The Innate Immune Response

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