PRINCIPLES OF INNATE IMMUNITY

PRINCIPLES OF INNATE IMMUNITY

THE INNATE IMMUNE SYSTEM

* First line of defense against pathogens

* Components* Complement system* Macrophages and neutrophils* Defensins* Coagulation system* Cytokines and inflammatory cytokines* Inflammatory response* Natural killer cells

THE COMPLEMENT SYSTEM

* A set of proteins widely distributed throughout body fluids and tissues

* Proteins act in a cascade of reactions to attack extracellular forms of pathogens

* Complement activation results in* Inflammatory response* Pathogens coated with complement

* Complement coating of pathogens* Enhanced engulfment and destruction by phagocytes* Direct killing of pathogens

PATHWAYS OF COMPLEMENT ACTIVATION

* Classic pathway* Activated by antibody

* First discovered

* Alternative pathway* Activated by some bacterial cell surfaces

* Antibody not involved

* Lectin pathway* Activated by mannose binding lectin

* Antibody not involved

THE COMPLEMENT SYSTEM

* Nomenclature has developed haphazardly

* Proteins of classic pathway named with capital “C” followed by a numeral (C1, C2, C3…..C9)

* Cleavage fragments named as parent followed by lower case letter* “a” for smaller fragment (C3a)* “b” for larger fragment (C3b)

* Some classic components participate in other 2 pathways

CLASSIC PATHWAY OF COMPLEMENT ACTIVATION

* C1 binds to Fc region of antibody part of Ab/Ag complex

* C1 is complex of 3 proteins* C1q is binding protein* C1r and C1s are proteases

* C1q binds to Fc region of antibody which activates C1r which activates C1s

* Most efficient at activating complement* IgM, IgG1 and IgG3

CLASSIC PATHWAY OF COMPLEMENT ACTIVATION

* Activated C1s cleaves C4 to* C4a and C4b

* Activated C1s cleaves C2 to* C2a and C2b

* C4b and C2b form complex covalently bonded to pathogen surface

* C4b/C2b complex (C3 convertase) cleaves C3 to* C3a and C3b

ANTIBODY AND COMPLEMENT ENHANCE PHAGOCYTOSIS

* Enhanced phagocytosis especially important* Streptococcus pneumoniae

* Haemophilus influenzae

* Cryptococcus neoformans

* Macrophages and neutrophils have receptors for* Antibody

* Fc-gamma for Fc region

* Complement* Complement receptor 1 (CR1) for C3b

COMPLEMENT RECEPTORS REMOVE IMMUNE COMPLEXES

* Immune complexes* Soluble antibody/antigen complexes* Form after immune response to most infections

* IC must be removed to prevent precipitation and deposition on endothelial membranes* Kidneys

* Removal of IC* Complement binds to IC* Erythrocytes bind to complement by CR1

DIRECT KILLING OF PATHOGENS BY COMPLEMENT SYSTEM

* Terminal complement proteins form “membrane attack complex”

* Mechanism of attack by classic pathway* C3b binds to C3 convertase (C4b,2b) / (C4b,2a) results in

* C5 convertase (C4b,2b,3b) / (C4b,2a, 3b)

* C5 binds C3b of C5 convertase

* C5 cleaved to* C5a and C5b

* C5b initiates assembly of attack membrane components* C6 – C9

* Deficiency increases susceptibility to Neisseria meningitidis and Neisseria gonorrhoeae

RECOGNITION OF PATHOGENS FOR PHAGOCYTOSIS

* Mechanism of recognition* Toll-like receptors (innate immune receptors)

* Toll-like receptors* Named for ‘Toll’  receptor in fruitfly* Polypeptides with horseshoe-shaped structure

* Recognition by macrophages initiates activation* Phagocytosis* Secretion of cytokines

ACTIVATION OF MACROPHAGES

* Activated macrophages secret* Cytokines

* Chemokines (chemoattractant cytokines)

* Inflammatory mediators

* Cytokines and chemokines* Interleukin-1 (IL-1), IL-6, IL-8, IL-12 and TNF-alpha

* Inflammatory mediators* Prostaglandins, leukotrienes, plasminogen activator, platelet-

activating factor (PAF)

Figure 8-15

MIGRATION OF NEUTROPHILS INTO TISSUE (EXTRAVASATION)

* Rolling adhesion* Slowing down leukocytes (margination)* Weibel-Palade bodies in vascular endothelial cells secreting

P and E selectins

* Tight binding* Interaction between LFA-1 and ICAM-1

* Diapedesis* Passage between vascular endothelial cells

* Migration to infection site

Figure 8-19

Chemokines (Chemoattractant Cytokines)

* Family of small soluble molecules that stimulate activation and migration of cells

* Group classification* CC

* Two adjacent cysteine amino acids * Chromosome 4

* CXC* Two separated cysteine amino acids* Chromosome 17

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BIOLOGICAL ACTIVITY OF IL-1, IL-6 AND TNF-ALPHA

* Induce hepatocytes to produce acute-phase proteins* C-reactive protein (CRP)* Mannose binding lectin (MBL)

* Induce bone marrow to release neutrophils

* Induce hypothalamus to raise temperature

* Induce fat and muscle cells to generate heat

DEFENSINS

* Family of amphipathic antimicrobial peptides* 35 to 40 amino acids

* Mechanism of action* Disruption of cell membranes

* Classification* Alpha

* Neutrophils and Paneth cells

* Beta* Epithelial cells of skin, respiratory tract and UG tract

THE INNATE RESPONSE TO VIRAL PATHOGENS

* Virus infected healthy cells produce* Interferon-alpha (IFN-alpha)

* Interferon-beta (IFN-beta)

* IFN-alpha and IFN-beta are type 1 interferons

* Type 1 interferons* Inhibit virus replication

* Activate natural killer (NK) cells

* Increases expression of MHC-1 molecules

Figure 8-25

NATURAL KILLER (NK) CELLS

* Large granular lymphocytes that circulate in blood

* Functions* Killing infected cells (cytotoxic)* Secretion of cytokines

* Activation by* Type 1 interferons

* Infected cells* Stimulates cytotoxic function

* IL-12 and TNF-alpha* Macrophages* Stimulates cytokine secretion

NATURAL KILLER (NK) CELLS

* Activated NK cells release IFN-gamma which activates* Macrophages

* Release IL-12

* Positive feedback system for NK and macrophages

* Differentiate infected from uninfected cells* NK cells express receptors for MHC class I molecules

* Binding of NK cells to MHC class I molecules turn off NK cells

* NK cells provide innate immunity to intracellular pathogens