02/16f Innate Immunity Flashcards
What are the three functions of the innate immune system?
1) Provide initial responses to microbes
2) Recognize and eliminate dead and damaged tissues and initiate repair processes
3) Stimulate the adaptive immune response
What the three types of barriers to microorganism entry? Give an example of each
Anatomic/mechanical - epithelial cells, cilia
Physiologic/chemical - lysozyme, low pH
Bacteriologic - normal microbiota
What is lysozyme?
Antimicrobial enzyme found in the granules of neutrophils and abundant in tears, saliva, mucous, and breastmilk
Targets Gram-positive bacteria
What are defensins?
Proteins that kill bacteria by punching holes in microbial membranes
Produced by neutrophils, NK cells, and epithelial cells
How does the innate immune system recognize threats to the host? What does it recognize?
By distinguishing self vs. non-self molecular patterns
Recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), sensed by pattern recognition receptors (PRRs)
What are some general pathogen signatures?
Viruses - abnormal surface proteins and nucleic acids
Parasites - foreign membrane phospholipids
Fungi - foreign surface carbohydrates and glycoproteins
Bacteria - lipopolysaccharide, peptidoglycans, flagellin
What are four specific classes of CELL-ASSOCIATED PRRs?
Toll-like receptors
NOD-like receptors
RIG-like receptors
C-type lectin receptors
What are Toll-like receptors? What responses do they elicit in the cell?
Integral membrane glycoprotein PRRs Activate NKkB (pro-inflammatory transcription factor) and interferon response factors
Where in the cell are Toll-like receptors found? How does their location affect what they recognize?
Cell surface and endosomal
Cell surface receptors recognize molecules present on bacterial membranes, while endosomal receptors recognize molecules present within the cell
What are NOD-like receptors? What responses do they elicit?
Cytosolic protein that sense cytoplasmic PAMPs and DAMPs
Recruit proteins that promote inflammation and generate active forms of the inflammatory cytokine IL-1
What are RIG-like receptors? What responses do they elicit?
Cytosolic sensors of viral RNA
Induce production of antiviral interferons
What are C-type lectin receptors? What responses do they elicit?
Recognize carbohydrates on the surface of various microbes
Facilitates phagocytosis of microbes and stimulates subsequent adaptive immune responses
What are four specific classes of SOLUBLE PRRs?
Complement
Collectins
Pentraxins
Germline/natural antibodies
What are collectins? What responses do they elicit?
Collagen lectins
Bind to oligosaccharide structures or lipids
Promote aggregation and opsonization, complement activation, and inhibition of microbial growth
Modulate inflammatory responses and adaptive immune responses
What are pentraxins? What responses do they elicit?
Bind various targets, particularly lipoproteins
Promote agglutination, bacterial capsular swelling, and phagocytosis
What is the complement system?
A cascade of plasma proteins that opsonize microbes, recruit phagocytes, and directly kill microbes
What are natural/germline antibodies?
Antibodies (IgM) that are produced by B cells without exposure to foreign antigens
Many are specific for oxidized lipids
What are some specific DAMPs?
Nuclear or cytosolic proteins that are released following cell injury
Proteins derived from the extracellular matrix that are produced following cell injury
ATP
Uric acid
Oxidized membrane lipids
What are four of the molecules of innate immunity that “sound the alarm” by mediating inflammation?
Cytokines
Chemokines
Lipid inflammatory mediators
Acute phase reactants
What are cytokines?
Small glyopeptides with multiple activities, that facilitate innate immune functions and assist in activating inflammation
What are the three major proinflammatory cytokines?
Tumor Necrosis Factor alpha (TNFalpha)
Interleukin-1 (IL-1)
Interleukin-6 (IL-6)
What cells produce TNFa? What does it do?
Produced by mast cells and macrophages
Stimulates almost all cell types by increasing expression of inflammatory mediators and inducing local and systemic inflammatory responses
What cells produce IL-1? What does it do?
Produced by many cells, particularly macrophages
Increases expression of inflammatory mediators in almost all cell types
What cells produce IL-6? What does it do?
Produced by macrophages, endothelial cells, and fibroblasts
Stimulates neutrophil production in the bone marrow and acute phase reactant production in the liver
Induces differentiation of T helper cell populations
What are the systemic effects of proinflammatory cytokines?
Fever
Production of acute phase reactants by the liver
Hypotension
Intravascular thrombosis
Prolonged production of TNF can cause cachexia
What are the lipid inflammatory mediators? What do they do?
Prostaglandins and leukotrienes
Promote vasodilation, bronchoconstriction, and chemotaxis of PMNs
What are acute phase reactants? What do they do?
Molecules produced in the liver in response to circulating cytokines
Promote opsonization, complement activation, and degradation of extracellular matrix
Also bind iron to sequester it from microbes
What are the four types of resident innate immune cells?
Mast cells
Macrophages and other mononuclear phagocytes
Dendritic cells
Innate-like lymphocytes
What are mast cells?
Granular cells that are resident in tissues
Rapidly release TNFa, histamine, prostaglandins, leukotrienes, IL-4, and other factors
What are the effects of mast cell activation and granule release?
Activation of endothelial cells and dendritic cells
Vasodilation and increased vascular permeability
Lymph node response
Mucosal edema and mucous secretion
Smooth muscle contraction
What are macrophages? What are their functions?
Large phagocytic cells covered in PRRs and cytokine receptors
Ingest and destroy microbes and dead host cells
Produce cytokines
Present antigen to and activate memory T cells
Promote repair of damaged tissue
How do macrophages kill microbes?
Activated by Toll-like receptors to produce reactive oxygen species, nitric oxide, and proteolytic enzymes
What are dendritic cells? What are their functions?
Antigen-presenting cells
Activate naive T cells in secondary lymphoid organs
Produce cytokines and chemokines
What are plasmacytoid dendritic cells?
Atypical dendritic cells that are specialized for viral infections
Major source of type 1 interferon
What are innate-like lymphoctyes?
Atypical lymphocytes that perform innate functions
What are the six types of innate-like lymphocytes?
Natural killer cells Natural killer T cells Gamma-delta T cells Intraepithelial T cells B-1 cells Marginal zone B cells
What are intraepithelial T cells? What are their functions?
Innate lymphocytes found in the epidermis and mucosal epithelia
Recognize molecules associated with infected epithelial cells
Secrete cytokines, activate phagocytes, and kill infected cells
What are natural killer T cells?
Innate lymphocytes that share properties of both T cells and natural killer cells, and are specialized to recognize lipids and glycolipids
What are B-1 cells? What are their functions?
Innate lymphocytes found in the peritoneum and mucosal sites
Secrete IgM against microbial polysaccharides and lipids, independent of T cells
What are the endothelial cell responses to inflammation?
Vasodilation and increased permeability cause warmth and swelling
Expression of cell adhesion molecules and chemokines lead to increased cell adhesion and migration
What are the five types of cells that are recruited during an inflammatory response?
Neutrophils Monocytes (become macrophages) Natural killer cells Eosinophils Basophils
What are neutrophils? What are their functions?
Highly phagocytic granular cells that destroy microorganisms
Granules are filled with enzyme and other microbicidal substances
Possess a robust phagocyte oxidase system to produce ROS
What are monocytes? What are their functions?
Precursors to macrophages and some dendritic cell types
Become resident macrophages and tissue specific phagocytes
Recruited to sites of inflammation to become highly active “exudate” macrophages during inflammatory responses
What are natural killer cells?
Lymphocytes that play an important role against intracellular viruses and bacteria, and distinguish infected/stressed cells from healthy cells
What are KIRs? What do they do?
Killer cell Ig-like receptors - inhibit NK cells (allow them to recognize self) Bind a variety of class I MHC molecules and block the signaling pathways of activating receptors
How do NK cells destroy infected cells?
Make perforin - punches holes in target cell membranes
Express destructive enzymes
Express cytokines to activate other cells
What are basophils? What are their functions?
Circulating granulocytes similar to mast cells
Synthesize many of the same substances as mast cells (histamine, prostaglandins, TNFa, etc.)
Triggered by antigen binding to IgE
What are eosinophils? What are their functions?
Eosinophilic blood granulocytes that contain enzymes that destroy the cells walls of parasites
Active in fighting parasite infections and in allergic responses
How to neutrophils respond to infection?
Arrive first to site of infection, but don’t last long
Phagocytose bacteria and produce destructive enzymes, ROS, and defensins
Most active in extracellular bacterial infections
How do monocytes and macrophages respond to infection?
Arrive after neutrophils to the site of infection, and are longer-lasting
Eat dead and dying cells, produce proinflammatory cytokines and chemokines, and mediate tissue repair
Most active against intracellular bacteria and viruses
How do natural killer cells respond to infection?
Recognize abnormal cells through a combination of inhibitory and activating signals and receptors
Kill cells that fail to respond properly, and produce cytokines to alert and activate other cells
Most active in viral infections and against neoplastic cells
What are the characteristics of the innate antiviral response?
Immediate response - production of Type I Interferons, which induce an antiviral state in adjacent cells to limit the spread of virus
NK cells are also activated to kill virally-infected cells
What are Type I Interferons? What are their effects?
Cytokines that are released in response to a viral infection
Confer cell resistance to viral infection by inhibiting viral protein synthesis and nucleic acid replication
Increase the destructive power of NK cells and cytotoxic T cells
