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Showing papers in "Immunological Reviews in 1999"


Journal ArticleDOI
TL;DR: Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen‐independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH.
Abstract: An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.

526 citations


Journal ArticleDOI
TL;DR: The current understanding of the nature and function of the MHC class I peptide loading complex is the topic of this review.
Abstract: Peptide binding to major histocompatibility complex (MHC) class I molecules occurs in the endoplasmic reticulum (ER). Efficient peptide binding requires a number of components in addition to the MHC class I-beta 2 microglobulin dimer (beta 2m). These include the two subunits of the transporter associated with antigen presentation (TAP1 and TAP2), which are essential for introducing peptides into the ER from the cytosol, and tapasin, an MHC-encoded membrane protein. Prior to peptide binding, MHC class I-beta 2m dimers form part of a large multisubunit ER complex which includes TAP and tapasin. In addition to these specialized components two soluble 'house-keeping' proteins, the chaperone calreticulin and the thiol oxidoreductase ERp57, are also components of this complex. Our current understanding of the nature and function of the MHC class I peptide loading complex is the topic of this review.

353 citations


Journal ArticleDOI
TL;DR: A model of the evolution of the human MHC is proposed and explanations for co‐occurrence of genomic polymorphism, duplication and HERVs are considered and it is asked how these features encode susceptibility to numerous and very diverse diseases.
Abstract: Summary: The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with insertion and deletion (indels), In the alpha block surrounding HLA-A, there are ten duplication units or beads on the 62,1 ancestral haplotype. Each bead contains or contained sequences representing Class 1, PERB11 (MHC Class I chain related (MIC)) and human endogenous retrovirus (HERV) 16, Here we consider explanations for co-occurrence of genomic polymorphism, duplication and HERVs and we ask how these features encode susceptibility to numerous and very diverse diseases. Ancestral haplotypes differ in their copy number and indels in addition to their coding regions. Disease susceptibility could be a function of all of these differences. We propose a model of the evolution of the human MHC. Population-specific integration of retroviral sequences could explain rapid diversification through duplication and differential disease susceptibility. If HERV sequences can be protective, there are exciting prospects for manipulation. In the mean-while, it will be necessary to understand the function of MHC genes such as PEKB11 (MIC) and many others discovered by genomic sequencing.

330 citations


Journal ArticleDOI
TL;DR: The mucosae and exocrine glands harbour the largest activated B‐cell system of the body, amounting to some 80–90% of all immunoglobulins (Ig)‐producing cells, and the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive.
Abstract: Summary: The mucosae and exocrine glands harbour the largest activated B-cell system of the body, amounting to some 80–90% of all immunoglobulins (Ig)-producing cells. The major product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristic appears to be sufficient functional justification for the J chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgG production; they probably represent a ‘spin-off’ from sequential downstream CH switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B-cell clones compatible with homing to these sites. Observations in IgA-deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin α4β7 and MAdCAM-1) that explain the “gut-seeking” properties of enterically induced B cells, the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive. Moreover, little is known about immune regulation underlying the striking disparity of both the class (IgD, IgM) and subclass (IgA1, IgA2, IgGI, IgG2) production patterns shown by local iinmttnocytes in various regions of the body, although the topical microbiota and other environmental stimuli might be important. Rational design of local vaccines will depend on better knowledge of both inductive and migratory properties of human mucosal B cells.

309 citations


Journal ArticleDOI
TL;DR: The adoptive transfer of tumor‐infiltrating lymphocytes along with interleukin (H.)‐2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression.
Abstract: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) along with interleukin (IL)-2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression. In the last few years, efforts have been made towards understanding the molecular basis of T-cell-mediated antitumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Tumor antigens identified thus far could be classified into several categories: tissue-specific differentiation antigens, tumor-specific shared antigens and tumor-specific unique antigens. CD4+ T cells play a central role in orchestrating the host immune response against cancer, infectious diseases and autoimmune diseases, and we thus have attempted to identify major histocompatibility complex (MHC) class II-restricted tumor antigens as well. The identification of tumor rejection antigens provides new opportunities for the development of therapeutic strategies against cancer. This review will summarize the current status of MHC class I- and class II-restricted human tumor antigens, and their potential application to cancer treatment.

300 citations


Journal ArticleDOI
TL;DR: The results indicate that B cells are promoting autoimmunity in mechanisms other than autoAb secretion, and a model depicting these B‐cell roles in the context of other inflammatory events in lupus is described.
Abstract: A standard view of B cells in systemic autoimmunity is that they promote lupus by producing autoantibodies (autoAb). However, this view is incomplete because recent studies have revealed that autoimmune disease can be dissociated from autoAb deposition. Furthermore, the spontaneous T-cell activation and organ infiltration in systemic lupus erythematosus patients and animal models are difficult to explain entirely via a direct autoAb-mediated mechanism. In this review, we describe work addressing the B-cell functions of autoantigen presentation and autoAb production in lupus pathogenesis. In the JHD-MRL-Faslpr strain (JHD/lpr), a B-cell-deficient version of the lupus-prone MRL-Faslpr (MRL/lpr) mouse, spontaneous nephritis and dermatitis is abrogated, demonstrating that B cells have a primary role in disease. B cells play a similar role in Fas-intact, lupus-prone MRL mice. To address the role of autoantigen presentation, we analyzed transgenic mice which have B cells that cannot secrete immunoglobulin (mIgM transgenic mice). The restoration of B cells without antibody caused substantial interstitial nephritis and vasculitis although less marked than the intact MRL/lpr controls. To address the role of autoAb, we infused serum from aged MRL/lpr mice into JHD/lpr mice. At most, mild to no nephritis was observed in the infused mice. These results indicate that B cells are promoting autoimmunity in mechanisms other than autoAb secretion, and we describe a model depicting these B-cell roles in the context of other inflammatory events in lupus.

282 citations


Journal ArticleDOI
TL;DR: Diverse functions of TNF/TNFRs are placed into context with the development of specific pathology in murine models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease to suggest that TNF may also directly promote or downregulate the adaptive immune response.
Abstract: The specific role of the tumor necrosis factor (TNF)/TNF receptor (TNFR) system in disease pathogenesis still remains an unresolved puzzle. Recent studies in transgenic and knockout animals, where the pathogenic influence of genetically perturbed TNF expression has been evaluated, indicate that several pathways of TNF/TNFR action may contribute independently or in concert to initiate, promote or downregulate disease pathogenesis. Evidently, organ-specific inflammatory or autoimmune pathology may ensue due to sustained activation by TNF of innate immune cells and inflammatory responses, which may consequently lead to tissue damage and to organ-specific chronic pathology. However, more cryptic functions of this molecule may be considered to play a significant part in the development of TNF-mediated pathologies. Direct interference of TNF with the differentiation, proliferation or death of specific pathogenic cell targets may be an alternative mechanism for disease initiation or progression. In addition to these activities, there is now considerable evidence to suggest that TNF may also directly promote or downregulate the adaptive immune response. It is therefore evident that no general scenario may adequately describe the role of TNF in disease pathogenesis. In this article, we aim to place these diverse functions of TNF/TNFRs into context with the development of specific pathology in murine models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.

268 citations


Journal ArticleDOI
TL;DR: It is suggested that more than one mechanism for Ii removal, probably involving different proteases, can co‐exist in the same antigen‐presenting cell, and may allow the development of protease inhibitors with possible therapeutic applications.
Abstract: Major histocompatibility complex class II antigen presentation requires the participation of lysosomal proteases in two convergent processes. First, the antigens endocytosed by the antigen-presenting cells must be broken down into antigenic peptides. Second, class II molecules are synthesized with their peptide-binding site blocked by invariant chain (Ii), and they acquire the capacity to bind antigens only after Ii has been degraded in the compartments where peptides reside. The study of genetically modified mice deficient in single lysosomal proteases has allowed us to determine their role in these processes. Cathepsins (Cat) B and D, previously considered major players in MHC class II antigen presentation, are dispensable for degradation of Ii and for generation of several antigenic determinants. By contrast, Cat S plays an essential role in removal of Ii in B cells and dendritic cells, whereas Cat L apparently does so in thymic epithelial cells. Accordingly, the absence of Cat S and L have major consequences for the onset of humoral immune responses and for T-cell selection, respectively. It is likely that other as yet uncharacterized lysosomal enzymes also play a role in Ii degradation and in generation of antigenic determinants. Experiments involving drugs that interfere with protein traffic suggest that more than one mechanism for Ii removal, probably involving different proteases, can co-exist in the same antigen-presenting cell. These findings may allow the development of protease inhibitors with possible therapeutic applications.

248 citations


Journal ArticleDOI
TL;DR: Interestingly, the cellular content of proteases involved in the production and destruction of antigenic peptides is modified by inter‐feron‐γ (IFN‐γ) treatment of cells, and changes are likely to enhance the yield of peptides with C termini appropriate for MHC binding and have been shown to enhanced the presentation of at least some antigens.
Abstract: The class I major histocompatibility complex (MHC class I) presents 8-10 residue peptides to cytotoxic T lymphocytes. Most of these antigenic peptides are generated during protein degradation in the cytoplasm and are then transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Several lines of evidence have indicated that the proteasome is the major proteolytic activity responsible for generation of antigenic peptides--probably most conclusive has been the finding that specific inhibitors of the proteasome block antigen presentation. However, other proteases (e.g. the signal peptidase) may also generate some epitopes, particularly those on certain MHC class I alleles. The proteasome is responsible for generating the precise C termini of many presented peptides, and appears to be the only activity in cells that can make this cleavage. In contrast, aminopeptidases in the cytoplasm and endoplasmic reticulum can trim the N terminus of extended peptides to their proper size. Interestingly, the cellular content of proteases involved in the production and destruction of antigenic peptides is modified by interferon-gamma (IFN-gamma) treatment of cells. IFN-gamma induces the expression of three new proteasome beta subunits that are preferentially incorporated into new proteasomes and alter their pattern of peptidase activities. These changes are likely to enhance the yield of peptides with C termini appropriate for MHC binding and have been shown to enhance the presentation of at least some antigens. IFN-gamma also upregulates leucine aminopeptidase, which should promote the removal of N-terminal flanking residues of antigenic peptides. Also, this cytokine downregulates the expression of a metallo-proteinase, thimet oligopeptidase, that actively destroys many antigenic peptides. Thus, IFN-gamma appears to increase the supply of peptides by stimulating their generation and decreasing their destruction. The specificity and content of these various proteases should determine the amount of peptides available for antigen presentation. Also, the efficiency with which a peptide is presented is determined by the protein's half life (e.g. its ubiquitination rate) and the sequences flanking antigenic peptides, which influence the rates of proteolytic cleavage and destruction.

241 citations


Journal ArticleDOI
TL;DR: Developing formulations based on efficient delivery of selected anti‐gens/tolerogens, cytokines and adjuvants may impact on the design of future vaccines and of specific immunotherapeutic approaches against diseases associated with untoward immune responses.
Abstract: The mucosal immune system of mammals consists of an integrated network of lymphoid cells which work in concert with innate host factors to promote host defense. Major mucosal effector immune mechanisms include secretory antibodies, largely of immunoglobulin A (IgA) isotype, cytotoxic T cells, as well as cytokines, chemokines and their receptors. Immunologic unresponsiveness (tolerance) is a key feature of the mucosal immune system, and deliberate vaccination or natural immunization by a mucosal route can effectively induce immune suppression. The diverse compartments located in the aerodigestive and genitourinary tracts and exocrine glands communicate via preferential homing of lymphocytes and antigen-presenting cells. Mucosal administration of antigens may result in the concomitant expression of secretory immunoglobulin A (S-IgA) antibody responses in various mucosal tissues and secretions, and under certain conditions, in the suppression of immune responses. Thus, developing formulations based on efficient delivery of selected antigens/tolerogens, cytokines and adjuvants may impact on the design of future vaccines and of specific immunotherapeutic approaches against diseases associated with untoward immune responses, such as autoimmune disorders, allergic reactions, and tissue-damaging inflammatory reactions triggered by persistent microorganisms.

232 citations


Journal ArticleDOI
TL;DR: The spondyloarthropathy‐like disease in rats is specific for HLA‐B27 but does not require Cys67, and Arthritis but not colitis is particularly sensitive to B27 peptide‐binding specificity.
Abstract: HLA-B27 is a human major histocompatibility complex (MHC) class I allele that is found with strikingly increased prevalence in patients with the spondyloarthropathies, a group of disorders that includes ankylosing spondylitis, reactive arthritis (formerly commonly referred to as Reiter’s syndrome), arthritis and spondylitis associated with inflammatory bowel disease or psoriasis, as well as a more general diagnosis of spondyloarthropathy that shares features of the other entities (1–3). Some of these disorders are known to be directly triggered by infectious agents, and microbial agents have been implicated in most of the rest of these disorders as well. A thorough elucidation of the basis for the association between B27 and disease would enhance our understanding of the roles that both genes and environmental agents play in producing chronic inflammatory diseases.

Journal ArticleDOI
TL;DR: This review provides an overview of prime‐boost immunisation strategies that result in protective CD8’ T‐cell responses against malaria with an emphasis on work from the laboratory.
Abstract: One of the current challenges in vaccine design is the development of antigen delivery systems or vaccination strategies that induce high protective levels of CD8+ T cells. These cells are crucial for protection against certain tumours and intracellular pathogens such as the liver-stage parasite of malaria. A liver-stage malaria vaccine should therefore include CD8+ T-cell-inducing components. This review provides an overview of prime-boost immunisation strategies that result in protective CD8+ T-cell responses against malaria with an emphasis on work from our laboratory. Possible mechanisms explaining why heterologous prime-boost strategies, in particular boosting with replication-impaired recombinant poxviruses, are so effective are discussed.

Journal ArticleDOI
TL;DR: New evidence indicates that the mechanisms employed by primate lentiviruses to downmodulate CD4 and MHC‐I are also exploited by a number of cellular regulatory processes.
Abstract: The human and simian immunodeficiency viruses (HIV and SIV) downregulate the cell surface expression of CD4, their primary receptor, and of class I histocompatibility complex (MHC-I), a critical mediator of immune recognition. While the first of these effects seems important to preserve viral infectivity, the second likely promotes immune evasion. Three HIV-1 proteins, Nef, Env and Vpu, contribute to downregulate CD4, Env forms a complex with CD4 in the endoplasmic reticulum, thereby retaining the receptor in this compartment. Nef and Vpu, on the other hand, act as connectors between CD4 and specific intracellular trafficking pathways, targeting the receptor for degradation in the lysosome and the proteasome, respectively. Some of the downstream partners of the viral proteins in these events have been identified, and include the adaptor complex of clathrin-coated pits, the beta subunit of COP-I coatomer, and the ubiquitin pathway-related h-beta TrCP protein. HIV-induced MHC-I downregulation, mostly the effect of Nef, also reflects a redistribution of this receptor, with its accumulation in the Golgi. The modalities of this process, however, are as yet imperfectly understood. New evidence indicates that the mechanisms employed by primate lentiviruses to downmodulate CD4 and MHC-I are also exploited by a number of cellular regulatory processes.

Journal ArticleDOI
TL;DR: Analysis of cathepsin‐deficient mice revealed a profound defect in invariant chain degradation in thymic cortical epithelial cells bur not in bone marrow‐derived antigen‐presenting cells (APCs) (B cells, dendritic cells, and macrophages).
Abstract: The recent analysis of cathepsin-deficient mice has shed light upon the role of lysosomal proteinases in the MHC class II processing and presentation pathway. Ubiquitous expression and involvement in the terminal degradation of proteins that intersect the endocytic pathway were previously perceived to be the hallmarks of these proteinases. However, recent evidence has demonstrated that several cathepsins are expressed in a tissue-specific fashion and that partial proteolysis of specific biological targets is a key function of cathepsins in antigen processing. Our work has focused on the differential expression of the cysteine proteinases cathepsins L (CL) and S (CS) and its pertinence to the generation of MHC class II: peptide complexes. Analysis of CL-deficient mice revealed a profound defect in invariant chain degradation in thymic cortical epithelial cells but not in bone marrow-derived antigen-presenting cells (APCs) (B cells, dendritic cells, and macrophages). The tissue-specific deficiency reflected the restricted pattern of expression of CL and CS in these cell types--CL is expressed in thymic cortical epithelial cells but not in DC or B cells, while CS exhibits the opposite expression pattern. The differential expression of proteinases by distinct APCs may affect the types of peptides that are presented to T cells and thereby the immune responses that are ultimately generated.

Journal ArticleDOI
TL;DR: The HLA‐G class Ib gene appears to be a functional locus and its functional properties, although incompletely understood, are likely to be important in the outcome of human pregnancies but also in normal adult life.
Abstract: Summary: In view of the recently published data, the HLA-G class Ib gene appears to be a functional locus. This is based on the following observations: 1) HLA-G is capable of presenting nonamer peptides and of exerting antigen-presenting functions; 2) HLA-G is a ligand for at least three natural killer (NK) and other cell inhibitory receptors of the immunoglobulin superfamily, namely leukocyte immunoglobulin-like receptor-1 /immunoglobulin-like transcript (ILT)-2, ILT-4 and p49; 3) in addition to the extravillous cytotrophoblast cells, HLA-G proteins have been detected in endothelial cells of placental chorionic villi, as well as in amniotic fluid and in some medullary thymic epithelial cells; 4) major histocompatibility complex (MHC) class Ib genes that share the unique characteristics of HLA-G, including a high expression in placenta, have been reported in other mammalian species. In addition to the classical MHC class I roles (antigen presentation and ligarion to NK receptors inducing inhibitory and/or activatory signals), HLA-G is likely to exert other, novel functions: first, HLA-G was shown to be involved in the control of HLA-E expression by furnishing the appropriate class I leader sequence nonamer peptide; second, we hypothesize that HLA-G could be a regulator of placental angiogenesis; third, soluble HLA-G isoforms may act as specific immunosuppressors during pregnancy. Such functional properties, although incompletely understood, are likely to be important in the outcome of human pregnancies but also in normal adult life.

Journal ArticleDOI
TL;DR: The similarities and differences found in the MHC class II repertoires of primate species including humans, chimpanzees, rhesus macaques, cotton‐top tamarins and common marmosets are discussed.
Abstract: In the past decade, the major histocompatibility complex (MHC) class II region of several primate species has been investigated extensively. Here we will discuss the similarities and differences found in the MHC class II repertoires of primate species including humans, chimpanzees, rhesus macaques, cotton-top tamarins and common marmosets. Such types of comparisons shed light on the evolutionary stability of MHC class II alleles, lineages and loci as well as on the evolutionary origin and biological significance of haplotype configurations.

Journal ArticleDOI
TL;DR: The genes that encode molecules involved in antigen presentation within the class I and class II regions of the mammalian major histocompatibility complex (MHC) include several that are highly polymorphic, and there is evidence that this polymorphism is maintained by positive selection, most likely overdominant selection, relating to their role in presenting foreign peptides to T cells.
Abstract: The genes that encode molecules involved in antigen presentation within the class I and class II regions of the mammalian major histocompatibility complex (MHC) include several that are highly polymorphic. There is evidence that this polymorphism is maintained by positive selection, most likely overdominant selection, relating to their role in presenting foreign peptides to T cells. This selection can maintain allelic lineages for much longer periods of time than neutral polymorphisms are expected to last, but sharing of polymorphic amino acid motifs among species of different mammalian orders is due to independent (or convergent) evolution rather than common ancestry. It has been suggested that interallelic recombination (gene conversion) plays a role in enhancing polymorphism, but there is evidence of striking differences among loci with respect to the rate at which such recombination has contributed to current polymorphism. Recent attempts to interpret linkage relationships in the MHC region as evidence of ancient genomic duplications are not supported by phylogenetic analysis. Rather, natural selection may have played a role in the linkage of other genes to those of the MHC.

Journal ArticleDOI
TL;DR: A single dominantly expressed class I gene determines the immune response to certain infectious pathogens, due to peptide‐binding specificity and cell‐surface expression level, in stark contrast to well‐studied mammals like humans and mice.
Abstract: Some years ago, we used our data for class I genes, proteins and peptide-binding specificities to develop the hypothesis that the chicken B-F/B-L region represents a "minimal essential MHC". In this view, the B locus contains the classical (highly expressed and polymorphic) class I alpha and class II beta multigene families, which are reduced to one or two members, with many other genes moved away or deleted from the chicken genome altogether. We found that a single dominantly expressed class I gene determines the immune response to certain infectious pathogens, due to peptide-binding specificity and cell-surface expression level. This stands in stark contrast to well-studied mammals like humans and mice, in which every haplotype is more-or-less responsive to every pathogen and vaccine, presumably due to the multigene family of MHC molecules present. In order to approach the basis for a single dominantly expressed class I molecule, we have sequenced a portion of the B complex and examined the location and polymorphism of the class I (B-F) alpha, TAP and class II (B-L) beta genes. The region is remarkably compact and simple, with many of the genes expected from the MHC of mammals absent, including LMP, class II alpha and DO genes as well as most class III region genes. However, unexpected genes were present, including tapasin and putative natural killer receptor genes. The region is also organised differently from mammals, with the TAPs in between the class I genes, the tapasin gene in between the class II (B-L) beta genes, and the C4 gene outside of the class I alpha and class II beta genes. The close proximity of TAP and class I alpha genes leads to the possibility of co-evolution, which can drive the use of a single dominantly expressed class I molecule with peptide-binding specificity like the TAP molecule. There is also a single dominantly expressed class II beta gene, but the reason for this is not yet clear. Finally, the presence of the C4 gene outside of the classical class I alpha and class II beta genes suggests the possibility that this organisation was ancestral, although a number of models of organisation and evolution are still possible, given the presence of the Rfp-Y region with non-classical class I alpha and class II beta genes as well as the presence of multigene families of B-G and rRNA genes.

Journal ArticleDOI
TL;DR: These studies contribute to the understanding of the evolution of the MHC in mammals, to the development of broadly effective vaccines, and to breeding strategies aimed at improving resistance to infectious diseases.
Abstract: This review focuses on recent advances in research on the bovine major histocompatibility complex (BoLA), with specific reference to the genetic organization, polymorphism and function of the class II genes. The BoLA region is unlike the MHC of humans and mice in that a large inversion has moved several class II genes, including the TAP/LMP cluster, close to the centromere of bovine chromosome 23. Therefore, close linkage of MHC genes and other genes associated with the MHC in humans and mice does not appear to be required for normal immunological function. In cattle, polymorphism in the class IIa genes influences both the magnitude and the epitope specificity of antigen-specific T-cell responses to foot-and-mouth disease virus peptides. Disease association studies have demonstrated that BoLA alleles affect the subclinical progression of bovine leukemia virus (BLV) infection. This association is strongly correlated with the presence of specific amino acid motifs within the DRB3 antigen-binding domain. In addition to the practical significance of these findings, the association between BoLA and BLV provides a unique model to study host resistance to retrovirus infection in a non-inbred species. These studies contribute to our understanding of the evolution of the MHC in mammals, to the development of broadly effective vaccines, and to breeding strategies aimed at improving resistance to infectious diseases.

Journal ArticleDOI
TL;DR: Spontaneous colitis In knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflaminatory bowel disease (Crohn's disease and interactive colitis) and a major benefit is in thedevelopment of therapeutic strategies for the treatment of inflammatory bowel disease.
Abstract: Summary: Spontaneous colitis In knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflaminatory bowel disease (Crohn's disease and interactive colitis). Genetic and environmental factors, particularly the normal enteric flora, are important factors in the development of mucosal inflammation. The normal mucosal homeostasis is disrupted when there is either cytokine imbalance, abrogation of oral tolerance, alteration of epithelial barrier and function or loss of immunoregulatory cells. Some but not all immunodeficiencies, in the appropriate setting, lead to colitis. CD4-’ T cells have been identified as the pathogenic T ceils in colitis, which mediate inflammation by either the Thl or the Th2 pathway. The Thi pathway dominates most colitis models and in Crohn's disease. In contrase. the colitis in TCRa KO mice shares many features of ulcerative colitis including the dominance of Th2 pathway in colonic inflammation. A major benefit of these models is in the development of therapeutic strategies for the treatment of inflammatory bowel disease.

Journal ArticleDOI
TL;DR: A review of what is currently understood about how immuno‐modulatory mechanisms work and how they might play a role in maintaining the virus in a persistent state of infection is focused on.
Abstract: Adenovirus is a human pathogen that infects mainly respiratory and gastrointestinal epithelia. While the pathology caused by this virus is generally not life threatening in immunocompetent individuals, there is a large literature describing its ability to establish a persistent infection. These persistent infections typically occur in apparently healthy individuals with no outward signs of disease. Such a long term and benign interaction between virus and immune system requires adenoviruses to dampen host antiviral effector mechanisms that would otherwise eliminate the virus and cause immune-mediated pathology to the host. Adenovirus devotes a significant portion of its genome to gene products whose sole function seems to be the modulation of host immune responses. This review focuses on what is currently understood about how these immunomodulatory mechanisms work and how they might play a role in maintaining the virus in a persistent state.

Journal ArticleDOI
TL;DR: IL‐12 is not only an important proinflammatory cytokine, which induces production of IFN‐γ and subsequent activation of phago‐cytic cells but also plays a major role in regulating the migration and proper positioning of effector cells.
Abstract: Interleukin (IL)-12 is required for the development of T-helper (Th) 1 cells, which have been shown to be important for protective cell-mediated immune responses against a variety of intracellular pathogens. Recent studies have clarified the sources and the regulation of IL-12 production leading to Th1 development against microbes. Expression of IL-12R is necessary for maintaining IL-12 responsiveness and controlling Th1 lineage commitment. Advances in this area have included a broader understanding of the factors involved in the regulation of the IL-12R beta 2 signaling component. Expression of this receptor subunit in humans is critically influenced by IL-12 and type I interferons. IL-12 signaling results in STAT4 activation and interferon (IFN)-gamma production. Recent evidence suggests that IL-12 also modulates a number of genes involved in leukocyte trafficking. Thus, IL-12 is not only an important proinflammatory cytokine, which induces production of IFN-gamma and subsequent activation of phagocytic cells but also plays a major role in regulating the migration and proper positioning of effector cells.

Journal ArticleDOI
TL;DR: Two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response are described, which can provide insights into virus‐host interactions and also provide new insights into the complex immune system.
Abstract: Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response The first strategy is the production of virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is "virus friendly" The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus-host interactions and also provide new insights into the complex immune system

Journal ArticleDOI
TL;DR: Most hematopoietic cells express a wide variety of receptors for tbe Fc portion of immunoglobulins (FcR) belonging to the immun‐noreceptor family, and ITAMs and cyiosolic effectors of cell signaling also determine FcyR's endocytic transport and antigen presentation capacities.
Abstract: Most hematopoietic cells express a wide variety of receptors for the Fc portion of immunoglobulins (FcR) belonging to the immunoreceptor family. FcRs are multichain complexes composed of ligand-binding alpha chains, which determine Ig binding, and signal tranduction subunits, bearing a conserved immunoreceptor tyrosine-based activation motif (ITAM). Besides signaling, most Fc gamma Rs also efficiently internalize antigen-antibodies complexes and thus induce efficient processing of antigens into peptides presented by major histocompatibility complex (MHC) class II molecules. Importantly, ITAMs and cytosolic effectors of cell signaling also determine Fc gamma R's endocytic transport and antigen presentation capacities.

Journal ArticleDOI
TL;DR: Two key steps control immune responses in mucosal tissues: the sampling and transepkhelial transport of antigens, and their targeting into professional antigen‐presenting cells in mucosa‐associated lymphoid tissue.
Abstract: Two key steps control immune responses in mucosal tissues: the sampling and transepithelial transport of antigens, and their targeting into professional antigen-presenting cells in mucosa-associated lymphoid tissue. Live Salmonella bacteria use strategies that allow them to cross the epithelial barrier of the gut, to survive in antigen-presenting cells where bacterial antigens are processed and presented to the immune cells, and to express adjuvant activity that prevents induction of oral tolerance. Two Salmonella serovars have been used as vaccines or vectors, S. typhimurium in mice and S. typhi in humans. S. typhimurium causes gastroenteritis in a broad host range, including humans, while S. typhi infection is restricted to humans. Attenuated S. typhimurium has been used successfully in mice to induce systemic and mucosal responses against more than 60 heterologous antigens. This review aims to revisit S. typhimurium-based vaccination, as an alternative to S. typhi, with special emphasis on the molecular pathogenesis of S. typhimurium and the host response. We then discuss how such knowledge constitutes the basis for the rational design of novel live mucosal vaccines.

Journal ArticleDOI
TL;DR: Using CD 1d knockout mice, it is demonstrated chat CDI d expression is required for the development of NK T cells, and α‐GalCer can inhibit disease in diabetes‐prone non‐obese diabetic mice, suggesting that α‐ GalCer may be useful for therapeutic intervention in these diseases.
Abstract: CD1 molecules represent a distinct lineage of antigen-presenting molecules that are evolutionarily related to the classical major histocompatibility complex (MHC) class I and class II molecules. Unlike the classical MHC products that bind peptides, CD1 molecules have evolved to bind lipids and glycolipids. Murine and human CD1d molecules can present glycolipid antigens such as alpha-galactosylceramide (alpha-GalCer) to CD1d-restricted natural killer (NK) T cells. Using CD1d knockout mice we demonstrated that CD1d expression is required for the development of NK T cells. These animals were also deficient in the rapid production of interleukin-4 and interferon-gamma in response to stimulation by anti-CD3 antibodies. Despite these defects, CD1d knockout animals were able to generate strong T-helper type 1 (TH1) and TH2 responses. Spleen cells from these animals neither proliferated nor produced cytokines in response to stimulation by alpha-GalCer. Repeated injection of alpha-GalCer into wild-type but not CD1d mutant mice was able to clear metastatic tumors. We further showed that alpha-GalCer can inhibit disease in diabetes-prone non-obese diabetic mice. Collectively, these findings with CD1d knockout animals indicate a critical role for CD1d-dependent T cells in various disease conditions, and suggest that alpha-GalCer may be useful for therapeutic intervention in these diseases.

Journal ArticleDOI
TL;DR: Investigation of genetic polymorphism at Mhc class II DRB loci in samples of musk‐ox from Canada and Greenland, moose from Sweden, Norway, Canada, and Alaska, roe deer from Norway and Sweden, and reindeer from Svalbard suggested trans‐species persistence of polymorphic sequence motifs rather than of allelic lineages.
Abstract: Genetic polymorphism at Mhc class II DRB loci was investigated in samples of musk-ox from Canada and Greenland; moose from Sweden, Norway, Canada, and Alaska; roe deer from Norway and Sweden; reindeer from Svalbard and Norway; fallow deer from Norway and Sweden; and red deer from Norway. The results were compared with published data on cattle, bison, goat, sheep, and red deer. Cattle-specific primers amplified a single DRB locus in all species except fallow deer and red deer, in which two loci were found. Single strand conformation polymorphism analysis and DNA sequence analysis were employed to detect genetic polymorphism. Complete monomorphism was found in musk-ox and fallow deer. Limited polymorphism was found in the moose, roe deer, and reindeer from Svalbard, whereas intermediate to extensive DRB diversity was present in reindeer from Norway and in bison, sheep, goat, cattle, and red deer. The restricted Mhc diversity in moose, roe deer, and fallow deer is notable in relation to the dramatic population expansion of moose and roe deer in Sweden during this century and since fallow deer is used for meat and game production with good results and without any marked disease problems. The results question the view that species or populations with restricted Mhc diversity have poor resistance to infectious diseases. A phylogenetic tree analysis revealed a clustering of DRB sequences within species rather than within allelic lineages across species. The results suggest trans-species persistence of polymorphic sequence motifs rather than of allelic lineages.

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TL;DR: Nef is a protein that may promote escape of HIV‐1 from immune surveillance and allow Infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens.
Abstract: Despite a strong cytotoxic T-lymphocyte (CTL) response directed against viral antigens, untreated individuals infected with the human immunodeficiency virus (HIV-1) develop AIDS. We have found that primary T cells infected with HIV-1 downregulate surface MHC class I antigens and are resistant to lysis by HLA-A2-restricted CTL clones. In contrast, cells infected with an HIV-1 in which the nef gene is disrupted are sensitive to CTLs in an MHC and peptide-specific manner. In primary T cells HLA-A2 antigens are downmodulated more dramatically than total MHC class I antigens, suggesting that nef selectively downmodulates certain MHC class I antigens. In support of this, studies on cells expressing individual MHC class I alleles have revealed that nef does not downmodulate HLA-C and HLA-E antigens. This selective downmodulation allows infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens. Downmodulation of MHC class I HLA-A2 antigens occurs not only in primary T cells, but also in B and astrocytoma cell lines. No effect of other HIV-1 accessory proteins such as vpu and vpr was observed. Thus Nef is a protein that may promote escape of HIV-1 from immune surveillance.

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TL;DR: The ability of infection‐ induced cytokines to stimulate non‐specific proliferation of memory phenotype T cells and partial activation of naive‐phenotype T cells implies that they play a complex role during primary immune responses w infectious agents.
Abstract: On the basis of cell surface markers, mature T cells are considered to have either a naive or a memory phenotype. These cells exhibit distinct types of kinetic behaviour in vivo. While naive-phenotype cells persist long term in a non-dividing state, memory-phenotype T cells include cycling cells and exhibit a more rapid rate of turnover; this has also been shown to be true for cells that can be definitively identified as naive or memory T cells respectively. The number of memory-phenotype (CD44hi) CD8+ T cells entering cell cycle is greatly increased after in vivo exposure to viruses, bacteria or components of bacteria. Accelerated turnover of memory T cells also occurs after the injection of a variety cytokines that are induced by infectious agents, including type I interferon (IFN-I). Although naive-phenotype T cells do not divide in response to these cytokines, they do exhibit signs of activation, including upregulation of CD69 after exposure to IFN-I. These findings suggest that the dissimilar in vivo kinetics of naive- and memory-phenotype T cells might reflect their divergent responses to cytokines. Furthermore, the ability of infection-induced cytokines to stimulate non-specific proliferation of memory-phenotype T cells and partial activation of naive-phenotype T cells implies that they play a complex role during primary immune responses to infectious agents.

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TL;DR: These results demonstrate that bystander activation is the must likely explanation for autoimmune disease development and suggests a further role for viruses in the reactivation and chronicity of autoimmune diseases.
Abstract: Conceptually, the initiation of autoimmune disease can be described as a three-stage process involving both genetic and environmental influences This process begins with the development of an autoimmune cellular repertoire, followed by activation of these autoreactive cells in response to a localized target and, finally, the immune system's failure to regulate these self-reactive constituents Viruses have long been associated with inciting autoimmune disorders Two mechanisms have been proposed to explain how a viral infection can overcome immunological tolerance to self-components and initiate an organ-specific autoreactive process; these mechanisms are molecular mimicry and bystander activation Both pathways, as discussed here, could play pivotal roles in the development of autoimmunity without necessarily excluding each other Transgene technology has allowed us and others to examine more closely the roles of these mechanisms in mice and to dissect the requirements for initiating disease These results demonstrate that bystander activation is the most likely explanation for disease development Additional evidence suggests a further role for viruses in the reactivation and chronicity of autoimmune diseases In this scenario, a second invasion by a previously infecting virus may restimulate already existing autoreactive lymphocytes, and thereby contribute to the diversity of the immune response