Innate Immunity PDF

# Innate Immunity - Block microbial invasion through epithelial barriers, two major reactions - Inflammation at site of infection/damage - Accumulation/activation of leukocytes and plasma proteins - Clearance of dead tissue and initiation of repair - Antiviral defense...

# Innate Immunity - Block microbial invasion through epithelial barriers, two major reactions - Inflammation at site of infection/damage - Accumulation/activation of leukocytes and plasma proteins - Clearance of dead tissue and initiation of repair - Antiviral defense - NK cells kill infected cells - Type I interferons block host cell viral replication # Antigen Recognition: Innate vs Adaptive - Both receptors encoded in germline DNA + normally discriminate self ## Innate: - Receptors are fixed and identical within each cell type, **nonclonal** - Can recognize a broad range of conserved microbial patterns ## Adaptive: - Highly specific for individual antigens - Receptors undergo somatic rearrangement and mutation for diversity - Can lead to autoimmunity # PAMPS/DAMPS - Recognized by pattern recognition receptors (PRRs) to initiate immune signaling - DAMPS are self-derived molecules released during tissue damage or cellular stress - PAMPS are microbial molecules like lipopolysaccharides and viral RNA # Toll-Like Receptors ## Cell-Surface TLRs 1. TLR-1, TLR-2, TLR-6: Bacterial lipopeptides 2. TLR-2: Bacterial peptidoglycan 3. TLR-4: LPS (lipopolysaccharide) 4. TLR-5: Bacterial flagellin ## Endosome TLRs 1. TLR-3: Double stranded RNA (dsRNA) 2. TLR-7, TLR-8: Single Stranded RNA (ssRNA) 3. TLR-9: CpG DNA # TLR Signaling 1. Through NF-kB - Activation of transcription factor and adaptive immunity - Acute inflammation 2. Through IFN regulatory factors - Activation of transcription factors - Antiviral action # Cell Surface/Extracellular Receptors 1. Toll-like receptors (TLRs) - various microbial structures (ex. cell wall lipid) 2. N-formylmethionine receptors - microbial peptides # Cytosolic Receptors - React to intracellular organisms and byproducts of damage 1. NOD (nucleotide oligomerization domain)-like receptors - DAMPS and PAMPS 2. RIG (retinoic acid-inducible gene) - like receptors - viral RNA 3. Cytosolic DNA sensors (CDSs) - microbial DNA 4. Lectin receptors - fungal glycans and mannose residues # Endosomal Receptors - Detect partially digested organism antigens 1. Toll-like receptors (TLRs)- various microbial structures (ex. nucleic acids of microbes) # Inflammasome - Various types of multi-protein complex that assembles in cytosol of cells in response to microbes or cell injury - Function is to activate caspase-1 and produce inflammatory cytokines # Functions of Epithelia - Physical barrier to infection - Killing of microbes by locally produced antibiotics (defensins and cathelicidins) - Killing of microbes by infected cells by intraepithelial lymphocytes - Following features help block microbes from entering: 1. Tight inter-epithelial junctions 2. Keratin on the skin 3. Mucus on the mucosa # Neutrophils - Produced in bone marrow, circulate in blood, extravasate in tissues during inflammation - Rapid response, short-lived; cytoplasm has enzyme-filled granules - Phagocytosis through: - Reactive oxygen species by phagocyte oxidase (respiratory burst) - TNF, IL-1, and chemokines involved in movement of neutrophils into infected tissue - Major responses: 1. Degranulation - destruct pathogens by extrusion of granular contents in environment. - Secretes lysosomal enzymes. 2. Rapid production of extracellular "traps" # Monocytes - Have indented/horse-shoe shaped nucleus - Can ingest microbes in blood and tissue - Circulate in blood, can move into tissues and differentiate into macrophages. # Macrophages - Differentiated from monocytes; found in blood and tissue - Have different names in different organs: 1. Liver - Kupffer cells 2. Brain - microglial cells 3. Lung - alveolar macrophages 4. Spleen - sinusoidal macrophages - Long-lived, perform tissue repair, activated by pathways using cytokines - Phagocytosis induced by reactive nitrogen species through nitric oxide/iNOS (respiratory burst) - Activated through PRRs, cytokine receptors, and complement receptors (classical, alt pathways) # Phagocytosis Steps 1. Microbe binds to phagocyte receptor 2. Phagocyte membrane engulfs receptor-bound microbe 3. Microbe is internalized into a phagosome 4. Phagosome fuses with a lysosome 5. Reactive oxygen species (neutrophils), nitric oxide (produced by macrophages), and lysosomal enzymes kill the microbe through respiratory burst # Complement Activation 1. **Classical Pathway** - Antibodies bound to antigens interact w/ C1 complex to link innate & adaptive immunity 2. **Alternative Pathway** - Activates spontaneously through hydrolysis of C3, which binds to pathogen surfaces w/o antibodies 3. **Lectin Pathway** - Mannose-binding lectin (MBL) binds to carbohydrate residues on pathogen surface to mark for destruction - All pathways converge at cleavage of C3 leading to robust immune response. - C3b coats pathogens for phagocyte recognition (opsonization) - C3a and C5a recruit immune cells and amplify inflammation - Membrane attack complex (MAC) forms pores in pathogen membranes, causing lysis - destruction # Natural Killer (NK) cells - IL-12 from macrophages activate NK cells - NK cells then produce IFN-y to boost macrophage-mediated killing of phagocytosed pathogens. - NK cells can directly kill virally infected cells by releasing perforin and granzymes. - When Class I MHC is present, NK cells are inhibited, preventing cell killing. ex: normal cells - When Class I MHC is absent or reduced, NK cells are activated and kill the target cell. ex: tumor cells, virally infected cells # Innate Immunity Cytokines - Dendritic cells, macrophages, mast cells, NK cells produce cytokines in response to microbes which initiates inflammation - TNF, IL-1, and chemokines help move neutrophils into infected cells # Interleukin 6 (IL-6) - Cell source - macrophages, endothelial cells, T cells - Target/effect - Proliferation of antibody-producing cells (B cells) # Interleukin 15 (IL-15) - Source - macrophages, other - Target/effect - T cell proliferation, NK cell proliferation # Acute Inflammatory Response - Eliminates pathogens, removes damaged tissue, and promotes tissue repair # Leukocyte Migration 1. **Endothelial Activation** - Cytokines (ex. TNF, IL-1) are released by resident immune cells (ex. macrophages, mast cells) in response to infection or tissue damage - These cytokines activate endothelial cells to upregulate selectins and other adhesion molecules on the surface of blood vessel lining 2. **Rolling** - Leukocytes in blood stream weakly bind to selectins (ex. E-selectin, P-selectin) expressed on surface of activated endothelial cells - Interactions are transient, causing leukocytes to "roll" along endothelial surface 3. **Stable Adhesion** - Leukocytes encounter chemokines presented on endothelial surface - This activates the leukocytes increasing their affinity for adhesion molecules (ex. ICAM-1, VCAM-1) - This arrests the rolling leukocytes 4. **Diapedesis** - Leukocytes use adhesion molecules to pass through endothelial layer between endothelial cells - This allows them to enter the underlying tissue, moving through the basement membrane 5. **Chemotaxis** - Once in the tissue, leukocytes follow a chemokine gradient to move toward the precise location of tissue injury/infection # Type I Interferon Response - INF-alpha + INF-beta bind to receptors on cells to activate antiviral pathways - Inhibition of viral replication achieved through: - Inhibition of protein synthesis - Degradation of viral RNA - Inhibition of viral gene expression and virion assembly # Immune Response Regulation - Anti-inflammatory cytokines, suppressor proteins, and receptor agonists protect tissue from excessive damage - Negative feedback mechanisms are also used - Anti-inflammatory cytokines IL-10 and TGF-beta inhibit inflammation by inhibiting. - Cytokine and chemokine production # Microbial Evasion of Innate Immunity 1. **Resistance to phagocytosis** - Bacterial capsules prevent phagocytes from recognizing and binding to microbial surfaces by masking PAMPS 2. **Resistance to ROS** - Production of catalase breaks down reactive oxygen intermediates 3. **Resistance to complement pathways** - Sialic acid inhibits C3 convertases - M proteins block C3 binding to organisms and C5b binding to complement receptors 4. **Resistance to antibiotics** - Modified LPS resists peptide antibiotics # Lymphocyte Activation - Cooperation between innate & adaptive immune system using 2 signals - First, microbial antigen interacts w/ specific receptor of adaptive immune system - Second, molecule induced during innate immune response (ex. cytokines) binds - This leads to proliferation and differentiation of lymphocytes # Cytokine Categories 1. **Anti-inflammatory** - TGF-beta, IL-10 2. **Anti-viral** - Type I IFN (alpha, beta) 3. **T/N cell proliferation** - IL-15 4. **B cell proliferation** - IL-6 5. **Macrophage activation** - INF-gamma 6. **Pro-inflammatory** - IL-1, TNF 7. **NK cell activation** - IL-12