaginous fish (e.g., sharks) are derived from the oldest vertebrate ancestor having an adaptive immune system, and thus are key models for examining MHC evolution. Previously, family studies in two shark species showed that classical class I (UAA) and class II genes are genetically linked. In this study, we show that proteasome genes LMP2 and LMP7, shark-specific LMP7-like, and the TAP1/2 genes are linked to class I/II. Functional LMP7 and LMP7-like genes, as well as multiple LMP2 genes or gene fragments, are found only in some sharks, suggesting that different sets of peptides might be generated depending upon inherited MHC haplotypes. Cosmid clones bearing the MHC-linked classical class I genes were isolated and shown to contain proteasome gene fragments. A non-MHC-linked LMP7 gene also was identified on another cosmid, but only two exons of this gene were detected, closely linked to a class I pseudogene (UAA-NC2); this region probably resulted from a recent duplication and translocation from the functional MHC. Tight linkage of proteasome and class I genes, in comparison with gene organizations of other vertebrates, suggests a primordial MHC organization. Another nonclassical class I gene (UAA-NC1) was detected that is linked neither to MHC nor to UAA-NC2; its high level of sequence similarity to UAA suggests that UAA-NC1 also was recently derived from UAA and translocated from MHC. These data further support the principle of a primordial class I region with few class I genes. Finally, multiple paternities in one family were demonstrated, with potential segregation distortions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Induction of MHC class I presentation of exogenous antigen by dendritic cells is controlled by CD4+ T cells engaging class II molecules in cholesterol-rich domains.

We investigated interactions between CD4+ T cells and dendritic cells (DC) necessary for presentation of exogenous Ag by DC to CD8+ T cells. CD4+ T cells responding to their cognate Ag presented by MHC class II molecules of DC were necessary for induction of CD8+ T cell responses to MHC class I-associated Ag, but their ability to do so depended on the manner in which class II-peptide complexes were formed. DC derived from short-term mouse bone marrow culture efficiently took up Ag encapsulated in IgG FcR-targeted liposomes and stimulated CD4+ T cell responses to Ag-derived peptides associated with class II molecules. This CD4+ T cell-DC interaction resulted in expression by the DC of complexes of class I molecules and peptides from the Ag delivered in liposomes and permitted expression of the activation marker CD69 and cytotoxic responses by naive CD8+ T cells. However, while free peptides in solution loaded onto DC class II molecules could stimulate IL-2 production by CD4+ T cells as efficiently as peptides derived from endocytosed Ag, they could not stimulate induction of cytotoxic responses by CD8+ T cells to Ag delivered in liposomes into the same DC. Signals requiring class II molecules loaded with endocytosed Ag, but not free peptide, were inhibited by methyl-beta-cyclodextrin, which depletes cell membrane cholesterol. CD4+ T cell signals thus require class II molecules in cholesterol-rich domains of DC for induction of CD8+ T cell responses to exogenous Ag by inducing DC to process this Ag for class I presentation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Functional characterization of class Ia- and non-class Ia-restricted Chlamydia-reactive CD8+ T cell responses in humans.

CD8(+) T cells are a key immune component for the eradication of many intracellular pathogens. This study aims to characterize the human CD8(+) T cell response to naturally processed chlamydial Ags in individuals exposed to the intracellular pathogen Chlamydia trachomatis. By using C. trachomatis-infected autologous dendritic cells (DCs) as stimulators, Chlamydia-reactive CD8(+) T cell responses were detected in all 10 individuals tested. The majority of the Chlamydia-reactive CD8(+) T cells were non-MHC class Ia restricted in all three of the individuals tested. From one donor, three non-class Ia-restricted and two class Ia-restricted Chlamydia-specific CD8(+) T cells were cloned and characterized further. All five T cell clones secreted IFN-gamma in response to autologous DCs infected with viable Chlamydia, but not with DCs pulsed with inactivated chlamydial elementary bodies. MHC class Ia-restricted and non-class Ia-restricted responses were inhibited by DC treatment with a proteasomal inhibitor and an endoplasmic reticulum-Golgi transport inhibitor, suggesting that these T cells recognize a peptide Ag translocated to the host cell cytosol during infection that is processed via the classical class Ia Ag-processing pathway. Even though both restricted and nonrestricted CD8(+) T cells produced IFN-gamma in response to Chlamydia-infected fibroblasts, only the non-class Ia-restricted cells were lytic for these targets. The class Ia-restricted CTLs, however, were capable of cytolysis as measured by redirected killing. Collectively, these data demonstrate that both class Ia-restricted and non-classically restricted CD8(+) T cells are elicited in C. trachomatis-exposed individuals. Their role in host immunity remains to be elucidated.

Antigen Presentation↗

PubMed1999

TNF-alpha suppresses IFN-gamma-induced MHC class II expression in HT1080 cells by destabilizing class II trans-activator mRNA.

Precise regulation of MHC class II gene expression is crucial for development and function of the immune system. Class II trans-activator (CIITA) has been shown to be required for constitutive and IFN-gamma-induced MHC class II transcription. TNF-alpha is commonly coexpressed with IFN-gamma during immune-mediated inflammatory responses and modulates IFN-gamma-stimulated MHC class II expression. The effect of TNF-alpha on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF-alpha suppresses IFN-gamma-induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF-alpha also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN-gamma or tetracycline, was destabilized in the presence of TNF-alpha, suggesting that TNF-alpha utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF-alpha blocked IFN-gamma-induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF-beta or IFN-beta. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.

Fibrosarcoma↗

PubMed2001

Cross-linking of MHC class II molecules with anti-MHC class II antibody or epitope peptide prevents resting B lymphocyte differentiation by inhibiting NF-kappaB-dependent gene expression.

To understand the mechanism(s) involved in anti-MHC class II antibody-mediated inhibition of B lymphocyte differentiation, we investigated the influence of anti-MHC class II antibody treatment on the gene expression of IL-6 in resting B lymphocytes, which had been known to be one of the most important cytokines involved in B cell physiology. The level of the IL-6 mRNA expression in the LPS-stimulated resting B cells was remarkably reduced by treatment of the corresponding anti-MHC class II antibodies. The inhibition was exerted in haplotype-specific and dose-dependent manners. Similarly, MHC class II-restricted epitope peptides, when applied as a dimer form, revealed haplotype-specific and dose-dependent inhibitory effects on the IL-6 gene expression by the LPS-stimulated B cells. In addition, treatment of the anti-MHC class II antibody and MHC class II-restricted epitope peptide inhibited, in haplotype-specific and dose-dependent manners, the activation of NF-kappaB, which had been known to be one of the critical transcription factors involved in the IL-6 gene expression. Interestingly, however, exogenous addition of the recombinant IL-6 did not reverse this inhibitory effect by the anti-MHC class II antibody. These results suggest that conjugation of the MHC class II molecules by the anti-MHC class II antibody inhibited B cell differentiation, possibly through the interruption of signaling pathways leading to the IL-6 gene expression via NF-kappaB activation in B lymphocytes.

Animals↗