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PubMed2005

Innate immunity and the heart.

The immune system of higher vertebrates consists of two components: the innate and adaptive immunity. While the adaptive immune system relies on somatically generated and clonally selected antigen receptors, the innate immune system detects the presence of pathogens by their evolutionarily highly conserved, relatively invariant structural motifs. Interestingly, recent data suggest that activation of the innate immune system could play an important role in various diseases without the direct involvement of infectious pathogens. For example, a number of inflammatory cytokines, including TNF (tumor necrosis factor), IL (interleukin)-1beta, IL-6 and IL-8, as well as iNOS (inducible nitric oxide synthase), all components of innate immunity, are also implicated in ischemia/reperfusion injury, and in the abnormal myocardial remodeling characteristic of chronic heart failure. Understanding of the regulation and activation of the innate immune system in diseases not obviously related to an immune response to specific pathogen could provide new therapeutic targets for cardiovascular diseases. Thus, in this review, we provide a general overview of the components of innate immunity with a focus on humoral factors, their role in the response to foreign pathogens, and their potential role in the response to tissue injury (i.e., the "Expanded Self-Non-Self" and the "Danger" theories of immune activation).

Animals↗

PubMed2004

Innate immunity in aging: impact on macrophage function.

Innate and adaptive immune functions decline with age, leading to increased susceptibility to infectious diseases and cancer, and reduced responses to preventive vaccination in the elderly population. Macrophages function as 'pathogen sensors' and play an important role in the initiation of inflammatory responses, elimination of pathogens, manipulation of the adaptive immune response and reparation of damaged tissue. In this paper, we review the literature addressing the impact of aging on the macrophage population.

Aging↗

PubMed2005

Defects in mucosal immunity leading to Crohn's disease.

Crohn's disease (CD) is characterized by patchy transmural inflammation involving any part of the intestinal tract. Animal models have provided a great deal of insight into the pathogenesis of CD, but no animal model has recapitulated the full spectrum of manifestations witnessed in human disease. The defects in mucosal immunity in CD can be divided into those that involve the epithelial barrier, those that involve the innate immune response, and finally, defects in the adaptive immune response. Defects in the epithelial barrier in CD include an increase in intestinal permeability, increased adherence of bacteria, and decreased expression of defensins. Murine and human studies have demonstrated an increased expression of T-helper 1 (Th1) cytokines by lamina propria lymphocytes. This increased Th1 cytokine expression is driven by interleukin-12 (IL-12)/IL-23 and tumor necrosis factor-like 1A (TL1A) production by antigen-presenting cells, resulting in Tbet expression by CD4+ T cells. Another dimension of the inappropriate immune response in CD is T-cell and B-cell reactivity to luminal microbes. With the identification of the nucleotide-binding oligomerization domain 2 (NOD2) gene as a susceptibility gene, defects in the innate immune response are beginning to be explored. One may consider a model in which defective innate immune clearance of pathogens or commensal bacteria in CD leads to an inappropriate adaptive immune response to the commensal flora.

Animals↗

PubMedDate not supplied

The relationship between major histocompatibility receptors and innate immunity in teleost fish.

Studies of the innate immune system have recently shown that, in addition to its role in producing the primary response that slows down pathogens, it may also play an important role in initiating and directing the type of response that the adaptive immune system makes. These discoveries have shown a complex web of control containing new roles for the innate immune system in organizing responses of T-cell to antigens being presented by major histocompatibility receptors, as well as new roles for those receptors in innate immune responses. Both of these activities are managed through feedback networks involving elements of both the innate and adaptive immune system. This paper will discuss these newly discovered interactions and how they are influencing current theories regarding the initiation of adaptive immune responses. In particular, it will highlight the recent progress that is being made towards understanding these relationships in the immune systems of teleost fish.

Adaptation, Physiological↗

PubMed2003

16. Immunologic lung disease.

This review summarizes the recent advances regarding pathogenesis, diagnosis, and treatment of immunological diseases of the lung. Rather than attempt a comprehensive analysis, we have focused on selected diseases that are of particular relevance to the practicing physician, and the material has been organized according to the dominant immunologic mechanisms underlying the disease. Because of the redundancy that characterizes the mammalian immune repertoire, this system of classification inevitably produces overlap but facilitates acquisition of what is otherwise a disparate collection of facts. The principal lung immunologic mechanisms are most broadly classified as innate or adaptive immune processes. Innate immunity includes neutrophils and complement that are important in diseases, such as pneumonia and the acute respiratory distress syndrome. Adaptive immunity involves T and B cells capable of recognizing discrete antigens. T(H)1- and T(H)2-dependent adaptive immune responses underlie some of the most common and important of lung diseases, including tuberculosis and asthma, respectively. Other important immunopathologic processes include granulomatous inflammation that characterizes sarcoidosis and Churg-Strauss vasculitis, and autoimmunity, which is characteristic of antiglomerular basement membrane disease and others.

Humans↗

PubMed2005

TLR signalling and the function of dendritic cells.

The recognition of microbes by innate immune cells initiates activation of the whole immune system. Toll-like receptors (TLRs) are known to recognize various components of invading pathogens. At present, the natural ligands for almost all TLR members have been identified. TLRs are expressed on many types of cells including macrophages and dendritic cells (DCs). The recognition of invading microbes by TLRs on DCs induces proinflammatory cytokine production and enhanced antigen presentation to naive T cells, and finally activates antigen-specific adaptive immune responses. The sequential activation of innate and subsequent adaptive immunity are crucial steps to eradicate invading pathogens. Recently, the TLR signalling pathway has been intensively investigated. Accumulating evidence indicates that, at least, four adaptor molecules are involved in TLR signalling and provide their signalling specificities. Distinct TLR ligands provide distinct activation status and cytokine production patterns for antigen presenting cells, resulting in the induction of differential immune responses. Thus, TLRs are critical molecules to induce not only inflammatory responses but also fine-tuned adaptive immune responses depending on invading pathogens.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Recognition strategies in the innate immune system of ancestral chordates.

Many components of the innate immune system in vertebrates can be reliably traced to urochordates and successful strategies for the detection and elimination of pathogens are present at that level of animal evolution, but the issue of where and how the adaptive immune system emerged is still obscure. There is a paucity of evidence for a gradual transition from the innate immune system of invertebrates to the recombinatorial immune system of higher vertebrates. None of the classical elements of MHC based transplantation immunity (MHC, TCR) or humoral immunity (Ig) have been found in urochordates or Agnathans. Nevertheless there is abundant evidence for adaptive immune responses in the agnathans. This remarkable paradox raises a number of questions. How do these ancestral chordates discriminate between the constituents of the external world and the constituents of "self"? Are these strategies universal within the animal kingdom and among chordates, or are different strategies used by representatives of the different taxonomic groups? The current state of our knowledge indicates that the immune system of lower chordates is very different from that of cartilaginous fishes. Pure homology hunting for vertebrate-specific immuno-relevant molecules in invertebrates is therefore of limited value. A more promising approach may involve unbiased functional screening methods. To understand better the evolution of adaptive immune systems, more comparative data from jawless vertebrates (lamprey or hagfish) and a representative of Acrania (e.g. Amphioxus) are clearly needed.

Animals↗

PubMed2002

Dendritic cells: a complex simplicity.

Dendritic cells (DC) are essential antigen-presenting cells that initiate and regulate adaptive immune responses. There are distinct DC populations of diverse origins, which develop from hematopoietic progenitors already committed to the lymphoid or the myeloid lineages and, in the latter case, even from terminally differentiated macrophages. One may assume that DC of lymphoid origin are dedicated to the adaptive immune system, along which they have phylogenetically co-evolved, whereas myeloid DC would be more involved as an interface between the innate and adaptive immune systems. However, any DC can ultimately present antigens in either an immunogenic or tolerogenic manner according to whether they are more or less or not at all activated towards maturation, depending on the condition under which they encountered antigen. Hence, DC either induce the appropriate immune response to pathogens or prevent autoimmune reactivity. Thus, besides default programming, which should be necessary to face the challenges of their usual setting, each type of DC can also display functions that are similar, in an instructive mode, to elicit immune responses deemed necessary for unexpected stimuli. In such a system, DC provide enough flexibility and sufficient redundancy to ensure that an essential function of the immune system, i.e., passing information from its innate to adaptive arms and affecting the latter's responses, occurs under optimal conditions. Working on the basis of such a unified theory of DC diversity should be useful for learning to adequately manipulate the immune system for the development of cellular immunotherapy.

Animals↗

PubMed2001

T cell senescence.

The aging of the immune system, referred to as immunosenescence, is associated with a dramatic reduction in responsiveness as well as functional dysregulation. This deterioration of immune function with advancing age contributes to the increased incidence among the elderly of morbidity and mortality from infectious disease, and possibly autoimmunity and cancer. In mammals, the defense for fighting infectious agents is composed of the innate and adaptive immune systems. Macrophages, granulocytes, and natural killer cells are the major components of the innate system whereas T and B lymphocytes comprise the adaptive system. Although both compartments are affected, adaptive immunity is most susceptible to the deleterious effects of aging. Innate immunity functions immediately after birth and manifests little change throughout life. In contrast, adaptive immunity is immature at birth, peaks at puberty and progressively declines thereafter. Though marginal alterations in B lymphocytes are apparent, the dramatic decline in humoral and cell-mediated responses is predominantly the consequence of senescent T cells. The following review focuses on the aging effect on T cells as reflected in altered function, subset representation, development, lifespan and activation. Age-associated alterations in antigen presenting cells are also discussed since these cells are required for T cell activation and may impact T cell function.

Aging↗

PubMed2006

Lipid-binding hSH3 domains in immune cell adapter proteins.

SH3 domains represent versatile scaffolds within eukaryotic cells by targeting proline-rich sequences within intracellular proteins. More recently, binding of SH3 domains to unusual peptide motifs, folded proteins or lipids has been reported. Here we show that the newly defined hSH3 domains of immune cell adapter proteins bind lipid membranes with distinct affinities. The interaction of the hSH3 domains of adhesion and degranulation promoting adapter protein (ADAP) and PRAM-1 (Promyelocytic-Retinoic acid receptor alpha target gene encoding an Adaptor Molecule-1), with phosphatidylcholine-containing liposomes is observed upon incorporation of phosphatidylserine (PS) or phosphoinositides (PIs) into the membrane bilayer. Mechanistically we show that stable association of the N-terminal, amphipathic helix with the beta-sheet scaffold favours lipid binding and that the interaction with PI(4,5)P(2)-containing liposomes is consistent with a single-site, non-cooperative binding mechanism. Functional investigations indicate that deletion of both amphipathic helices of the hSH3 domains reduces the ability of ADAP to enhance adhesion and migration in stimulated T cells.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Toll-like receptors and acquired immunity.

Toll-like receptors are a family of pattern recognition receptors (PRRs) that evolved to detect microbial infection. These receptors recognize conserved molecular products derived from different classes of microorganisms, including Gram-positive and -negative bacteria, fungi, protozoa and viruses. Following recognition of ligands TLRs initiate signaling events that result in acute innate responses. In addition, TLRs are responsible for initiation of adaptive immune responses against pathogen-derived antigens primarily through triggering dendritic cell activation. Control of adaptive immunity by TLRs is a complex phenomenon and much needs to be understood about how different TLRs tailor the outcome of adaptive immune responses to the advantage of the host. Although TLRs have evolved to induce protective immune responses, under some circumstances, activation of these receptors may lead to autoimmune diseases.

Animals↗

PubMed2007

IL-17 family cytokines and the expanding diversity of effector T cell lineages.

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.

Animals↗

PubMed2002

Control of Mycobacterium tuberculosis through mammalian Toll-like receptors.

An efficient immune response against the intracellular pathogen Mycobacterium tuberculosis is critically dependent on rapid detection of the invader by the innate immune response and the activation of the adaptive immune response. Toll-like receptors (TLRs) contribute to innate immunity by the detection of Mycobacteria-associated molecular patterns and mediating the secretion of antibacterial effector molecules. TLRs influence the adaptive immune response by upregulation of immunomodulatory molecules supporting the development of a Th1-biased T cell response. In this manner, activation of TLRs contributes to defense against microbial infection.

Animals↗

PubMed2006

One day is enough: rapid and specific host-parasite interactions in a stickleback-trematode system.

Red Queen models of host-parasite coevolution are based on genotype by genotype host-parasite interactions. Such interactions require a genotype specific host defence and, simultaneously, a genotype specific parasite infectivity. Specificity is defined here as defence or infection ability successful against only a subset of genotypes of the same species. A specific defence depends on detectable genotypic variation on the parasite side and on a host defence mechanism that differentiates between parasite genotypes. In vertebrates, the MHC-based adaptive immune system can provide such a defence mechanism, but it needs at least several days to get fully mounted. In contrast, the innate immune system is immediately ready. The trematode parasite species used here reaches the immunologically protected eye lens of its three-spined stickleback (Gasterosteus aculeatus) host within 24 h. Thus, it disappears too fast for the fully mounted MHC-based adaptive immune system. In a complete cross-infection experiment using five fish-families and five parasite-clones, we found for the first time fish-family by parasite-clone interactions in vertebrates, although the parasite was only exposed to the immune system for maximally one day. Such interactions require a fast genotype specific defence, suggesting the importance of other defence mechanisms than the too slow, fully mounted adaptive immune system in vertebrates.

Adaptation, Physiological↗

PubMed2005

Adapting to a changing world: RAG genomics and evolution.

The origin of the recombination-activating genes (RAGs) is considered to be a foundation hallmark for adaptive immunity, characterised by the presence of antigen receptor genes that provide the ability to recognise and respond to specific peptide antigens. In vertebrates, a diverse repertoire of antigen-specific receptors, T cell receptors and immunoglobulins is generated by V(D)J recombination performed by the RAG-1 and RAG-2 protein complex. RAG homologues were identified in many jawed vertebrates. Despite their crucial importance, no homologues have been found in jawless vertebrates and invertebrates. This paper focuses on the RAG homologues in humans and other vertebrates for which the genome is completely sequenced, and also discusses the main contribution of the use of RAG homologues in phylogenetics and vertebrate evolution. Since mutations in both genes cause a spectrum of severe combined immunodeficiencies, including the Omenn syndrome (OS), these topics are discussed in detail. Finally, the relevance to genomic diversity and implications to immunomics are addressed. The search for homologues could enlighten us about the evolutionary processes that shaped the adaptive immune system. Understanding the diversity of the adaptive immune system is crucially important for the design and development of new therapies to modulate the immune responses in humans and/or animal models.

Acclimatization↗

PubMed2002

A newly discovered function of palatine tonsils in immune defence: the expression of defensins.

The palatine tonsils have an undoubted role in the immune defence system. After antigen contact an effective adaptive immune response by B- and T-cell lymphocytes will be released. In addition the palatine tonsils seem to exert influence to the defence by the innate immune system. Therefore, we studied the ability of palatine tonsils to express different alpha and beta defensins and to find out any distinctions in chronic inflamed tonsils. Total RNA of 49 specimens of hyperplastic tonsils and chronic tonsillitis with pathological provided evidence of Actinomyces israelii was isolated using TRIzol protocol, reverse transcribed and the HNP-1, HNP-4, HBD-1 and HBD-2 gene expression densitometric determined, standardised in relation to glycerinaldehyd-3-phosphatdehydrogenase gene expression, after a semiquantitative polymerase chain reaction was performed. mRNA of HNP-1, HNP-4, HBD-1 and HBD-2 was detected in tissue samples, but their amount differed within the two defensin families and tissue of origins. HBD-1 was detected in all 49 tissues of hyperplastic tonsils and chronic tonsillitis. Only in chronic inflamed tonsils the amount of HBD-2 mRNA expression was significant increased. In these specimens also mean relative expression rate of all defensins was observed to be manifestly increased. Palatine tonsils express mRNA for different alpha and beta defensins and this expression suggest a newly supposed function in immune defence: the participation in the innate, non-adaptive immune system. Thus, palatine tonsils have a potentially influence in the growth and control of the physiological mouth bacteria by their bactericidal activity.

Actinomyces↗

PubMed2006

The leukocyte receptor complex in chicken is characterized by massive expansion and diversification of immunoglobulin-like Loci.

The innate and adaptive immune systems of vertebrates possess complementary, but intertwined functions within immune responses. Receptors of the mammalian innate immune system play an essential role in the detection of infected or transformed cells and are vital for the initiation and regulation of a full adaptive immune response. The genes for several of these receptors are clustered within the leukocyte receptor complex (LRC). The purpose of this study was to carry out a detailed analysis of the chicken (Gallus gallus domesticus) LRC. Bacterial artificial chromosomes containing genes related to mammalian leukocyte immunoglobulin-like receptors were identified in a chicken genomic library and shown to map to a single microchromosome. Sequencing revealed 103 chicken immunoglobulin-like receptor (CHIR) loci (22 inhibitory, 25 activating, 15 bifunctional, and 41 pseudogenes). A very complex splicing pattern was found using transcript analyses and seven hypervariable regions were detected in the external CHIR domains. Phylogenetic and genomic analysis showed that CHIR genes evolved mainly by block duplications from an ancestral inhibitory receptor locus, with transformation into activating receptors occurring more than once. Evolutionary selection pressure has led not only to an exceptional expansion of the CHIR cluster but also to a dramatic diversification of CHIR loci and haplotypes. This indicates that CHIRs have the potential to complement the adaptive immune system in fighting pathogens.

Alternative Splicing↗

PubMed2005

Augmenting T helper cell immunity in cancer.

Cancer specific immunity elicited with vaccines has traditionally focused on the activation of the CD8 cytolytic T lymphocyte (CTL) often involving direct stimulation of immunity using HLA-class I binding peptide epitopes. Recently it has become clear that activation of the CTL immune effector arm alone is insufficient to mediate an anticancer response. A major problem is that CD8 T cells alone can not be sustained without the concomitant activation of CD4 T helper (Th) cells. In fact, it is now widely recognized that the Th cell regulates nearly all aspects of the adaptive immune response. In addition, Th cells can recruit the innate immune system during immune augmentation. Therefore, the focus of the immune response in cancer has shifted away from activating CTL immunity alone to activating Th cell immunity alone or concurrently with CTL. Evidence suggests that activating the Th cell is sufficient to get a complete adaptive immune response because, once activated, the Th cell will elicit endogenous CD8 T cell and humoral immunity. In this review, we discuss the role of the Th cell in the adaptive immune response to cancer, how peptides that are capable of activation of Th cells are identified, and the clinical translation of newly identified candidate Th cell peptide epitopes to human cancer specific vaccines. Over the next decade, studies should begin to further define how we can manipulate the Th immune effector arm to achieve effective antitumor immunity.

Animals↗