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Major Histocompatibility Complex (major + histocompatibility_complex)
Kinds of Major Histocompatibility Complex Terms modified by Major Histocompatibility Complex Selected AbstractsBALANCING SELECTION, RANDOM GENETIC DRIFT, AND GENETIC VARIATION AT THE MAJOR HISTOCOMPATIBILITY COMPLEX IN TWO WILD POPULATIONS OF GUPPIES (POECILIA RETICULATA)EVOLUTION, Issue 12 2006Cock van Oosterhout Abstract Our understanding of the evolution of genes of the major histocompatibility complex (MHC) is rapidly increasing, but there are still enigmatic questions remaining, particularly regarding the maintenance of high levels of MHC polymorphisms in small, isolated populations. Here, we analyze the genetic variation at eight microsatellite loci and sequence variation at exon 2 of the MHC class IIB (DAB) genes in two wild populations of the Trinidadian guppy, Poecilia reticulata. We compare the genetic variation of a small (Ne, 100) and relatively isolated upland population to that of its much larger (Ne, 2400) downstream counterpart. As predicted, microsatellite diversity in the upland population is significantly lower and highly differentiated from the population further downstream. Surprisingly, however, these guppy populations are not differentiated by MHC genetic variation and show very similar levels of allelic richness. Computer simulations indicate that the observed level of genetic variation can be maintained with overdominant selection acting at three DAB loci. The selection coefficients differ dramatically between the upland (s 0.2) and lowland (s, 0.01) populations. Parasitological analysis on wild-caught fish shows that parasite load is significantly higher on upland than on lowland fish, which suggests that large differences in selection intensity may indeed exist between populations. Based on the infection intensity, a substantial proportion of the upland fish would have suffered direct or indirect fitness consequences as a result of their high parasite loads. Selection by parasites plays a particularly important role in the evolution of guppies in the upland habitat, which has resulted in high levels of MHC diversity being maintained in this population despite considerable genetic drift. [source] Remodeling of the actin cytoskeleton of target hepatocytes and NK cells during induction of apoptosisCYTOSKELETON, Issue 2 2001W. Marty Blom Abstract Natural Killer cells are immune cells that recognize and eliminate altered and non-self cells from the circulation. To study the interaction between NK cells and target cells, we set up an experimental system consisting of rat Interleukin-2 activated Natural Killer cells (A-NK cells) and rat hepatocytes with a masked Major Histocompatibility Complex (MHC). The masking of the MHC induces recognition of the hepatocytes by the NK cells as non-self. We showed that in vitro apoptosis is rapidly induced in the hepatocytes [Blom et al., 1999] after co-incubation with A-NK cells. Now we describe the morphological changes that occur during and after interaction of A-NK cells with hepatocytes. Confocal laser scanning microscopy showed that the actin cytoskeleton of the NK cells was remodeled during attack of hepatocytes. Some NK cells were in close contact with the hepatocytes while others had formed actin-containing dendrites of varying length that made contact with the hepatocytes. However, dendrite formation is not obligatory for induction of apoptosis because cells that were unable to form these did induce FAS-dependent apoptosis in hepatocytes. Apparently both direct as well as distant contact resulted in apoptosis. Formation of the dendrites was calcium-dependent as EGTA largely prevented it. Importantly, chelation of the calcium also suppressed killing of the hepatocytes. Within 1 h after addition of the A-NK cells, morphological changes in hepatocytes that are characteristic of apoptosis, such as the formation of apoptotic bodies and fragmented nuclei, became apparent. Specifically, the actin cytoskeleton of the hepatocytes was remodeled resulting in the formation of the apoptotic bodies. Inhibition of caspase activity by z-Val-Ala-DL-Asp-fluoromethylketone (100 ,M) partly protected against the rearrangement of the actin filaments in the hepatocytes. Cell Motil. Cytoskeleton 49:78,92, 2001. © 2001 Wiley-Liss, Inc. [source] The magnocellular theory of developmental dyslexiaDYSLEXIA, Issue 1 2001John Stein Abstract Low literacy is termed ,developmental dyslexia' when reading is significantly behind that expected from the intelligence quotient (IQ) in the presence of other symptoms,incoordination, left,right confusions, poor sequencing,that characterize it as a neurological syndrome. 5,10% of children, particularly boys, are found to be dyslexic. Reading requires the acquisition of good orthographic skills for recognising the visual form of words which allows one to access their meaning directly. It also requires the development of good phonological skills for sounding out unfamiliar words using knowledge of letter sound conversion rules. In the dyslexic brain, temporoparietal language areas on the two sides are symmetrical without the normal left-sided advantage. Also brain ,warts' (ectopias) are found, particularly clustered round the left temporoparietal language areas. The visual magnocellular system is responsible for timing visual events when reading. It therefore signals any visual motion that occurs if unintended movements lead to images moving off the fovea (,retinal slip'). These signals are then used to bring the eyes back on target. Thus, sensitivity to visual motion seems to help determine how well orthographic skill can develop in both good and bad readers. In dyslexics, the development of the visual magnocellular system is impaired: development of the magnocellular layers of the dyslexic lateral geniculate nucleus (LGN) is abnormal; their motion sensitivity is reduced; many dyslexics show unsteady binocular fixation; hence poor visual localization, particularly on the left side (left neglect). Dyslexics' binocular instability and visual perceptual instability, therefore, can cause the letters they are trying to read to appear to move around and cross over each other. Hence, blanking one eye (monocular occlusion) can improve reading. Thus, good magnocellular function is essential for high motion sensitivity and stable binocular fixation, hence proper development of orthographic skills. Many dyslexics also have auditory/phonological problems. Distinguishing letter sounds depends on picking up the changes in sound frequency and amplitude that characterize them. Thus, high frequency (FM) and amplitude modulation (AM) sensitivity helps the development of good phonological skill, and low sensitivity impedes the acquisition of these skills. Thus dyslexics' sensitivity to FM and AM is significantly lower than that of good readers and this explains their problems with phonology. The cerebellum is the head ganglion of magnocellular systems; it contributes to binocular fixation and to inner speech for sounding out words, and it is clearly defective in dyslexics. Thus, there is evidence that most reading problems have a fundamental sensorimotor cause. But why do magnocellular systems fail to develop properly? There is a clear genetic basis for impaired development of magnocells throughout the brain. The best understood linkage is to the region of the Major Histocompatibility Complex (MHC) Class 1 on the short arm of chromosome 6 which helps to control the production of antibodies. The development of magnocells may be impaired by autoantibodies affecting the developing brain. Magnocells also need high amounts of polyunsaturated fatty acids to preserve the membrane flexibility that permits the rapid conformational changes of channel proteins which underlie their transient sensitivity. But the genes that underlie magnocellular weakness would not be so common unless there were compensating advantages to dyslexia. In developmental dyslexics there may be heightened development of parvocellular systems that underlie their holistic, artistic, ,seeing the whole picture' and entrepreneurial talents. Copyright © 2001 John Wiley & Sons, Ltd. [source] Binding interactions between peptides and proteins of the class II Major Histocompatibility ComplexMEDICINAL RESEARCH REVIEWS, Issue 2 2002Benjamin J. McFarland Abstract The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators. © 2002 John Wiley & Sons, Inc. Med Res Rev, 22, No. 2, 168,203, 2002; DOI 10.1002/med.10006 [source] Polymorphic Alu Insertions and their Associations with MHC Class I Alleles and Haplotypes in the Northeastern ThaisANNALS OF HUMAN GENETICS, Issue 4 2005D. S. Dunn Summary Polymorphic Alu insertions (POALINs) are known to contribute to the strong polymorphic nature of the Major Histocompatibility Complex (MHC). Previous population studies on MHC POALINs were limited to only Australian Caucasians and Japanese. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA-A and -B associations, and the three and four locus alpha block POALIN haplotype frequencies in the Northeastern (NE) Thai population. Of the five POALINs, the lowest frequency was 0.018 for AluyHF and the highest frequency was 0.292 for AluyHJ and AluyHG. The strongest positive associations between the POALINs and HLA class I alleles was between AluyMICB and HLA-B*57, AluyHJ and HLA-A*24 and HLA-A*01, and AluyHG and HLA-A*02, supporting previous findings in Caucasians and Japanese. Single POALIN haplotypes were found more frequently than multiple POALIN haplotypes. However, of the seven different POALIN haplotypes within the MHC alpha block, there were only two significant differences between the NE Thais, Caucasians and Japanese. This study confirms that the MHC POALINs are in linkage disequilibrium with HLA-A and ,B alleles and that there are significant frequency differences for some of the POALINs when compared between NE Thai, Caucasians and Japanese. [source] Simultaneous analysis of multiple PCR amplicons enhances capillary SSCP discrimination of MHC allelesELECTROPHORESIS, Issue 8 2010Miguel Alcaide Abstract Major histocompatibility complex (MHC) genotyping still remains one of the most challenging issues for evolutionary ecologists. To date, none of the proposed methods have proven to be perfect, and all provide both important pros and cons. Although denaturing capillary electrophoresis has become a popular alternative, allele identification commonly relies upon conformational polymorphisms of two single-stranded DNA molecules at the most. Using the MHC class II (, chain, exon 2) of the black kite (Aves: Accipitridae) as our model system, we show that the simultaneous analysis of overlapping PCR amplicons from the same target region substantially enhances allele discrimination. To cover this aim, we designed a multiplex PCR capable to generate four differentially sized and labeled amplicons from the same allele. Informative peaks to assist allele calling then fourfold those generated by the analysis of single PCR amplicons. Our approach proved successful to differentiate all the alleles (N=13) isolated from eight unrelated birds at a single optimal run temperature and electrophoretic conditions. In particular, we emphasize that this approach may constitute a straightforward and cost-effective alternative for the genotyping of single or duplicated MHC genes displaying low to moderate sets of divergent alleles. [source] N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITAEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2003Felix Schnappauf Abstract Major histocompatibility complex (MHC) class II molecules play an essential role for the cellular immune response by presenting peptide antigens to CD4+ T cells. MHC class II molecules and genes show a highly complex expression pattern, which is orchestrated through a master regulatory factor, called CIITA (class II transactivator). CIITA controls MHC class II expression not only qualitatively, but also quantitatively, and has therefore a direct influence on the CD4 T cell-dependent immune response. CIITA is itself tightly regulated not only on the transcriptional level, but as we show here also on the protein level. CIITA is subjected to a very rapid protein turnover and shows a half-life of about 30,min. Inhibition of degradation by proteasome inhibitors and the identification of ubiquitylated CIITA intermediates indicate that the degradation of CIITA is mediated by the ubiquitin-proteasome system. We identified two regions mediating degradation within the N-terminal domain of CIITA. N-terminal fusions or deletions stabilized CIITA, indicating that the N termini contribute to degradation. Several non-functional CIITA mutants are partially stabilized, but we provide evidence that transcriptional activity of CIITA is not directly linked to degradation. [source] Major histocompatibility complex (MHC) class II but not MHC class I molecules are required for efficient control of Strongyloides venezuelensis infection in miceIMMUNOLOGY, Issue 1pt2 2009Rosângela M. Rodrigues Summary Strongyloides stercoralis is an intestinal nematode capable of chronic, persistent infection and hyperinfection of the host; this can lead to dissemination, mainly in immunosuppressive states, in which the infection can become severe and result in the death of the host. In this study, we investigated the immune response against Strongyloides venezuelensis infection in major histocompatibility complex (MHC) class I or class II deficient mice. We found that MHC II,/, animals were more susceptible to S. venezuelensis infection as a result of the presence of an elevated number of eggs in the faeces and a delay in the elimination of adult worms compared with wild-type (WT) and MHC I,/, mice. Histopathological analysis revealed that MHC II,/, mice had a mild inflammatory infiltration in the small intestine with a reduction in tissue eosinophilia. These mice also presented a significantly lower frequency of eosinophils and mononuclear cells in the blood, together with reduced T helper type 2 (Th2) cytokines in small intestine homogenates and sera compared with WT and MHC I,/, animals. Additionally, levels of parasite-specific immunoglobulin M (IgM), IgA, IgE, total IgG and IgG1 were also significantly reduced in the sera of MHC II,/, infected mice, while a non-significant increase in the level of IgG2a was found in comparison to WT or MHC I,/, infected mice. Together, these data demonstrate that expression of MHC class II but not class I molecules is required to induce a predominantly Th2 response and to achieve efficient control of S. venezuelensis infection in mice. [source] Pathogen evasion strategies for the major histocompatibility complex class I assembly pathwayIMMUNOLOGY, Issue 1 2008Antony N. Antoniou Summary Major histocompatibility complex (MHC) class I molecules bind and present short antigenic peptides from endogenously or exogenously derived sources to CD8+ cytotoxic T lymphocytes (CTL), with recognition of a foreign peptide normally targeting the cell for lysis. It is generally thought that the high level of MHC polymorphism, which is concentrated mostly within the peptide-binding groove, is driven by the ,evolutionary arms race' against pathogens. Many pathogens have developed novel and intriguing mechanisms for evading the continuous sampling of the intracellular and intercellular environments by MHC molecules, none more so than viruses. The characterization of immunoevasion mechanisms has improved our understanding of MHC biology. This review will highlight our current understanding of the MHC class I biosynthetic pathway and how it has been exploited by pathogens, especially viruses, to potentially evade CTL recognition. [source] Differential modulation of CD8, by rat ,, and ,, T cells after activationIMMUNOLOGY, Issue 3 2001Frank Straube Summary Major histocompatibility complex (MHC) class I-restricted ,, T cells express the CD8,, heterodimer, which acts as a MHC class I-specific co-receptor. Rats are so far the only species with frequent expression of the CD8,, by MHC-unrestricted ,, T cells. This study compares CD8,, expression by splenic rat ,, and ,, T cells and reveals a lineage-specific difference in the control of CD8, expression. After activation in vitro, many ,, T cells, but not ,, T cells, persistently down-modulate the expression of CD8,, but not CD8,, at the RNA level. Down-regulation occurred after stimulation with T-cell receptor (TCR)-specific monoclonal antibody (mAb) and interleukin-2 (IL-2) or CD28-mediated costimulation, and after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Functional differences between modulating and non-modulating cells were not found with respect to interferon-, (IFN-,) production and cytolytic activity. The modulation could be indicative for a fundamental difference between ,, and ,, T cells and also limits the use of CD8, as a stable marker of ,, T-cell subsets. Possibly, CD8, modulation provides a mechanism to escape over-stimulation by (auto-)antigens by increasing the threshold of TCR-mediated activation in ,, T cells. [source] Human MHC architecture and evolution: implications for disease association studiesINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2008J. A. Traherne Summary Major histocompatibility complex (MHC) variation is a key determinant of susceptibility and resistance to a large number of infectious, autoimmune and other diseases. Identification of the MHC variants conferring susceptibility to disease is problematic, due to high levels of variation and linkage disequilibrium. Recent cataloguing and analysis of variation over the complete MHC has facilitated localization of susceptibility loci for autoimmune diseases, and provided insight into the MHC's evolution. This review considers how the unusual genetic characteristics of the MHC impact on strategies to identify variants causing, or contributing to, disease phenotypes. It also considers the MHC in relation to novel mechanisms influencing gene function and regulation, such as epistasis, epigenetics and microRNAs. These developments, along with recent technological advances, shed light on genetic association in complex disease. [source] MICA-STR, HLA-B haplotypic diversity and linkage disequilibrium in the Hunan Han population of southern ChinaINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2006W. Tian Summary Major histocompatibility complex (MHC) class I chain-related gene A (MICA) is located 46 kb centromeric to HLA-B and encodes a stress-inducible protein. MICA allelic variation is thought to be associated with disease susceptibility and immune response to transplants. This study was aimed to investigate the haplotypic diversity and linkage disequilibrium between human leukocyte antigen (HLA)-B and (GCT)n short tandem repeat in exon 5 of MICA gene (MICA-STR) in a southern Chinese Han population. Fifty-eight randomly selected nuclear families with 183 members including 85 unrelated parental samples were collected in Hunan province, southern China. HLA-B generic typing was performed by polymerase chain reaction,sequence-specific priming (PCR,SSP), and samples showing novel HLA-B-MICA-STR linkage were further typed for HLA-B allelic variation by high-resolution PCR,SSP. MICA-STR allelic variation and MICA gene deletion (MICA*Del) were detected by fluorescent PCR,size sequencing and PCR,SSP. Haplotype was determined through family segregation analysis. Statistical analysis was applied to the data of the 85 unrelated parental samples. Nineteen HLA-B specificities and seven MICA-STR allelic variants were observed in 85 unrelated parental samples, the most predominant of which were HLA-B*46, -B60, -B*13, and -B*15, and MICA*A5, MICA*A5.1 and MICA*A4, respectively. Genotype distributions of HLA-B, MICA-STR loci were consistent with Hardy,Weinberg proportions. The HLA-B-MICA-STR haplotypic phases of all 85 unrelated parental samples were unambiguously assigned, which contained 30 kinds of HLA-B, MICA-STR haplotypic combinations, nine of them have not been reported in the literature. Significant positive linkage disequilibria between certain HLA-B and MICA-STR alleles, including HLA-B*13 and MICA*A4, HLA-B*38 and MICA*A9, HLA-B*58 and MICA*A9, HLA-B*46 and MICA*A5, HLA-B*51 and MICA*A6, HLA-B*52 and MICA*A6, and HLA-B60 and MICA*A5.1, were observed. HLA-B*48 was linked to MICA*A5, MICA*A5.1 and MICA*Del. HLA-B*5801-MICA*A10 linkage was found in a family. Our data indicated a high degree of haplotypic diversity and strong linkage disequilibrium between MICA-STR and HLA-B in a southern Chinese Han population, the data will inform future studies on anthropology, donor,recipient HLA matching in clinical transplantation and HLA-linked disease association. [source] Suppression of adenoviral gene expression in the liver: role of innate vs adaptive immunity and their cell lysis mechanismsLIVER INTERNATIONAL, Issue 3 2005Masahiro Minagawa Abstract Background: Injection of adenoviral constructs causes liver infection prompting immunity, which suppress viral gene expression. Innate and adaptive immunity mediate these processes raising the question which pathways are the most prominent. Methods: Adenovirus expressing the ,-galactosidase (,-gal) gene was injected into normal and immunodeficient mice. Elimination of ,-gal-expressing hepatocytes and increases in liver enzymes were assayed. Major histocompatibility complex (MHC) class I densities, perforin channel insertion and apoptosis by Fas and tumor necrosis factor (TNF)-, were assayed. Results: At high virus doses, suppression of viral gene expression was as efficient in immunodeficient as in normal mice, while at low doses effects of cytotoxic T lymphocytes (CTL) were demonstrable. Despite CTL priming and elimination of infected hepatocytes no liver injury is detected. Hepatocyte MHC I densities were able to trigger CTL granule exocytosis and perforin lysis in vitro but not in vivo. This is we show is because of decreased sensitivity of hepatocytes from infected mice to perforin and increased sensitivity to Fas and TNF-, lysis. Conclusion: Effector cells of the innate immune system are exceedingly effective in suppressing adenoviral gene expression. Perforin-independent pathways, those mediated by TNF-, and Fas are very efficient in hepatocytes from virus-infected livers. [source] Genetic variation in BoLA microsatellite loci in Portuguese cattle breedsANIMAL GENETICS, Issue 1 2009C. Bastos-Silveira Summary Major histocompatibility complex (MHC) typing based on microsatellites can be a valuable approach to understanding the selective processes occurring at linked or physically close MHC genes and can provide important information on variability and relationships of populations. Using microsatellites within or in close proximity with bovine lymphocyte antigen (BoLA) genes, we investigated the polymorphisms in the bovine MHC, known as the BoLA, in eight Portuguese cattle breeds. Additional data from non-BoLA microsatellite loci were also used to compare the variability between these regions. Diversity was higher in BoLA than in non-BoLA microsatellites, as could be observed by the number of alleles, allelic richness and observed heterozygosity. Brava de Lide, a breed selected for aggressiveness and nobility, presented the lowest values of observed heterozygosity and allelic richness in both markers. Results from neutrality tests showed few statistically significant differences between the observed Hardy,Weinberg homozygosity (F) and the expected homozygosity (FE), indicating the apparent neutrality of the BoLA microsatellites within the analysed breeds. Nevertheless, we detected a trend of lower values of observed homozygosity compared with the expected one. We also detected some differences in the levels of allelic variability among the four BoLA microsatellites. Our data showed a higher number of alleles at the BoLA-DRB3 locus than at the BoLA-DRBP1 locus. These differences could be related to their physical position in the chromosome and may reflect functional requirements for diversity. [source] Expression, refolding, crystallization and preliminary crystallographic study of MHC H-2Kk complexed with octapeptides and nonapeptidesACTA CRYSTALLOGRAPHICA SECTION D, Issue 7 2004Christine Kellenberger Major histocompatibility complex (MHC) molecules are heterodimeric cell-surface receptors that play a crucial role in the cellular immune response by presenting epitope peptides to T-cell antigen receptors (TCR). Although the structural basis of the peptide,MHC binding mechanism is becoming better understood, it is still difficult to predict a binding mode for an MHC of unknown structure. Therefore, as the first stage of a TCR,MHC interaction study, the crystal structures of the mouse H-2Kk molecule in complex with both an octapeptide from Influenza A virus and a nonapeptide from simian virus SV40 were solved. Here, the expression, refolding, purification and crystallization of the two complexes are reported. For the H-2Kk,HA(259,266) complex, crystals were obtained via an extensive screen using a nanodrop-dispensing robot and diffracted to 2.5,Å resolution. For the H-2Kk,SV40(560,568) complex, microscopic needles were initially obtained and their size was improved by macroseeding and a stepwise increase in precipitant concentration. Diffraction data to a resolution of 3.0,Å were collected at a synchrotron facility. [source] T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and toleranceIMMUNOLOGICAL REVIEWS, Issue 1 2009Robert J. Salmond Summary:, T-cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T-cell repertoire, while activation of naive peripheral T cells induces proliferation, gain of effector function, and, ultimately, long-lived T-cell memory. The T-cell immune response is initiated upon engagement of the T-cell receptor (TCR) and coreceptor, CD4 or CD8, by cognate antigen/major histocompatibility complexes presented by antigen-presenting cells. TCR/coreceptor engagement induces the activation of biochemical signaling pathways that, in combination with signals from costimulator molecules and cytokine receptors, direct the outcome of the response. Activation of the src- family kinases p56lck (Lck) and p59fyn (Fyn) is central to the initiation of TCR signaling pathways. This review focuses on our current understanding of the mechanisms by which these two proteins orchestrate T-cell function. [source] Nomenclature for factors of the dog major histocompatibility system (DLA), 2000: second report of the ISAG DLA Nomenclature CommitteeANIMAL GENETICS, Issue 4 2001L. J. Kennedy The International Society for Animal Genetics (ISAG) Dog Leukocyte Antigen (DLA) Nomenclature Committee met during the ,Comparative Evolution of the Mammalian major Histocompatibility Complex (MHC)' meeting in Manchester, UK on 10 September 2000. The main points discussed were the naming of class I genes and alleles, and the inclusion of alleles from other canidae. [source] MHC and Preferences for Male Odour in the Bank VoleETHOLOGY, Issue 9 2008Jacek Radwan Highly polymorphic major histocompatibility complex (MHC) genes are thought to play a central role in the choice of genetically compatible sexual partners in some vertebrates, although the evidence is variable across species. Here, we investigate the association between similarity in the MHC region and sexual preferences in the bank vole Myodes (=Clethrionomys) glareolus (Arvicollinae) in a laboratory setting. Females in post-partum oestrus were given the choice between the scents of two males in a Y-maze. Both males were unrelated to the female, but differed in their MHC similarity to the female. We found that females spent more time near the scent of MHC dissimilar males than those, with whom they shared MHC alleles. This suggests that bank voles use MHC-related cues to choose compatible mates. [source] Interactions between major histocompatibility complex class II surface expression and HIV: implications for pathogenesisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2001W. Kamp Although it has been almost 20 years since the first cases of acquired immunodeficiency syndrome (AIDS) were documented, the pathogenesis is still not completely understood. Interactions between major histocompatibility complex (MHC) Class I and human immunodeficiency virus (HIV), resulting in down-regulation of MHC-I surface expression, have been reported to contribute to pathogenesis by suppressing the host's immune response. Interactions between MHC Class II and HIV have also been described, but it is unclear how these contribute to the pathogenesis. MHC-II surface expression on HIV-infected monocytes and monocytic cell lines has been described to be increased as well as decreased when compared to uninfected control monocytes. HIV-specific mechanisms appear to down-regulate MHC-II expression on blood monocytes during HIV-1 infection, whereas host mechanisms up-regulate MHC-II expression in response to infection of blood monocytes as well as brain macrophages. A balance between these two may determine MHC-II expression levels in individual patients. Altogether, HIV seems to be able to benefit from both low and high levels of MHC-II surface expression. The first results in reduced immune surveillance of the host, allowing the virus to replicate faster; the second increases infectivity of the virus as a result of higher MHC-II density on macrophages and virion particles. [source] BALANCING SELECTION, RANDOM GENETIC DRIFT, AND GENETIC VARIATION AT THE MAJOR HISTOCOMPATIBILITY COMPLEX IN TWO WILD POPULATIONS OF GUPPIES (POECILIA RETICULATA)EVOLUTION, Issue 12 2006Cock van Oosterhout Abstract Our understanding of the evolution of genes of the major histocompatibility complex (MHC) is rapidly increasing, but there are still enigmatic questions remaining, particularly regarding the maintenance of high levels of MHC polymorphisms in small, isolated populations. Here, we analyze the genetic variation at eight microsatellite loci and sequence variation at exon 2 of the MHC class IIB (DAB) genes in two wild populations of the Trinidadian guppy, Poecilia reticulata. We compare the genetic variation of a small (Ne, 100) and relatively isolated upland population to that of its much larger (Ne, 2400) downstream counterpart. As predicted, microsatellite diversity in the upland population is significantly lower and highly differentiated from the population further downstream. Surprisingly, however, these guppy populations are not differentiated by MHC genetic variation and show very similar levels of allelic richness. Computer simulations indicate that the observed level of genetic variation can be maintained with overdominant selection acting at three DAB loci. The selection coefficients differ dramatically between the upland (s 0.2) and lowland (s, 0.01) populations. Parasitological analysis on wild-caught fish shows that parasite load is significantly higher on upland than on lowland fish, which suggests that large differences in selection intensity may indeed exist between populations. Based on the infection intensity, a substantial proportion of the upland fish would have suffered direct or indirect fitness consequences as a result of their high parasite loads. Selection by parasites plays a particularly important role in the evolution of guppies in the upland habitat, which has resulted in high levels of MHC diversity being maintained in this population despite considerable genetic drift. [source] PATHOGEN RESISTANCE AND GENETIC VARIATION AT MHC LOCIEVOLUTION, Issue 10 2002Philip W. Hedrick Abstract., Balancing selection in the form of heterozygote advantage, frequency-dependent selection, or selection that varies in time and/or space, has been proposed to explain the high variation at major histocompatibility complex (MHC) genes. Here the effect of variation of the presence and absence of pathogens over time on genetic variation at multiallelic loci is examined. In the basic model, resistance to each pathogen is conferred by a given allele, and this allele is assumed to be dominant. Given that s is the selective disadvantage for homozygotes (and heterozygotes) without the resistance allele and the proportion of generations, which a pathogen is present, is e, fitnesses for homozygotes become (1 ,s)(n-1)e and the fitnesses for heterozygotes become (1 ,s)(n-2)e, where n is the number of alleles. In this situation, the conditions for a stable, multiallelic polymorphism are met even though there is no intrinsic heterozygote advantage. The distribution of allele frequencies and consequently heterozygosity are a function of the autocorrelation of the presence of the pathogen in subsequent generations. When there is a positive autocorrelation over generations, the observed heterozygosity is reduced. In addition, the effects of lower levels of selection and dominance and the influence of genetic drift were examined. These effects were compared to the observed heterozygosity for two MHC genes in several South American Indian samples. Overall, resistance conferred by specific alleles to temporally variable pathogens may contribute to the observed polymorphism at MHC genes and other similar host defense loci. [source] Alloantigen gene therapy for head and neck cancer: Evaluation of animal models,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 4 2003Lyon L. Gleich MD Abstract Background. Human trials of alloantigen gene therapy, using the class I major histocompatibility complex (MHC) HLA-B7, have demonstrated the potential efficacy of this treatment for head and neck cancer. Its mechanism remains unclear. An immune-competent mouse model of MHC gene therapy to test factors potentially important to the tumor response is needed. Methods. Two cell lines were used, B4B8 cells that grow in Balb/c mice and SCC-VII cells that grow in C3H mice. The mouse MHC H2-Kb was used as the therapeutic gene, because it is an alloantigen to both mice strains. Plasmids that encode the H2-Kb cDNA were prepared, and the cell lines were transfected. Mice were injected subcutaneously with naive cells to determine the tumor kinetics and serve as controls. Mice were injected with H2-Kb transfected cells and tumor growth was compared with controls. Mice that did not grow tumor were rechallenged with naive cells to assess for tumor immunity. Mice were injected with transfected and naive cells admixed to determine whether the concentration of the alloantigen is important. Results. B4B8 tumors grew slowly, whereas SCC-VII tumors grew rapidly. Transfection with H2-Kb plasmid prevented or inhibited tumor growth of both the B4B8 and SCC-VII tumors. This growth inhibition was independent of the number of cells injected. In the mice that did not grow tumor, tumor immunity was demonstrated after challenge with naive cells in both models. There was no relationship between induction of immunity and the timing of the challenge or initial cell quantity. The mice injected with a mixture of naive and transfected cells grew tumor, although growth was delayed in the B4B8 model. Conclusions. The results demonstrate that the two mouse models can serve as a rapid and slow growing tumor model of alloantigen gene therapy. In addition, it was noted that initial tumor cell number is not a significant factor for predicting tumor response and demonstrated that in both of these models alloantigen gene therapy results in significant antitumor immunity. © 2003 Wiley Periodicals, Inc. Head Neck 25: 274,279, 2003 [source] Cross-Primed CD8+ Cytotoxic T cells Induce Severe Helicobacter -associated Gastritis in the Absence of CD4+ T cellsHELICOBACTER, Issue 5 2007Toshiro Fukui Abstract Background:, Although previous studies have reported important roles of CD4+ type1-helper T cells and regulatory T cells in Helicobacter -associated gastritis, the significance of CD8+ cytotoxic T cells remains unknown. To study the roles of CD8+ T cells, we examined the immune response in the gastric mucosa of Helicobacter felis -infected major histocompatibility complex (MHC) class II-deficient (II,/,) mice, which lack CD4+ T cells. Materials and methods:, Stomachs from H. felis -infected wild-type and infected MHC II,/, mice were examined histologically and immunohistochemically. Gastric acidity and serum levels of anti- H. felis antibodies were measured. The expression of pro-inflammatory and anti-inflammatory cytokine, Fas-ligand, perforin, and Foxp3 genes in the gastric mucosa was investigated. Results:,H. felis -infected MHC II,/, mice developed severe gastritis, accompanied by marked infiltration of CD8+ cells. At 1 and 2 months after inoculation, mucosal inflammation and atrophy were more severe in MHC II,/, mice, although gastritis had reached similar advanced stages at 3 months after inoculation. There was little infiltration of CD4+ cells, and no Foxp3 -positive cells were detected in the gastric mucosa of the infected MHC II,/, mice. The expression of the interleukin-1, and Fas-ligand genes was up regulated, but that of Foxp3 was down regulated in the infected MHC II,/, mice. Serum levels of anti- H. felis antibodies were lower in the infected MHC II,/, mice, despite severe gastritis. Conclusions:, The present study suggests that cross-primed CD8+ cytotoxic T cells can induce severe H. -associated gastritis in the absence of CD4+ helper T cells and that Foxp3 -positive cells may have an important role in the control of gastric inflammation. [source] Mechanism of T cell tolerance induction by murine hepatic Kupffer cells,HEPATOLOGY, Issue 3 2008Qiang You The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KCs could promote immune tolerance by acting as incompetent antigen-presenting cells (APC), as well as actively suppressing T cell activation induced by other potent APCs. The expression of antigen presentation-related molecules by KCs was phenotyped by flow cytometry. The abilities of KCs to act as APCs and to suppress T cell activation induced by splenic dendritic cells (DC) were examined by in vitro proliferation assays using CD4+ OVA-TCR (ovalbumin T cell receptor) transgenic T cells. We found that, compared with DCs, KCs expressed significantly lower levels of major histocompatibility complex (MHC) II, B7-1, B7-2, and CD40. This result is consistent with our observation that KCs were not as potent as DCs in eliciting OVA-specific T cell proliferation. However, KCs isolated from polyinosinic:polycytidylic acid,treated mice expressed significantly higher levels of MHC II and costimulatory molecules than did naïve KCs and could stimulate stronger T cell responses. More importantly, we found that KCs could inhibit DC-induced OVA-specific T cell activation. Further investigation of the underlying mechanism revealed that prostaglandins produced by KCs played an important role. The results ruled out the possible involvement of interleukin-10, nitric oxide, 2,3-dioxygenase, and transforming growth factor , in KC-mediated T cell suppression. Conclusion: Our data indicate that KCs are a tolerogenic APC population within the liver. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance. (HEPATOLOGY 2008.) [source] The Impact of Interferon Gamma Receptor Expression on the Mechanism of Escape From Host Immune Surveillance in Hepatocellular CarcinomaHEPATOLOGY, Issue 3 2000Mitsuo Nagao M.D. Interferon gamma (IFN-,) plays an important role in host defense mechanism and participates in the progression of chronic liver disease. IFN-, exerts its pleiotrophic effects by transcriptional regulation of expression of numerous genes, such as major histocompatibility complex (MHC) class I and Fas, through interaction with IFN-, receptor (IFN-,-R). Although hepatocytes in normal liver express weak or no IFN-,-R, those in acute and chronic liver disease up-regulate its expression. A study using IFN-,-R ,-chain knock-out mice revealed the actions of IFN-, on tumor cells as an extrinsic tumor-suppressor mechanism. However, it is unclear whether or how hepatocellular carcinoma (HCC) blocks the signal transduction of IFN-, to evade host immune surveillance. We examined the expression of IFN-,-R and IFN-,,inducible genes in 44 cases with HCC using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. In noncancerous liver tissues (n = 38), IFN-,-R expression on the cell surface was up-regulated in 27 cases. In IFN-,-R,negative cases (n = 15), tumor size was larger (P = .032), serum ,-fetoprotein (AFP) level was higher (P = .001), intrahepatic and extrahepatic metastasis was more common (P = .044 and .013, respectively), and Ki-67 labeling index (LI) was higher (P = .041), compared with IFN-,-R,positive cases. Accordingly, the evasion mechanism may play an important role in progression, especially metastasis, in HCC. The significant correlation between the status of IFN-,-R and the expression of Fas and MHC implies that the loss of IFN-,-R might contribute to the mechanism of escape from host immune rejection in HCC. [source] Genetic background of primary biliary cirrhosisHEPATOLOGY RESEARCH, Issue 2007Atsushi Tanaka The clustering of patients in a representative family as well as relatively high concordance rate in monozygotic twins strongly indicate that genetic factors play a crucial role in modulating primary biliary cirrhosis (PBC) by conferring susceptibility to, or providing protection from, the disease. Therefore, much like other autoimmune diseases, intensive investigations have attempted to elucidate which genes are incriminated in the etiology of PBC. So far, a number of genes, including major histocompatibility complex (MHC) class I and II, cytokines and cell surface molecules, have been examined to seek the possibility of whether single nucleotide polymorphisms (SNP) of the gene might be associated with susceptibility to PBC. Nevertheless, it appears that methodologicaldifficulties, mainly the limitation of the number of individuals tested in each study, hamper the detection of a convincing and reproducible link between genetic polymorphisms and the etiology of PBC. Also, the difference in genetic background among several ethnic groups may play a role in concealing the association. In this review, I will highlight the genetic association in PBC, and review the association of genetic polymorphisms with the etiology of PBC, which have been reported in various ethnicities. [source] Genetics and genomics of ankylosing spondylitisIMMUNOLOGICAL REVIEWS, Issue 1 2010Gethin P. Thomas Summary:, Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major differences in the genes involved in the two conditions, presumably explaining their different presentations. Genomic and proteomic studies are in an early phase but have potential both as diagnostic/prognostic tools and as a further hypothesis-free tool to investigate AS pathogenesis. Given the slow progress in studying the mechanism of association of HLA-B27 with AS, these may prove to be more fruitful approaches to investigating the pathogenesis of the disease. [source] Interferons as pathogenic effectors in autoimmunityIMMUNOLOGICAL REVIEWS, Issue 1 2005Roberto Baccala Summary:, Interferons (IFNs) type-1 (IFN ,/,) and type-II (IFN-,) are the most pleiotropic molecules in the intricate cytokine network. This dominance arises from three crucial factors: (i) initiation of IFN-,/, and IFN-, production at the inception of most innate immune responses, which primes for the ensuing adaptive immune responses, primarily through the sine qua non upregulation of major histocompatibility complex and costimulatory molecules; (ii) magnification of their production and signaling by cross-talk between themselves, and synergistic or antagonistic effects on other cytokines; and (iii) direct or indirect initiation of transcription of hundreds of immunologically relevant genes. Considering that aberrant immune responses against self-molecules seem to depend on the same constituents and pathways as those against exogenous antigens, it follows that IFNs are also major effectors in the pathogenesis of autoimmunity. Here, we review the diverse biological effects of IFNs on the immune system, discuss findings pertaining to the nature of exogenous and endogenous stimuli that might induce IFN production through the engagement of Toll-like receptors, and summarize the detrimental and, in some instances, beneficial effects of IFNs in systemic and organ-specific autoimmune diseases. [source] Regulatory T cells and autoimmune diseaseIMMUNOLOGICAL REVIEWS, Issue 1 2005Silke Paust Summary:, Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4+CD25+ T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T-effector cells as a target molecule for Treg-dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T-cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa-1 on effector T cells is not addressed in this review. [source] Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigensIMMUNOLOGICAL REVIEWS, Issue 1 2004William R. Heath Summary:, Cross-presentation involves the uptake and processing of exogenous antigens within the major histocompatibility complex (MHC) class I pathway. This process is primarily performed by dendritic cells (DCs), which are not a single cell type but may be divided into several distinct subsets. Those expressing CD8, together with CD205, found primarily in the T-cell areas of the spleen and lymph nodes, are the major subset responsible for cross-presenting cellular antigens. This ability is likely to be important for the generation of cytotoxic T-cell immunity to a variety of antigens, particularly those associated with viral infection, tumorigenesis, and DNA vaccination. At present, it is unclear whether the CD8,-expressing DC subset captures antigen directly from target cells or obtains it indirectly from intermediary DCs that traffic from peripheral sites. In this review, we examine the molecular basis for cross-presentation, discuss the role of DC subsets, and examine the contribution of this process to immunity, with some emphasis on DNA vaccination. [source] | ||||||||||||||||||||||||||||||||||||||||