Download IMMUNITY MEDIATED BY B LYMPHOCYTES AND ANTIBODIES

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, plateletactivating 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
Figure 8-16 part 1 of 3
Figure 8-16 part 2 of 3
Figure 8-16 part 3 of 3
BIOLOGICAL ACTIVITY OF IL-1, IL6 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