T helper cell differentiation occurs in the context of the extracellular cytokine milieu evoked by diverse microbes and other pathogenic stimuli along withTcell receptor stimulation. The culmination of these signals results in specification of T helper lineages, which occurs through the combinatorial action of multiple transcription factors that establish distinctive transcriptomes. In this manner, inducible, but constitutively active, master regulators work in conjunction with factors such as the signal transducer and activator of transcriptions (STATs) that sense the extracellular environment. The acquisition of a distinctive transcriptome also depends on chromatin modifications that impact key cis elements as well as the changes in global genomic organization. Thus, signal transduction and epigenetics are linked in these processes of differentiation. In this review, recent advances in understanding T helper lineage specification and deciphering the action of transcription factors are summarized with emphasis on comprehensive views of the dynamic T cell epigenome. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224760 [PubMed - as supplied by publisher]
Cancer and Inflammation: An Old Intuition with Rapidly Evolving New Concepts.
Annu Rev Immunol. 2011 Mar 24;
Authors: Trinchieri G
Abstract
Recent scientific advances have contributed much to the dissection of the complex molecular and cellular pathways involved in the connection between cancer and inflammation. The evidence for this connection in humans is based on the association between infection and chronic sterile inflammation with cancer. The decreased incidence of tumors in individuals who have used nonsteroidal anti-inflammatory drugs is supportive of a role for inflammation in cancer susceptibility. The increased incidence of tumors in overweight patients points to a role for adipose tissue inflammation and energy metabolism in cancer. Energy metabolism, obesity, and genetic instability are regulated in part by the relationship of the organism with commensal bacteria that affect inflammation with both local and systemic effects. Different aspects of inflammation appear to regulate all phases of malignant disease, including susceptibility, initiation, progression, dissemination, morbidity, and mortality. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224761 [PubMed - as supplied by publisher]
Induced CD4(+)Foxp3(+) Regulatory T Cells in Immune Tolerance.
Annu Rev Immunol. 2011 Mar 24;
Authors: Bilate AM, Lafaille JJ
Abstract
Regulatory T lymphocytes are essential to maintain homeostasis of the immune system, limiting the magnitude of effector responses and allowing the establishment of immunological tolerance. Two main types of regulatory T cells have been identified-natural and induced (or adaptive)-and both play significant roles in tuning down effector immune responses. Adaptive CD4(+)Foxp3(+) regulatory T (iTreg) cells develop outside the thymus under a variety of conditions. These include not only antigen presentation under subimmunogenic or noninflammatory conditions, but also chronic inflammation and infections. We speculate that the different origin of iTreg cells (noninflammatory versus inflammatory) results in distinct properties, including their stability. iTreg cells are also generated during homeostasis of the gut and in cancer, although some cancers also favor expansion of natural regulatory T (nTreg) cells. Here we review how iTreg cells develop and how they participate in immunological tolerance, contrasting, when possible, iTreg cells with nTreg cells. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224762 [PubMed - as supplied by publisher]
Innate Lymphoid Cells: Emerging Insights in Development, Lineage Relationships, and Function.
Annu Rev Immunol. 2011 Mar 24;
Authors: Spits H, Cupedo T
Abstract
Innate lymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array of effector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barrier surfaces. Their ability to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. Here, we review current data on developmental requirements, lineage relationships, and effector functions of two families of ILCs: (a) Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and (b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs in the pathology of immune-mediated inflammatory and infectious diseases including allergy. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224763 [PubMed - as supplied by publisher]
The Microbiome in Infectious Disease and Inflammation.
Annu Rev Immunol. 2011 Mar 24;
Authors: Honda K, Littman DR
Abstract
The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224764 [PubMed - as supplied by publisher]
Monogenic autoimmune syndromes provide a rare yet powerful glimpse into the fundamental mechanisms of immunologic tolerance. Such syndromes reveal not only the contribution of an individual breakpoint in tolerance but also patterns in the pathogenesis of autoimmunity. Disturbances in innate immunity, a system built for ubiquitous sensing of danger signals, tend to generate systemic autoimmunity. For example, defects in the clearance of self-antigens and chronic stimulation of type 1 interferons lead to the systemic autoimmunity seen in C1q deficiency, SPENCDI, and AGS. In contrast, disturbances of adaptive immunity, which is built for antigen specificity, tend to produce organ-specific autoimmunity. Thus, the loss of lymphocyte homeostasis, whether through defects in apoptosis, suppression, or negative selection, leads to organ-specific autoimmunity in ALPS, IPEX, and APS1. We discuss the unique mechanisms of disease in these prominent syndromes as well as how they contribute to the spectrum of organ-specific or systemic autoimmunity. The continued study of rare variants in autoimmune disease will inform future investigations and treatments directed at rare and common autoimmune diseases alike. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224765 [PubMed - as supplied by publisher]
Signaling by Myeloid C-Type Lectin Receptors in Immunity and Homeostasis.
Annu Rev Immunol. 2011 Mar 24;
Authors: Sancho D, Reis E Sousa C
Abstract
Myeloid cells are key drivers of physiological responses to pathogen invasion or tissue damage. Members of the C-type lectin receptor (CLR) family stand out among the specialized receptors utilized by myeloid cells to orchestrate these responses. CLR ligands include carbohydrate, protein, and lipid components of both pathogens and self, which variably trigger endocytic, phagocytic, proinflammatory, or anti-inflammatory reactions. These varied outcomes rely on a versatile system for CLR signaling that includes tyrosine-based motifs that recruit kinases, phosphatases, or endocytic adaptors as well as nontyrosine-based signals that modulate the activation of other pathways or couple to the uptake machinery. Here, we review the signaling properties of myeloid CLRs and how they impact the role of myeloid cells in innate and adaptive immunity. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224766 [PubMed - as supplied by publisher]
The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224768 [PubMed - as supplied by publisher]
The mechanisms that drive normal B cell differentiation and activation are frequently subverted byBcell lymphomas for their unlimited growth and survival. B cells are particularly prone to malignant transformation because the machinery used for antibody diversification can cause chromosomal translocations and oncogenic mutations. The advent of functional and structural genomics has greatly accelerated our understanding of oncogenic mechanisms in lymphomagenesis. The signaling pathways that normal B cells utilize to sense antigens are frequently derailed in B cell malignancies, leading to constitutive activation of prosurvival pathways. These malignancies co-opt transcriptional regulatory systems that characterize their normal B cell counterparts and frequently alter epigenetic regulators of chromatin structure and gene expression. These mechanistic insights are ushering in an era of targeted therapies for these cancers based on the principles of pathogenesis. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224767 [PubMed - as supplied by publisher]
Authors: Pillai S, Netravali IA, Cariappa A, Mattoo H
Abstract
Sialic acid-binding Ig-like lectins, or Siglecs, vary in their specificity for sialic acid-containing ligands and are mainly expressed by cells of the immune system. Many Siglecs are inhibitory receptors expressed in innate immune cells that regulate inflammation mediated by damageassociated and pathogen-associated molecular patterns (DAMPs and PAMPs). This family also includes molecules involved in adhesion and phagocytosis and receptors that can associate with the ITAM containing DAP12 adaptor. Siglecs contribute to the inhibition of immune cells both by binding to cis ligands (expressed in the same cells) and by responding to pathogen-derived sialoglycoconjugates. They can help maintain tolerance in B lymphocytes, modulate the activation of conventional and plasmacytoid dendritic cells, and contribute to the regulation of T cell function both directly and indirectly. Siglecs modulate immune responses, influencing almost every cell in the immune system, and are of relevance both in health and disease. Expected final online publication date for the Annual Review of Immunology Volume 30 is March 19, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
PMID: 22224769 [PubMed - as supplied by publisher]
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