What transcription factors are activated leading to the production of type I interferons?
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IRF3, IRF7, and NF-κB.
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What transcription factors are activated leading to the production of type I interferons?
IRF3, IRF7, and NF-κB.
What is the function of cyclic GMP-AMP (cGAMP) in the STING pathway?
It binds to STING and initiates signaling for type I IFN gene expression.
What is the NLRP3 inflammasome responsible for processing?
Pro-interleukin-1β (pro-IL-1β) to active IL-1.
What additional function does STING have besides inducing type I IFN production?
It stimulates autophagy for degrading organelles and pathogens.
What types of receptors are found in innate immunity?
Innate immunity features various types of invariant receptors, such as Toll-like receptors and RIG-like receptors.
How does the innate immune system respond to DAMPs?
It serves to eliminate damaged cells and initiate tissue repair.
What is the role of innate immune receptors?
They are encoded by inherited genes and are identical across all cells expressing them.
How are most microbial infections acquired?
Through the epithelial barriers of the skin and gastrointestinal, respiratory, and genitourinary systems.
What molecule does cytosolic dsDNA bind to for signaling?
Cyclic guanosine monophosphate – adenosine monophosphate (cGAS).
What pathway do most innate cytosolic DNA sensors engage to induce type I IFN production?
The stimulator of IFN genes (STING) pathway.
What are the five major families of cellular receptors in innate immunity?
TLRs, C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and cytosolic DNA sensors (CDSs).
What is the primary role of innate immunity?
To provide early defense against infections.
What stimulates the production of neutrophils?
Cytokines known as colony-stimulating factors (CSFs).
How do microbes evade innate immunity compared to adaptive immunity?
Microbes cannot easily evade innate immunity by mutation, while they can evade adaptive immunity by mutating antigens, which are not essential for their survival.
What is the role of transcription factors activated by TLR signals?
They stimulate expression of cytokines and proteins involved in inflammatory and antiviral responses.
What role do cytosolic DNA sensors (CDSs) play in the immune response?
They recognize microbial dsDNA and activate signaling pathways for antimicrobial responses.
What are TLRs and where are they located?
TLRs (Toll-Like Receptors) are located on cell surfaces and endosomes, recognizing microbial proteins, lipids, and polysaccharides.
What do NLRs contain at their C-terminal?
A nucleotide oligomerization domain (NOD).
What is an example of a DAMP?
High mobility group box protein 1 (HMGB1) and extracellular adenosine triphosphate (ATP).
What can mutations affecting TLRs or their signaling molecules lead to?
Rare autosomal recessive diseases characterized by recurrent infections.
What infections are individuals with TLR-3 mutations particularly susceptible to?
Herpes simplex virus infections.
What is the role of leukocytes in inflammation?
They accumulate and activate at infection or tissue injury sites to kill extracellular microbes and eliminate damaged tissues.
What inflammatory diseases are associated with polymorphisms of the NOD2 gene?
Inflammatory bowel disease.
What is a key function of healthy cells in relation to innate immunity?
Healthy cells express molecules that block innate immune responses.
What are the questions focused on regarding innate immunity in this chapter?
How innate immunity recognizes microbes and damaged cells, how its components combat different microbes, and how it stimulates adaptive immune responses.
What are innate lymphoid cells?
Cells that produce cytokines and help in the defense against infections.
What does the formyl peptide receptor 1 recognize?
Polypeptides with an N-terminal formylmethionine, a specific feature of bacterial proteins.
What is the end result of TLR signaling?
Production of cytokines, adhesion molecules, and stimulation of adaptive immunity.
What is the role of pattern recognition receptors in innate immunity?
They recognize shared microbial structures, making innate immunity a highly effective defense mechanism against pathogens.
What are some other forms of inflammasomes that exist?
NLRP1, NLRC4, or AIM2.
Which two important NLRs are expressed in various cell types?
NOD1 and NOD2.
What is innate immunity?
A type of host defense that is always present and functional, ready to recognize and eliminate microbes and dead cells.
How does innate immunity differ from adaptive immunity?
Innate immunity provides immediate defense against infections, while adaptive immunity requires antigen stimulation and takes several days to develop.
What is the function of inflammasomes?
To activate inflammatory responses in the presence of pathogens.
What do TLRs in endosomes recognize?
They recognize nucleic acids released from ingested microbes.
Which kinases are recruited and activated by STING?
TBK1 (TANK-binding kinase 1).
What is the normal range of neutrophils in the blood?
4000 to 10,000 per μL.
What are defensins and cathelicidins?
Antimicrobial substances produced by epithelia.
What are the three steps depicting the functions of epithelia in innate immunity?
What distinguishes innate immunity from adaptive immunity?
Innate immunity has nonclonal receptors that recognize the same microbe, while adaptive immunity has diverse antigen receptors formed by gene rearrangement.
How does the adaptive immune system prevent autoimmunity?
By eliminating or inactivating self-reactive lymphocytes upon encounter with self antigens.
What are tissue-resident macrophages?
Macrophages that are always present in most healthy organs and tissues.
What is the function of mast cells in the immune response?
They release histamine and other mediators during allergic responses and inflammation.
What is the role of cytokines in innate immunity?
They are signaling molecules that mediate and regulate immunity and inflammation.
How do keratin and mucus contribute to pathogen defense?
Keratin forms a physical barrier, while mucus provides a chemical barrier against infection.
What protein does activated caspase-1 cleave during inflammasome activation?
Gasdermin D.
What is the estimated number of molecular patterns recognized by innate immunity?
About 1,000 molecular patterns.
What role do epithelia play in innate immunity?
They provide physical barriers and produce antimicrobial substances.
What do NOD1 and NOD2 recognize?
Different dipeptides derived from bacterial cell wall peptidoglycan.
What transcription factor do NOD1 and NOD2 activate?
NF-κB transcription factor.
Where is NOD2 highly expressed?
In intestinal Paneth cells in the small bowel.
How do neutrophils enhance phagocytosis?
By expressing receptors for complement activation products and antibodies that coat microbes.
What roles do phagocytes like Neutrophils and Macrophages play?
They are responsible for engulfing and destroying microbes.
How does the response of the innate immune system change with repeat encounters with a microbe?
The innate immune system responds in essentially the same way and does not remember prior encounters.
What mechanisms of defense does the innate immune system provide?
Defense at every stage of microbial infections.
What are mannose receptors involved in?
Phagocytosis of fungi and bacteria, and inflammatory responses to these pathogens.
What do NOD-like receptors (NLRs) sense?
DAMPs and PAMPs in the cytosol.
What is the function of intraepithelial T lymphocytes?
They presumably react against infectious agents that breach the epithelia, although their specificity is poorly understood.
What do RIG-like receptors (RLRs) recognize?
Viral RNA.
What induces the synthesis of pro-IL-1β?
Various PAMPs or DAMPs through pattern recognition receptor signaling.
What are damage-associated molecular patterns (DAMPs)?
Molecules released from damaged or necrotic host cells that the innate immune system recognizes.
What role does IRF3 play after phosphorylation?
It moves to the nucleus to induce type I IFN gene expression.
What diseases are associated with excessive accumulation of self DNA in the cytosol?
Systemic inflammatory diseases called interferonopathies.
What do RIG-I and MDA5 receptors recognize?
Cytosolic viral RNA.
What is the role of innate immunity in relation to the adaptive immune system?
Innate immunity instructs the adaptive immune system to respond effectively to different microbes.
Which cells detect microbes that breach epithelial barriers?
Resident macrophages, dendritic cells, and mast cells.
What is a key feature of the innate immune response in terms of its speed?
The innate immune response combats microbes immediately upon infection.
What enhances the binding of LPS to TLR-4?
MD2 protein.
What are some examples of microbial molecules that stimulate innate immunity?
Double-stranded RNA (dsRNA) and unmethylated CG-rich (CpG) oligonucleotides.
What is the role of NF-κB in TLR signaling?
To enter the nucleus and stimulate the production of proteins for inflammation and antiviral defense.
What is an essential part of tissue repair following an infection?
The regeneration of cells and restoration of tissue structure.
What is pyroptosis?
A form of programmed cell death characterized by cell swelling, loss of plasma membrane integrity, and release of inflammatory cytokines.
What are PAMPs and their significance in innate immunity?
PAMPs (pathogen-associated molecular patterns) indicate the presence of infectious agents and are recognized by innate immune receptors, which are specific for these shared structures.
What other active cytokine is produced by the inflammasome besides IL-1?
IL-18.
What are neutrophils also known as?
Polymorphonuclear leukocytes (PMNs).
What type of receptors are involved in recognizing microbes and damaged cells in innate immunity?
Cellular Receptors.
What are Toll-Like Receptors?
Receptors that recognize specific patterns on microbes to initiate immune responses.
How does the specificity of innate immunity differ from adaptive immunity?
Innate immunity has more limited and generalized responses compared to the specific responses of adaptive immunity.
What is the outcome of RIG-I and MDA5 activation?
Stimulation of type I interferon (IFN) production.
What are the main functions of the innate immune response?
It blocks microbial invasion, destroys microbes, and assists in clearing dead tissues and repairing damage.
What are monocytes and how do they relate to neutrophils?
Monocytes are less abundant than neutrophils and can differentiate into macrophages during inflammatory reactions.
What is the source of macrophages during early development?
Stem cells in the yolk sac of the fetal liver.
What enzyme is responsible for cleaving pro-IL-1β to its active form?
Caspase-1.
What is a characteristic of Natural Killer cells?
They can identify and destroy infected or cancerous cells without prior sensitization.
What is involved in the recruitment of phagocytes to infection sites?
Chemical signals from damaged tissues and pathogens attract phagocytes.
What diseases are associated with inflammasome activation?
Autoinflammatory syndromes, gout, and potentially atherosclerosis.
How do the receptors of innate immunity differ from those of adaptive immunity?
Innate immunity receptors are encoded in the germline with limited diversity, while adaptive immunity receptors are produced by somatic recombination and have greater diversity.
Which transcription factors are most important in TLR signaling?
Nuclear factor κ B (NF-κB) and interferon regulatory factors (IRFs).
What are some examples of second messenger molecules recognized by STING?
Cyclic di-GMP (c-di-GMP) and cyclic di-AMP (c-di-AMP).
What receptors are involved in recognizing fungal glucans in innate immunity?
Dectins, which are carbohydrate-recognizing proteins.
What do NOD and RIG refer to?
Founding members of families of structurally homologous cytosolic receptors for bacterial and viral products.
What do Paneth cells express in response to ingested pathogens?
Antimicrobial substances called defensins.
Which cells mediate innate immune defense against intracellular viruses?
Natural killer (NK) cells.
What is the role of cytokines in the immune response?
They initiate the process of inflammation.
Where do tissue-resident macrophages derive from?
Progenitors in the yolk sac or fetal liver during fetal development.
What type of stimuli can activate the NLRP3 inflammasome?
A wide variety of stimuli, including crystalline substances like uric acid.
How many different TLR proteins are there in humans?
10 different TLR proteins.
What physical and chemical barriers do epithelial cells provide?
They protect against infection at interfaces like skin, gastrointestinal tract, respiratory tract, and genitourinary tract.
What types of cellular stress or damage does the NLRP3 inflammasome recognize?
Nuclear damage, cholesterol crystals, extracellular ATP, reduced potassium ion concentration, and reactive oxygen species.
What triggers the activation of the NLRP3 inflammasome?
ATP, bacterial products, crystals, potassium efflux, and reactive oxygen species.
What physical barriers do epithelial cells form?
Keratin in the skin and secreted mucus in various systems.
What types of reactions does the innate immune system primarily perform?
Inflammation and antiviral defense.
What are NOD-Like Receptors responsible for?
Detecting intracellular pathogens and stress signals.
What are the earliest defense mechanisms at portals of entry for microbes?
Epithelia and mucus that provide physical barriers and antimicrobial molecules.
In what types of organisms is innate immunity present?
It is present in all multicellular organisms, including plants, invertebrates, and vertebrates.
What do different TLRs recognize?
Structurally diverse products of microbes.
What type of cytokine production is associated with neutrophils versus macrophages?
Neutrophils produce low levels per cell; macrophages produce large amounts requiring transcriptional activation.
What are pattern recognition receptors?
Receptors used by the innate immune system to detect microbes and damaged cells.
What is the role of signaling by the formyl peptide receptor 1?
Promotes migration and antimicrobial activities of phagocytes.
What are defensins and cathelicidins?
Antimicrobial peptides produced by epithelial cells that kill bacteria and some viruses.
What is the distribution of receptors in innate immunity?
Innate immunity receptors are nonclonal, meaning identical receptors are present on all cells of the same lineage.
How is the discrimination of self and nonself handled in innate immunity?
Innate immunity can recognize healthy host cells and often does not react to them.
How many types of innate immune receptors are estimated to exist?
About 100 types capable of recognizing around 1000 PAMPs and DAMPs.
What is the lifespan of neutrophils in tissues?
Only several hours.
What is the role of reactive oxygen species in neutrophils compared to macrophages?
Neutrophils rapidly induce reactive oxygen species, while macrophages have less prominent activity.
What active forms of cytokines do inflammasomes generate?
Interleukin-1β (IL-1β) and IL-18.
What role do plasma proteins, including those of the complement system, play in the blood?
They react against microbes that enter the circulation and promote their destruction.
What are Toll-Like Receptors (TLRs) named after?
A Drosophila protein called Toll, known for its role in development and fungal infection protection.
What are the main components of the innate immune system?
Epithelial cells, sentinel cells, circulating phagocytes, innate lymphoid cells, NK cells, and plasma proteins.
What are the two primary RLRs involved in antiviral response?
RIG-I and MDA-5.
What role do neutrophils play in infections?
They are the first and most numerous cell type to respond, particularly to bacterial and fungal infections.
What condition can mutations in MyD88 make individuals susceptible to?
Bacterial pneumonias.
What is the role of dendritic cells in innate immunity?
To capture and present antigens to T cells, bridging innate and adaptive immunity.
What types of microbial structures does the innate immune system recognize?
Shared structures not present in normal host cells, such as bacterial endotoxin and peptidoglycans.
Which TLRs recognize nucleic acids?
Endosomal TLRs, specifically TLR-3, TLR-7, TLR-8, and TLR-9.
What do TLR-4 specifically recognize?
Bacterial LPS (endotoxin) made by gram-negative bacteria.
What are intraepithelial lymphocytes?
T cell lineage lymphocytes that express antigen receptors of limited diversity, found in epithelial layers.
What role does gasdermin D play in pyroptosis?
The N-terminal fragment oligomerizes to form channels in the plasma membrane, allowing the egress of IL-1β and influx of ions, leading to cell swelling and pyroptosis.
What are the main differences between neutrophils and macrophages regarding their life span in tissues?
Neutrophils live for 1-2 days, while macrophages can live for days, weeks, or even years.
What do cytosolic RNA and DNA sensors detect?
Viral nucleic acids in the cytosol, signaling an immune response.
What do type I interferons (IFNs) do?
They block viral replication within host cells.
How does the innate immune system differentiate between self and non-self?
It evolved receptors specific for microbial structures and products of damaged cells, not substances in healthy cells.
What happens to monocytes during inflammatory reactions?
They enter extravascular tissues and differentiate into macrophages.
What do all TLRs contain that is crucial for their function?
A ligand-binding domain composed of leucine-rich motifs and a TIR domain.
What does TLR-3 specifically recognize?
dsRNA.
What cytokines do RLRs induce the production of when they sense viral RNA?
Type I interferons (IFNs).
How do neutrophils and macrophages differ in their response to activating stimuli?
Neutrophils respond rapidly and are short-lived; macrophages respond more slowly and have prolonged activity.
What are inflammasomes?
Multiprotein complexes that assemble in the cytosol of cells in response to microbes or cell injury.
What is the function of phagocytes in tissues?
They engulf and destroy microbes and damaged cells.
What is the function of TLRs in the plasma membrane?
To recognize cell wall components of bacteria.
What is the significance of the complement system?
It is a group of proteins that enhance the ability to clear microbes and promote inflammation.
What is phagocytosis?
The process by which phagocytes engulf and destroy pathogens.
How do RLRs initiate signaling for type I IFN production?
By interacting with a mitochondrial membrane protein called MAVS.