Immunology F20_Module 2.pdf

2.1 Principles of Innate Immunity Innate immunity includes physical and chemical barriers to infection Lysozyme degrades bacterial cell walls Defensins disturb microbial membrane integrity Antibodies bridge adaptive and innate immunity Summary 2.1 Organisms are protected by multipl...

2.1 Principles of Innate Immunity Innate immunity includes physical and chemical barriers to infection Lysozyme degrades bacterial cell walls Defensins disturb microbial membrane integrity Antibodies bridge adaptive and innate immunity Summary 2.1 Organisms are protected by multiple layers of immunity -Barriers and chemical defenses are first defense -Innate immune cells provide broadly effective protection -Adaptive immune cells mount targeted, specific responses Barrier tissues prevent microbial colonization -Mechanical and chemical defenses kill and/or remove pathogens -Native flora outcompete pathogenic flora Antimicrobial agents provide broad protection against infection -Lysozyme degrades bacterial cell walls -Defensins disturb bacterial membrane integrity Antibodies allow adaptive immunity to use innate immune effector mechanisms -Opsonization marks targets for phagocytosis -Complement fixation induces multiple mechanisms of pathogen control 2.2 The Classical Complement Pathway  All complement pathways converge on cleavage of C3 Inflammation Phagocytosis Membrane attack The classical pathway starts with C1 C1q binds to antibodies C1r/C1s make up protease domain  C4a C2b C4 C2 C1 C4b C2a C4b2a = C3 convertase  Pathogen C3b Phagocytosis Inflammation C3a C3 C4b C2a C4b C2a C3b C3 convertase C4b2a3b = C5 convertase Membrane Attack 2.3 The Lectin and Alternative Complement Pathways MBL= Mannose binding Lectin MASP- Mannan-binding lectin serine protease Summary 2.2 and 2.3 Complement proteins are an ancient antimicrobial defense system -Able to bind bacterial sugars and antibody coated pathogens -Host cells are protected 3 major pathways of complement fixation -Lectin pathway triggered by carbohydrates on pathogen surfaces -Classical pathway triggered primarily by antibodies -Alternative pathway begins spontaneously and/or amplifies other 2 pathways All 3 pathways converge on generation of a C3 convertase -Many complement proteins require cleavage to be activated -Many complement proteins possess protease activity Cleavage of C3 initiates multiple antimicrobial processes -Inflammation (activation and recruitment of immune cells) -Phagocytosis (opsonization) -Membrane attack 2.4 Complement Effector Functions Inflammation Phagocytosis Membrane attack  Pathogen C3b Phagocytosis Inflammation C3a C3 C4b C2a C4b C2a C3b C3 convertase C4b2a3b = C5 convertase Membrane Attack C3b binding to a C3 convertase creates a C5 convertase  C5a C5b6789 = C5 Membrane Attack Complex C4b C2a C3b C5b C6 C5 convertase C7 C8 C9 Outcomes of anaphylatoxin signaling C3b serves as an opsonin C3b mediates clearance of immune complexes Summary 2.4 C3b initiates important complement effector functions -Common component of C5 convertase -Serves as an opsonin C5 convertase initiates MAC formation -C5b recruits C6, C7, C8, and C9 -C9 forms pore in membrane that kills target cell Complement cleavage products can serve as anaphylatoxins -C3a and C5a induce immunological signaling -Anaphylatoxins promote inflammation Complement proteins promote phagocytosis -C3b and C5a promote CR1-mediated phagocytosis of pathogens -C3b targets immune complexes for clearance  2.5 Phagocytosis and Programmed Cell Death Phagocytic receptors recognize pathogen associated molecular patterns (PAMPs) and/or opsonins. Phagocytosis allows antigen presentation of external pathogens Phagocytosis clears dead cell debris Apoptosis can be induced intrinsically by infection or extrinsically by effector cells Cytoplasm contains DAMPs (damage associated molecular patterns) than can induce inflammation -These remain trapped in apoptotic bodies Apoptotic cells “bleb,” sequestering DAMPs Programmed cell death contributes to innate immunity Infection can trigger programmed form of necrosis called “necroptosis” Necroptotic cells “pop,” releasing DAMPs DAMP signaling is immunogenic Summary 2.5 Phagocytosis is a major immune effector function -Phagocytic receptors allow recognition and binding of targets -Links innate and adaptive responses via antigen presentation Phagocytic cells break down targets in phagolysosomes -Lysosomal compartment is harsh and antimicrobial -Neutrophils use cytoplasmic granules to augment antimicrobial activity Programmed cell death contributes to control of infection -Removes replicative niche for pathogens -Can exert regulatory activity on immune cells Cell death programs are differentially immunogenic -DAMPs can activate inflammatory signaling -Sequestration vs. release of DAMPs defines immunologic activity of PCD