The molecular apparatus that protects us against infection can also injure us by causing autoimmune or autoinflammatory disease. It now seems that at times, defects within the sensing arm of innate ...immunity contribute to diseases of this type. The initiation of an immune response is often microbe dependent and, in many cases, Toll‐like receptor (TLR) dependent. Positive feedback loops triggering immune activation may occur when TLR signaling pathways stimulate host cells in an unchecked manner. Or, immune activation may persist because of failure to eradicate an inciting infection. Or on occasion, endogenous DNA may trigger specific immune responses that beget further responses in a TLR‐dependent autoamplification loop. Specific biochemical defects that cause loop‐related autoimmunity have been revealed by random germline mutagenesis and by gene targeting. We have also developed some insight into critical points at which feedback loops can be interrupted.
TLRs and innate immunity Beutler, Bruce A.
Blood,
02/2009, Volume:
113, Issue:
7
Journal Article
Peer reviewed
Open access
One of the most fundamental questions in immunology pertains to the recognition of non-self, which for the most part means microbes. How do we initially realize that we have been inoculated with ...microbes, and how is the immune response ignited? Genetic studies have made important inroads into this question during the past decade, and we now know that in mammals, a relatively small number of receptors operate to detect signature molecules that herald infection. One or more of these signature molecules are displayed by almost all microbes. These receptors and the signals they initiate have been studied in depth by random germline mutagenesis and positional cloning (forward genetics). Herein is a concise description of what has been learned about the Toll-like receptors, which play an essential part in the perception of microbes and shape the complex host responses that occur during infection.
Precursor messenger RNA (pre-mRNA) splicing is catalyzed by an intricate ribonucleoprotein complex called the spliceosome. Although the spliceosome is considered to be general cell "housekeeping" ...machinery, mutations in core components of the spliceosome frequently correlate with cellor tissue-specific phenotypes and diseases. In this review, we expound the links between spliceosome mutations, aberrant splicing, and human cancers. Remarkably, spliceosome-targeted therapies (STTs) have become efficient anti-cancer strategies for cancer patients with splicing defects. We also highlight the links between spliceosome and immune signaling. Recent studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to missplicing of immune-related genes. Furthermore, several core spliceosome components harbor splicing-independent immune functions within the cell, expanding the functional repertoire of these diverse proteins.
The last common ancestor of plants and animals may have lived 1 billion years ago. Plants and animals have occasionally exchanged genes but, for the most part, have countered selective pressures ...independently. Microbes (bacteria, eukaryotes, and viruses) were omnipresent threats, influencing the direction of multicellular evolution. Receptors that detect molecular signatures of infectious organisms mediate awareness of nonself and are integral to host defense in plants and animals alike. The discoveries leading to elucidation of these receptors and their ligands followed a similar logical and methodological pathway in both plant and animal research.
Microbe recognition based on a small collection of germline-encoded receptors carries a hidden liability: the possibility that mutational changes in the proteome will lead to self-recognition. The ...risk of self-recognition is enhanced, because innate immune receptors display low specificity, as they are driven to accommodate heterogeneous signature molecules found in the microbial world. The proteome structure is globally constrained by the innate immune sensing apparatus to satisfy a proscription against self-reactivity. But accidents happen, and here it is proposed that mutations creating neo-ligands for innate immune receptors are the proximal cause of sterile inflammatory diseases, which in turn embody the selective pressure that constrains the proteome. Such mutations are predictably dominant and may occur in the germline and also in somatic cells (e.g. in lymphocytes), causing inflammatory effects upon clonal expansion. They may also account for the inflammatory character of selected neoplastic diseases. The neo-ligand hypothesis accounts for the heritability, ambiguous linkage characteristics, phenotypic heterogeneity, and natural history of diverse forms of sterile inflammation. It explains sterile inflammatory diseases as conditions in which aberrant immune signaling is caused by proteome encroachment upon the ligand-recognition space over which the innate immune system stands guard.
This focus analyzes some of the ways the innate immune system influences adaptive immune responses. Here the main principles and themes that govern this intricate relationship are discussed.
The BTB-ZF (broad-complex, tramtrack and bric-à-brac - zinc finger) proteins are encoded by at least 49 genes in mouse and man and commonly serve as sequence-specific silencers of gene expression. ...This review will focus on the known physiological functions of mammalian BTB-ZF proteins, which include essential roles in the development of the immune system. We discuss their function in terminally differentiated lymphocytes and the progenitors that give rise to them, their action in hematopoietic malignancy and roles beyond the immune system.
The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1β (IL-1β) and IL-18. We found here that activation of the ...NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3-dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division.
Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body iron content. Several proteins induce expression of the hepcidin-encoding gene Hamp in response ...to infection or high levels of iron. However, mechanism(s) of Hamp suppression during iron depletion are poorly understood. We describe mask: a recessive, chemically induced mutant mouse phenotype, characterized by progressive loss of body (but not facial) hair and microcytic anemia. The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6. Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter element(s). TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption.
The significance of type I interferons (IFN-alpha/beta) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune ...responses. This relevance is bolstered by discoveries that unambiguously establish IFN-alpha/beta, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-alpha/beta in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.
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