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The Innate Immune Response. Chapter 15. Overview of Innate Defenses. First line of defense are barriers that shield interior of body from external surroundings Anatomical barriers include skin and mucous membranes Provide physical separation Membranes bathed in antimicrobial secretions. - PowerPoint PPT Presentation
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The Innate Immune Response
Chapter 15
Overview of Innate Defenses
First line of defense are barriers that shield interior of body from external surroundings
Anatomical barriers include skin and mucous membranes Provide physical separation Membranes bathed in
antimicrobial secretions
Sensor system signals when first line barriers have been breached Two important groups of receptors
Toll-like receptors and NOD proteins Cell membrane proteins that recognize and bind to
families of compounds unique to microbes nucleotide-oligomerization domains
Complement System
Overview of Innate Defenses
Overview of Innate Defenses
Toll-like receptors and NOD proteins Found on variety of
cells Recognize families of
compounds Enables cells to sense
invasion Sends signal to body
to respond
Overview of Innate Defenses
Complement System Acts in response to
stimuli Activation sets off
chain reaction that results in destruction or removal of invader
Overview of Innate Defenses
Phagocytes are specialized cells that engulf and digest microbes and cellular debris
Act as sentries Alerted to signs of invasion Release cytokine chemicals
More phagocytes can be recruited from bloodstream Attracted by chemical gradient
of the released cytokines
Phagocytosis movie
Overview of Innate Defenses
Cells of the immune system have an elaborate communication system
Communication achieved through productions of proteins Proteins act as chemical messengers
Called cytokines Cytokines from one cell diffuse to another
Bind to cytokine receptor on cell Receptor transmits signal to cell interior
Induces changes in cellular activities
Inflammation is initiated by microbial invasion or tissue damage
During inflammation cells in blood vessels undergo changes that allow certain immune particles to leak out of the blood
Overview of Innate Defenses
First Line of Defense
Physical barriers Skin is most visible barrier Covers majority of surfaces
in obvious contact with environment
Mucous membranes barrier that lines digestive tract, respiratory tract and genitourinary tract
Mucous protects these surfaces from infections
Skin Provides the most difficult barrier to penetrate Composed of two main layers
Dermis Contains tightly woven fibrous connective tissues
Makes extremely tough Epidermis
Composed of many layers of epithelial cells As cells reach surface become increasingly flat
Outermost sheets of cells embedded with keratin Makes skin water repellent
Outer layers slough off taking microbes with it
First Line of Defense
Mucous membranes Constantly bathed with mucus
Helps wash surfaces Some mucous membranes have mechanisms
to propel microorganisms and viruses to areas where they can be eliminated
First Line of Defense
Antimicrobial substances Both skin and mucous membranes are protected by variety
of antimicrobial substances including Lysozyme
Enzymes that degrades peptioglycan Found in tears, saliva, blood and phagocytes
Peroxidase Found in saliva, body tissues and phagocytes Breaks down hydrogen peroxide to produces reactive oxygen
Lactoferrin Sequesters iron from microorganisms
Iron essential for microbial growth Found in saliva, some phagocytes, blood and tissue fluids
Defensins (Antibiotics) Antimicrobial peptides inserted into microbial membrane Found on mucous membranes and in phagocytes
First Line of Defense
Normal flora Defined as microorganisms found growing on
body surfaces of healthy individuals Not technically part of immune system
However, provides significant protection Protects through competitive exclusion
Covers binding sites Pathogens can’t bind
Completes for nutrients Nutrients unavailable for pathogens
First Line of Defense
Cells of the Immune System
Always found in normal blood Numbers increase during infection
Some cells play dual roles in both innate and adaptive immunity
Blood cell formation called hematopoiesis Blood cells including immune cells originate
from hematopoietic stem cells in bone marrow Blood cells stimulated to differentiate by
colony-stimulating factor
General categories of blood cells Red blood cells (RBC)
A.k.a erythrocytes Carry oxygen in blood
Platelets Fragments of megakaryocytes Important component in blood clotting
White blood cells (WBC) A.k.a leukocytes Important in host defenses Divided into four categories
Granulocytes - Mononuclear phagocytes Dendritic cells - Lymphocytes
Cells of the Immune System
Cells of the Immune System
Granulocytes Contain cytoplasmic
granuals Divided into three types
Neutrophils Basophils Eosinophils
Cells of the Immune System
Neutrophils Most abundant and important
in innate response Sometimes called
polymorphonuclear neutrophilic leukocytes (PMNs)
Basophils Involved in allergic reaction
Eosinophils Important in expelling
parasitic worms Active in allergic reactions
Cells of the Immune System
Mononuclear phagocytes Constitutes collection of
phagocytic cells called mononuclear phagocyte system
Includes monocytes Circulates in blood Macrophages
differentiate from monocytes
Present in most tissues Abundant in liver,
spleen, lymph nodes, lungs and peritoneal cavity
Cells of the Immune System
Dendritic cells Branched cells
involved in adaptive immunity
Functions as scout in tissues
Engulf materials in tissue and bring it to cells of adaptive immunity
Cells of the Immune System
Lymphocytes Involved in adaptive
immunity Two major groups
B lymphocytes B cells
T lymphocytes T cells
Another type Natural killer
Lacks specificity of B and T cells
In order for immune system to respond cells must communicate with environment and with each other
Cell surface receptors are the “eyes” and “ears” of the cell
Cytokines are the “voice” Adhesion molecules act as the “hands”
Cell Communication
Surface receptors Membrane proteins to which signal molecules
bind Receptors specific to molecule to which it
bonds Binding molecules called ligands
When ligand binds, receptor becomes modified and send signal to cell
Cell responds by initiating some action
Cell Communication
Cytokines Cytokines bind to surface receptors regulate cell function Numerous cytokine classes
Chemokines = important in chemotaxis Enhance ability of cells to migrate to appropriate site in body
Colony stimulating factors = important in multiplication and differentiation of leukocytes
During immune response directs immature leukocytes to correct maturation pathway
Interferons = important in control of viral infections Also associated with inflammatory response
Interleukins = produced by leukocytes Important in innate and adaptive immunity
Tumor necrosis factor = kill tumor cells Instrumental in initiation of inflammation
Cell Communication
Adhesion molecules Allows cells to adhere to each other Responsible for the recruitment of phagocytes
to area of injury Endothelial cells lining blood vessels produce
adhesion molecules that catch phagocytes as they pass by
Causes phagocytes to slow and leak out of vessels to area of injury
Cell Communication
Sensor Systems
System within blood and tissue detect signs of tissue damage or microbial invasion
Responds to patterns associated with danger by Directly destroy invading microbe Recruiting other host defenses
Sensor Systems
Toll-like receptors (TLR) and NOD proteins Pattern recognition receptors TLR allow cells to “see”
molecules signifying presence of microbes outside the cell
TLR found in variety of cell types
Recognize distinct “danger” compounds
Signal is transmitted Results in change of
gene expression of cell
NOD proteins do same for inside cell
Complement system Series of proteins circulating in blood and fluids
Circulate in inactive form Augment activities of adaptive immune response Stimulation of inactive proteins initiates cascade of
reactions Results in rapid activation of components
Three pathways of activation Alternative pathway Lectin pathway Classical pathway
Sensor Systems
Sensor Systems
Alternative pathway Quickly and easily initiated Relies on binding of
complement protein C3b to cell surface
Initiates activation of other compliment proteins
Allows formation of complement complex
C3b always circulating in blood
Sensor Systems
Lectin pathway Activation requires
mannan-binding lectins (MBL)
Pattern recognition molecules
Detect mannan Polymer of mannose
Found in microbial cells
MBL attaches to surface Activates complement
proteins
Sensor Systems
Classical pathway Activation requires
antibodies Antibodies interact
with complement C1 Activates protein
Leads to activation of all complex proteins
Complement Complement system composed of nine proteins
C1 – C9 Numbered as discovered not order of activation
Certain proteins split into “a” and “b” fragments after activation
C3 can spontaneously split to C3a and C3b Insures enough C3b for activation of alternative pathway
Activation of complement leads to major protective outcomes
Inflammation Opsonization Lysis of foreign cells
Sensor Systems
Sensor Systems
Inflammation Complement components C3a and C5a
induce changes in endothelial cells Effects vascular permeability associated with
inflammation
Opsonization C3b binds foreign material
Allows phagocytes to easily “grab” particles
Sensor Systems
Lysis of foreign cells Complexes of C5b, C6, C7,
C8 and multiple C9 spontaneously assemble
Forms donut shaped structure called membrane attack complex (MAC)
Creates pores in membrane
Most effective on Gram-negative cells
Little effect on Gram-positive cells
Phagocytosis
Process of phagocytosis Chemotaxis
Cells recruited to infection
Recognition/attachment Use receptors to bind
invading microbes Engulfment
Phagocyte engulfs invader forming phagosome
Phagosome lysosome fusion
Phagosome binds lysosome forming phagolysosome
Destruction and digestion Organism killed due to
lack of oxygen and decreased pH
Exocytosis Phagocyte expels material
to external environment
Inflammation
Inflammation occurs in response to tissue damage
Four cardinal signs Heat Pain Redness Swelling
Loss of function Fifth sign that can also be
present
Inflammation
Factors that initiate inflammatory response Microbial products trigger toll-like receptors of
macrophages Causing release of pro-inflammatory cytokines
Microbial cell surface can trigger complement Leads to the production of C3a and C5a
Tissue damage results in enzymatic cascade Cascades initiate inflammation
Inflammation
The inflammatory process Initiation leads to a cascade of
events Results in dilation of blood
vessels, leakage of fluid from vessels and migration of leukocytes and phagocytes
Leakage of phagocytes from blood vessels called diapedesis
Certain pro-inflammatory mediators cause the diameter of blood vessels to increase
Resulting in increased blood flow
Increased blood flow responsible for cardinal signs of inflammation
Inflammation
Outcomes of inflammation Intent is to limit damage and restore function
Inflammation itself can cause considerable damage Release of toxic products and enzymes from phagocytic
cell responsible for tissue damage If inflammation is limited to area of injury damage
is usually nominal If inflammation results in delicate systems
consequences are more sever Inflammation around brain and spinal cord can lead
to meningitis
Inflammation
Apoptosis Programmed cell death
Destroys cell without eliciting inflammatory response
During apoptosis cells undergo changes to signal macrophages
Cells are engulfed without triggering inflammatory cascade
Fever
One of the strongest indicators of infection Especially of bacterial infection
Important host defense mechanism Temperature regulation center of body responds to
fever-inducing substances called pyrogens Fever-inducing cytokines termed endogenous pyrogens Microbial products termed exogenous pyrogens
Resulting fever inhibits growth of pathogens by Elevating temperature above maximum growth
temperature Activating and speeding up other body defenses