CH 14 - Innate Immune Response Flashcards
Apoptosis
(definition)
Programmed death of “self” cells that does not cause inflammation
Complement system
(definition)
Series of proteins in blood & tissue fluids that can be activated to help destroy & remove invading microbes
Cytokines
(definition)
Proteins that function as chemical messengers, allowing cells involved in host defenses to communicate
Inflammatory response
(definition)
Coordinated innate response with purpose of:
- Containing site of damage
- Localizing the response
- Eliminating the invader
- Restoring tissue function
Innate immunity
(definition)
Host defenses involving:
- Anatomical barriers
- Sensor systems that recognize patterns associated with microbes or tissue damage
- Phagocytic cells
- Inflammatory response
- Fever
Macrophage
(definition)
Type of phagocytic cell that wanders or resides in tissues
Has multiple roles including: scavenging debris & producing pro-inflammatory cytokines
Membrane attack complexes (MACs)
(definition)
Complement system components assembled to form pores in membranes of invading cells
Neutrophil
(definition)
Major type of phagocytic cell in blood
Quickly move to infected tissues, where they use multiple mechanisms to destroy invading microbes
Opsonization
(definition)
Coating of an object with molecules for which phagocytes have receptors, making it easier for phagocytosis to occur
Pattern recognition receptors (PRRs)
(definition)
Proteins on or in cells that recognize specific compounds unique to microbes or tissue damage
Phagocyte
(definition)
Cell type that specializes in engulfing & digesting microbes & cell debris (phagocytosis)
Innate Immunity
- Response time
- Specificity
- Diversity
- Memory responses
- Self/non-self discrimination
- Soluble components of blood/tissue fluids
- Minutes/hours
- Specific for molecules/molecular patterns associated with pathogens
(non-specific) - Limited # of germ line-encoded receptors
- NO memory responses
- Perfect self/non-self discrimination
(NO microbe-specific patterns in host) - Many antimicrobial peptides & proteins
Adaptive Immunity
- Response time
- Specificity
- Diversity
- Memory responses
- Self/non-self discrimination
- Soluble components of blood/tissue fluids
- Days
- Highly specific
- Highly diverse (genetic recombination of receptor genes)
- Persistent memory (faster + greater response on subsequent infection)
- Very good self/non-self discrimination (occasional failures = autoimmune disease)
- Antibodies
Innate Immunity:
Major Cell Types
- Phagocytes
- Monocytes
- Macrophages
- Neutrophils - Natural killer (NK) cells
- Dendritic cells
Adaptive Immunity:
Major Cell Types
- T cells
- B cells
- Antigen-presenting cells (APCs)
- Dendritic cells
- B cells
- Macrophages
1st Line of Defense
- Physical barriers
- Skin
- Mucous membranes - Antimicrobial substances
- Lysozyme
- Peroxidase
- Iron-binding proteins
- Defensins
- Complement proteins - Normal flora
Physical Barriers:
Skin
- Dermis
- Under epidermis
- Tightly woven fibrous CT
- Extremely tough - Epidermis
- Exposed to outside
- Layers of epithelial cells
- Keratin (water-repellant) embedded in outermost sheets of cells
- Outer layers slough off
Physical Barriers:
Mucous Membranes
Lines digestive tract, respiratory tract, genitourinary tract
- Where exchanges occur (only 1 cell separates)
Mucous protects surface from infections
- Secretions wash microbes from surface
Mechanisms that move microbes toward elimination areas:
1. Peristalsis
2. Ciliated cells (mucociliary escalator)
3. Turnover/shed of mucosal epithelial cells
Physical Barriers:
Antimicrobial Substances
- Lysozyme
- Peroxidase
- Iron-binding proteins
- Defensins
- Complement proteins
Lysozyme
Enzyme that degrades PTG (cleaves)
More effective on G+ bacteria
Found in:
1. Tears
2. Saliva
3. Blood
4. Phagocytes
Peroxidase
Breaks down hydrogen peroxide to produce ROS
- Kills microbes on contact
Found in:
1. Saliva
2. Body tissues
3. Phagocytes
Iron-binding proteins
Sequesters iron from microorganisms
- Require iron to survive
- Lactoferrin
- Saliva & phagocytes - Transferrin
- Blood & tissue fluid
Defensins
Antimicrobial peptides inserted into microbial membrane
- Kill on contact
Found in:
1. Mucous membranes
2. Phagocytes
Physical Barriers:
Normal Flora
Microorganisms found growing on body surfaces of healthy individuals
- NOT technically part of immune system
Provide protection through competitive exclusion:
1. Covers binding sites
2. Competes for nutrients
3. Stimulates immune response (exercise)
4. Directly kills other microbes (release toxic substances)
General Categories of Blood Cells
- Red blood cells (RBCs)
- Non-living (no nucleus)
- Carry O2 in blood - Platelets
- Fragments of megakaryocytes
- Non-living (no nucleus)
- Blood clotting - White blood cells (WBCs)
- Host defenses
4 Categories of WBCs
- Granulocytes (contain granules)
- Eosinophils
- Basophils
- Neutrophils - Mononuclear phagocytes
- Monocytes
- Macrophages - Lymphocytes
- B cells
- T cells - Dendritic cells
(sentinels - 1st to notice infection & alert)
Macrophages
Derived from blood monocytes
- Migrate to tissue & differentiate
- Various names based on tissue found
- Present in nearly all tissues
Part of reticuloendothelial system (RES)
Phagocytize & digest engulfed material
- Clear microorganisms out of host
- Destruction of old/imperfect cells
- Often 1st to respond to invaders
2 major functions:
1. Phagocytosis
2. Antigen presentation (MHC II)
Macrophages:
Morphological Forms
- Kupffer cells - liver
- Alveolar macrophages - lungs
- Splenic macrophages - spleen
- Peritoneal macrophages - peritoneum
- Microglial cells - brain
- Osteoclasts - bone
- Mesangial cells - kidneys
Steps of Phagocytosis
(macrophages)
- Bacterium becomes attached to pseudopodia (membrane envaginations)
- Bacterium ingested, forming phagosome
- Phagosome fuses with lysosome
- Lysosomal enzymes digest captured material
- Digestion products released from cell (exocytosis)
Modes of Phagocyte Intracellular Killing:
- Antimicrobial species generated from O2 & N
- ROS
- RNS - Acidification
- pH within phagosome = 3.5-4.0 - Antimicrobial peptides (toxic)
- Defensins
- Cationic peptides - Enzymes (cleave)
- Lysozyme
-Acid hydrolases - Competitors (keep out nutrients)
- Lactoferrin - Vitamin B12 binding protein
Reactive Oxygen Species (ROS):
Generated within Phagosome
- Superoxide anion (O2-)
- Hydroxyl radical (OH-)
- Hydrogen peroxide (H2O2)
- Hypochlorite anion (ClO-)
Reactive Nitrogen Species (RNS):
Generated within Phagosome
- Nitric oxide (NO)
- Nitrogen dioxide (NO2)
- Peroxynitrite (ONOO-)
Pattern Recognition Receptors:
Types
- Toll-like receptors (TLR)
- NOD proteins
Toll-like Receptors (TOLR)
Located inside & outside cell
Recognize specific components of foreign invaders:
1. LPS
2. PTG
3. Flagellin
4. Bacterial nucleotide sequences
TLR engagement & induction sends signal to cell nucleus
- Gene expression
- Cytokines, chemokines, etc.
Present on phagocytes, endothelial cells, etc.
Outside TLRs Recognize:
- Bacterial parasites (TLR1 & 2)
- G+ bacteria & fungi (TLR2 & 6)
- G- bacteria (TLR4)
- Flagellated bacteria (TLR5)
Internal TLRs Recognize:
- Viral dsRNA (TLR3)
- Viral ssRNA (TLR7 & 8)
- Bacterial DNA elements (TLR9)
NOD Proteins
Intracellular pathogen-recognition molecules
Recognize bacterial cell wall components (bacteria replicating in cytoplasm)
Mutation in NOD2 = predisposing factor in development of Crohn’s disease (inflammatory bowel disease)
Receptors of the Innate Immune System
- Complement
- Mannose-binding lectin (MBL)
- C-reactive protein (CRP)
- Lipopolysaccharide (LPS) receptor & LPS-binding protein
- Toll-like receptors (TLR)
- NOD family receptors
- Scavenger receptors
Complement Receptor
(location, target, effect)
Located in bloodstream & tissue fluids
Target microbial cell wall components
Effect of recognition:
1. Complement activation
2. Opsonization
3. Lysis
Receptors of the innate immune system
Mannose-Binding Lectin (MBL) Receptor
(location, target, effect of recognition)
Located in bloodstream & tissue fluids
Targets mannose-containing microbial carbohydrates (cell walls)
Effect of recognition:
1. Complement activation
2. Opsonization
Receptor of innate immune system
C-Reactive Protein (CRP)
(location, target, effect of recognition)
Located in bloodstream & tissue fluids
Targets phosphatidylcholine & pneumococcal polysaccharide
(microbial membranes)
Effect of recognition:
1. Complement activation
2. Opsonization
LPS Receptor & LPS-Binding Protein
(location, target, effect of recognition)
Located in bloodstream & tissue fluids
LPS bound at cell membrane by complex of proteins (CD14, MD-2, TLR)
Targets bacterial LPS (G- cell wall)
Effect of recognition:
1. Delivery to cell membrane
TLRs
Cell surface or internal compartments
Targets microbial components (NOT found in hosts)
Induces innate responses
NOD Family Receptors
Intracellular
Targets bacterial cell wall components
Induces innate responses
Receptors of the innate immune system
Scavenger Receptors (SRs)
(location, target, effect of recognition)
Located in cell membrane
Targets G-/G+ bacteria & apoptotic host cells
Induces phagocytosis or endocytosis
Cytokines
Protein “messages”
- Bind to surface receptors
- Regulate cell function
Cytokine classes:
1. Chemokines
2. Colony-stimulating factors
3. Interferons
4. Interleukins
5. Tumor necrosis factor
Chemokines
Chemotaxis
Enhance cell ability to migrate to infection site
Colony Stimulating Factors
Important in multiplication & differentiation
Directs immature WBCs to correct maturation pathway (developmental factor)
Interferons
cytokines
Important in control of viral infections
Associated with inflammatory response
Changes way cells respond to infection
(to enhance killing)
Interleukins
cytokines
Produced mainly by WBCs
Important in innate & adaptive immunity
Changes way cells respond to infection
(to enhance killing)
Tumor Necrosis Factor
Kills tumor cells
Initiation of inflammatory response
Changes way cells respond to infection
(to enhance killing)
Chemotaxis:
Adhesion molecules
Allow cells to adhere to each other
- Responsible for recruitment of phagocytes to area of injury
Produced by endothelial cells in blood vessels
- Catch passing phagocytes
- Cause phagocytes to slow & leak out of vessels to area of injury
Neutrophils = 1st to arrive
Initiation of Extravasation
(image)
- Selectin-mucin interactions mediate rolling
- Chemokines/chemoattractants induce change in integrins
- Integrins adhere firmly to ICAMs
Functions of Complement Pathway
- Lysis of cells
- MAC - Opsonization
- Promotes phagocytosis
(enhances macrophage recognition) - Binding to specific complement receptors on cells of immune system
- Inflammation
- Secretion of immunoregulatory molecules (ex: cytokines, chemokines, etc.)
- Degranulation
- Extravasation - Immune clearance
- Removes immune complexes from circulation & deposits in spleen/liver for disposal
3 Pathways of Complement Activation
- Classical
- Alternative
- Lectin
Classical Pathway
1st pathway discovered
Initiated by antigen-antibody complex
(Ab binding to microbe)
- Ag-Ab dependent (IgG or IgM)
- Requires suitable Ab bound to Ag & complement proteins 1, 4, 2, 3
Abs interact complement C1 (C1qrs)
- Activates protein & leads to activation of all complex proteins
- Activity limited by C1-esterase inhibitor (C1INH); prevents inappropriate activation of complement
Part of adaptive response
Alternative Pathway
Initiated by binding of C3b to cell surfaces
- Regulatory proteins protect host cell surfaces
- Initiates activation of other complement proteins
Non-specific resistance against infection without antibody participation
Requires preformed C3b & factors B & D
- C3 always cleaving at low level
- Properdin helps stabilize complex
Lectin Pathway
Initiated by binding of mannan-binding lectins to cell surfaces
3 proteins involved:
1. Mannan-binding lectin (MBL)/mannan-binding protein (MBP)
- Pattern recognition molecule
- Detects mannan found in microbial cells
2 & 3. Mannan-binding lectin-associated serine proteases
- MASP
- MADSP2
MBL interacts with MASP & MADSP2 (analogous to C1r & C1s)
- Generates complex analogous to C1qrs
- Leads to antibody-independent activation of classical pathway
Complement System
Composed of 9 main proteins (C1-9)
- Numbered in order of discovery
(NOT activation)
Proteins split int a & b fragments after activation
- C3 spontaneously splits –> C3a & C3b
- C4a & C4b
- C5a & C5b
Membrane Attack Complex (MAC)
Complexes of C5b, C6, C7, C8, & multiple C9
- Spontaneously assemble
- Donut shape
Creates pores in membranes
- Lysis of foreign cells
- Most effect on G- (little effect on G+)
- NON-SPECIFIC
Biologically Active Components of Complement Activation
- Anaphylotoxins
- C4a, C3a, C5a
- Cause basophil/mast cell degranulation & smooth muscle contraction (anaphylaxis) - Chemotactic factors
- C5a & C3a
- Potent activators of neutrophils, basophils, & macrophages
- Causes induction of adhesion molecules on vascular endothelial cells - Opsonins
- C3b & C4b (on microorganism surface)
- Attach to complement receptor 1 (CR1) on phagocytic cells
- Promote phagocytosis
Activation of Complement Leads to Major Protective Outcomes:
- Inflammation
- Lysis of foreign cells (MAC)
- Opsonization
Unattended Activation of Complement Proteins Regulated by:
- Short half-life of some complement proteins
- 100 us in fluid phase - Specific host proteins that inactivate complement proteins
- Serum proteins (DAF, Factor I, Factor H)
4 Cardinal Signs of Inflammation
- Heat (calor)
- Pain (dolor)
- Redness (rubor)
- Swelling (tumor)
5 - loss of function (function laesa)
Initiation of Inflammatory Process Leads to:
- Dilation of blood vessels
- Leakage of fluid from vessels
- Migration of leukocytes & phagocytes
Rolling & Extravasation
(image)
- Rolling
- Activation
- Arrest/adhesion
- Transendothelial migration
Inflammatory Process
- Pro-inflammatory mediators (cytokines) cause dilation of small blood vessels & increased blood flow
- Increased vascular permeability leads to leakage of fluid from blood vessels & accumulation of fluid in tissues (edema)
- Attraction of phagocytes causes cells to move to site of damage & inflammation
- Diapedesis
- Pus formation (dead neutrophils)
- Clotting factors initiate clotting (entraps microbes)
Factors that Initiate Inflammatory Response:
- Microbial products trigger TLRs of macrophages & other cells
- Release of pro-inflammatory cytokines
- TNF-alpha triggers liver synthesis of acute-phase proteins (C-reactive protein)
- Facilitate complement activation & phagocytosis - Microbial cell surface can trigger complement
- Production of C3a & C5a
- Mast cell release of pro-inflammatory cytokines & histamine - Tissue damage
- Enzymatic cascade initiates inflammation
- Coagulation cascade
- Kinin synthesis
- Increased vascular permeability, endothelial cell adhesion, potent nerve stimulators (pain/itching)
Inflammatory Response Triggered by Tissue Damage
- Tissue damage causes release of vasoactive & chemotactic factors
- Trigger local increase in blood flow & capillary permeability - Permeable capillaries allow influx of exudate & cells
- Phagocytes migrate to site of inflammation (chemotaxis)
- Phagocytes & antibacterial exudate destroy bacteria
More Severe Consequences of Inflammation
(affects delicate systems)
- Arthritis
- Meningitis
- Inflammation around brain/spinal cord - Septic shock
- Response to bloodstream infections with LPS (G- bacteria)
- Fever, low BP, extensive tissue damage, wide-spread clot formation
- Leads to disseminated intravascular coagulation (DIC)
Fever
Host defense mechanism
- 1 of strongest indicators of infection (especially bacteria)
Temperature regulation center of body responds to fever-inducing cytokines
- Endogenous pyrogens (IL-1, TNF-alpha)
Inhibits growth of pathogens by:
1. Elevating body temp about max growth temp
2. Activating/speeding up other body defenses (immune response works better)
Apoptosis
Programmed cell death
- Cells engulfed by macrophages
- Normally occurs during development
Cells undergo changes to signal macrophages:
1. Nuclear DNA degradation
2. Nuclear degeneration
3. Blebbing
4. Condensation
NO inflammatory response
Necrosis
Death of tissue cells due to chemical/physical injury
Leaves extensive cellular debris
(must be removed by phagocytes)
Induces inflammation
