Chapter 2 Study Guide 1.pdf

Chapter 2 • • 1 The two principal types of reactions of the innate immune system are inflammation and antiviral defense. The innate immune system responds in essentially the same way to repeat encounters with a microbe, whereas the adaptive immune system mounts stronger, more rapid, and thus more...

Chapter 2 • • 1 The two principal types of reactions of the innate immune system are inflammation and antiviral defense. The innate immune system responds in essentially the same way to repeat encounters with a microbe, whereas the adaptive immune system mounts stronger, more rapid, and thus more effective responses on successive encounters with a microbe. • Can the innate system or adaptive system recognize more antigens? Adaptive Immune Response. The cells and molecules of innate immunity recognize and respond to a limited number of microbial structures, much less than the almost unlimited number of microbial and nonmicrobial antigens that can be recognized by the adaptive immune system. • What are PAMPs? PAMPs, or pathogen-associated molecular patterns, are microbial molecules that stimulate innate immunity. They are present in infectious agents (pathogens) and shared by microbes of the same type, signifying that they are molecular patterns. • Question: What has the greater number of types of receptors? INNATE Answer: Innate Immunity: Has more different types of invariant receptors (<100). Adaptive Immunity: Has only two types of receptors (Ig and TCR), but there are millions of variations of each. • Difference in genetics of innate and adaptive. The innate immune system and the adaptive immune system differ in the genetics of their receptors. The receptors of the innate immune system are encoded by inherited genes that are identical in all cells. The pattern recognition receptors of the innate immune system are nonclonally distributed, meaning identical receptors are expressed on all cells of a particular type, such as macrophages. This allows many cells of innate immunity to recognize and respond to the same microbe. In contrast, the antigen receptors of the adaptive immune system are encoded by genes formed by rearrangement of gene segments during lymphocyte development, resulting in many clones of B and T lymphocytes, each expressing a unique receptor. The cellular locations of receptors in the innate immune system vary. • What is the outcome of stimulation? The stimulation of Toll-like receptors (TLRs) triggers signaling mechanisms that involve adaptor proteins, ultimately leading to the activation of transcription factors. These transcription factors, in turn, stimulate the production of proteins responsible for mediating inflammation and antiviral defense. Chapter 2 • 2 What is the difference between RIG-like receptors and the NLRP3 inflammasome? RLRs primarily detect viral RNA and induce an antiviral response, while the NLRP3 inflammasome responds to various forms of cellular stress or damage, activating inflammatory processes. • The RIG-like receptors (RLRs) are cytosolic proteins that sense viral RNA and induce the production of the antiviral type I IFNs. RIG-like receptors (RLRs): Cytosolic receptors of the innate immune system that recognize viral RNA and induce production of type I interferons. The two best-characterized RLRs are RIG-I (retinoic acid–inducible gene I) and MDA5 (melanoma differentiation-associated gene 5). One of the best-characterized inflammasomes uses NLRP3 (NOD-like receptor family, pyrin domaincontaining 3) as a sensor. The NLRP3 inflammasome is expressed in innate immune cells, including macrophages and neutrophils, as well as keratinocytes in the skin and other cells. How NLRP3 recognizes such diverse types of cellular stress or damage is not clearly understood. Inflammasome activation is tightly controlled by post-translational modifications such as ubiquitination and phosphorylation, which block inflammasome assembly or activation, and some micro-RNAs, which inhibit NLRP3 messenger RNA. NLRP3 (a NOD-like pattern recognition receptor). • What is the difference between RIG-like receptors and the STING pathway? RLRs primarily recognize viral RNA, whereas the STING pathway is activated in response to cytosolic DNA. RLRs signal through interactions with MAVS on the mitochondrial membrane, while the STING pathway involves cGAMP binding to STING on the endoplasmic reticulum. RLR activation leads to the production of type I interferons, contributing to an antiviral response. In contrast, the STING pathway also leads to type I interferon production but is more broadly involved in detecting cytosolic DNA from various pathogens. T The RIG-like receptors (RLRs) are cytosolic proteins that sense viral RNA and induce the production of the antiviral type I IFNs. RIG-like receptors (RLRs): Cytosolic receptors of the innate immune system that recognize viral RNA and induce production of type I interferons. The two best-characterized RLRs are RIG-I (retinoic acid–inducible gene I) and MDA5 (melanoma differentiation-associated gene 5). Most innate cytosolic DNA sensors engage the Stimulator of IFN genes (STING) pathway to induce type 1 IFN production. In this pathway, cytosolic dsDNA binds to the enzyme cyclic GMP-AMP synthase (cGAS), which activates the production of a cyclic dinucleotide signaling molecule called cyclic GMP-AMP (cGAMP). This cGAMP molecule binds to an endoplasmic reticulum membrane adaptor protein called stimulator of interferon gene (STING). In addition, bacteria themselves produce other cyclic dinucleotides that also bind to STING. Upon binding these cyclic dinucleotides, STING initiates signaling events that lead to transcriptional activation and expression of type I IFN genes. STING also stimulates autophagy, a mechanism by which cells degrade their own organelles in lysosomes. Autophagy is used in innate immunity to deliver cytosolic microbes to the lysosome, where they are killed by proteolytic enzymes. Other cytosolic DNA sensors besides cGAS can also activate STING (Stimulator of IFN Genes), an adaptor protein located in the endoplasmic reticulum membrane, which is utilized by several cytoplasmic DNA sensor molecules to transduce signals that activate the IRF3 transcription factor, leading to type 1 IFN gene expression. Chapter 2 • • • 3 What happens when macrophages are activated? In innate immune responses, macrophages are activated and lead to the production of proteins that mediate inflammatory and microbicidal functions of these cells. Cell surface complement receptors promote the phagocytosis of complement-coated microbes as well as activation of the macrophages. Macrophages serve several important roles in host defense: they ingest and destroy microbes, they clear dead tissues and initiate the process of tissue repair, and they produce cytokines that induce and regulate inflammation. How does the NK cell respond differently to virally infected cells than to macrophages that have phagocytosed a microbe? In summary, NK cells have distinct responses to virally infected cells and macrophages with internalized microbes. They directly kill infected cells, contributing to the elimination of viral reservoirs, and collaborate with macrophages to enhance the antimicrobial activity against phagocytosed microbes. NK cells recognize infected and stressed cells and respond by killing these cells and by secreting the macrophage-activating cytokine IFN-γ. NK cells kill host cells infected by intracellular microbes, eliminating reservoirs of infection. NK cells respond to interleukin-12 (IL-12) produced by macrophages and secrete interferon-γ (IFN-γ), activating the macrophages to kill phagocytosed microbes. Activated NK cells also synthesize and secrete the cytokine interferon-γ (IFN-γ), activating macrophages to become more effective at killing phagocytosed microbes. Cytokines secreted by macrophages and dendritic cells encountering microbes enhance NK cells' ability to protect against infections. What are the 3 pathways of complement activation and how are they different and similar? • Alternative pathway: triggered by complement proteins on microbial surfaces in the absence of complement regulatory proteins on microbes, component of innate immunity. • Classical pathway: triggered by antibodies binding to microbes or antigens, component of the humoral arm of adaptive immunity. Lectin pathway: activated by mannose-binding lectin (MBL) binding to carbohydrate ligands on microbes, initiates classical pathway, component of innate immunity in the absence of antibodies. • What is the difference between TNF and Chemokines? Tumor Necrosis Factor (TNF) is produced primarily by macrophages, T cells, and mast cells. Its effects are diverse, with key cellular targets including endothelial cells (leading to activation and involvement in inflammation and coagulation), neutrophils (activation), the hypothalamus (inducing fever), the liver (stimulating synthesis of acute-phase proteins), and various cell types (contributing to apoptosis, muscle catabolism, and cachexia). Chemokines, on the other hand, are primarily sourced from macrophages, dendritic cells, endothelial cells, T lymphocytes, fibroblasts, and platelets. These signaling proteins play a crucial role in immune responses, with their principal effects directed towards leukocytes. They induce increased integrin affinity, promote chemotaxis (movement toward a chemical signal), and contribute to the activation of leukocytes in the immune system. Chapter 2 • 4 What changes a rolling leukocyte to firmly adhering? In summary, the transition of a rolling leukocyte to firmly adhering involves the activation of integrins, leading to their binding to endothelial ligands. This process is triggered by chemokines and is essential for the subsequent steps of leukocyte extravasation, including transmigration into the tissues where the immune response is needed. Rolling of leukocytes: The neutrophils become tethered to the endothelium, flowing blood disrupts this binding, the bonds reform downstream, and this repetitive process results in the rolling of the leukocytes along the endothelial surface. Firm adhesion: Leukocytes express another set of adhesion molecules called integrins, The firm binding of integrins to their ligands arrests the rolling leukocytes on the endothelium. The cytoskeleton of the leukocytes is reorganized, and the cells spread out on the endothelial surface. • What role do chemokines play in the migration of leukocytes to sites of infection? Chemokines play a crucial role in promoting the movement of leukocytes from the blood into the tissues. In the context of a site of infection, tissue macrophages and endothelial cells produce chemokines. These chemokines bind to proteoglycans on the luminal surface of endothelial cells and are displayed at a high concentration to the leukocytes that are rolling on the endothelium. This interaction is essential in the immune response: the immobilized chemokines bind to chemokine receptors on the leukocytes, leading to a rapid increase in the affinity of leukocyte integrins for their ligands on the endothelium. This process facilitates the firm adhesion of leukocytes to the endothelium, allowing them to migrate into the tissues and carry out their immune functions.