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 Antimicrobial substances

and Normal Flora pH changes

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, they become increasingly flat

Outermost sheets of cells embedded with keratin Makes skin water-repellent

Outer layers slough off, taking microbes with it

Mucous membranes› Constantly bathed with mucus

Help wash surfaces

› Some mucous membranes have mechanisms (cilia)to propel microorganisms and viruses to areas where they can be eliminated

Antimicrobial substances› Both skin and mucous membranes are

protected by variety of antimicrobial substances including Lysozyme

Enzymes that degrade peptioglycan Found in tears, saliva, blood and phagocytes

Peroxidase Found in saliva, body tissues and phagocytes Breaks down hydrogen peroxide to produce reactive

oxygen Lactoferrin

Sequesters iron from microorganisms Iron essential for microbial growth

Found in saliva, some phagocytes, blood and tissue fluids Defensins

Antimicrobial peptides inserted into microbial membrane Found on mucous membranes and in phagocytes

Normal Microbiota (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

Competes for nutrients Nutrients unavailable for pathogens

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

Granulocytes› Contain

cytoplasmic graduals

› Divided into three types Neutrophils Basophils Eosinophils

Granulocytes› Contain cytoplasmic graduals

Neutrophils› Most abundant and important in innate

response› Granules contain chemicals which kill

microbes› Sometimes called polymorphonuclear

neutrophilic leukocytes (PMNs)

Basophils› Granules contain

histamine and other chemicals which increase capillary permeability.

› Similar to mast cells

› Involved in allergic reaction

Eosinophils› Important in

expelling parasitic worms

› Active in allergic reactions

› Granules contain histamase and antimicrobial chemicals

Mononulcear phagocytes› Constitute collection of phagocytic cells called

mononuclear phagocyte system› Include monocytes

Circulate in blood Macrophages differentiate from monocytes

Present in most tissues Abundant in liver, spleen, lymph nodes, lungs

and peritoneal cavity Dendritic cells

› Branched cells involved in adaptive immunity› Function as scout in tissues

Engulf material in tissue and bring it to cells of adaptive immunity

Lymphocytes› Involved in adaptive immunity› Two major groups

B lymphocytes B cells-mature in bone marrow

T lymphocytes T cells-mature in the thymus

› Another type Natural killer

Lacks specificity of B and T cells

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 sends signal to cell Cell responds by initiating some action

Cytokines› Cytokines bind to surface receptors and regulate cell

function› Numerous cytokine classes

Chemokines – important in chemotaxis

Colony stimulating factors – Important in multiplication and differentiation of leukocytes

Interferons – important in control of viral infections

Interleukins – produced by leukocytes

Tumor necrosis factor – kill tumor cells

Adhesion molecules› Allow cells to adhere to each other› Responsible for the recruitment of

phagocytes to area of injury Epithelia cells lining blood vessels produce

adhesion molecules that catch phagocytes as they pass by Cause phagocytes to slow and leak out of vessels to

area of injury

Systems within blood detect signs of tissue damage or microbial invasion

Respond to patterns associated with danger by› Directly destroying invading microbe› Recruiting other host defenses

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

Figure 15.7

Classical pathway› Activation requires antibodies

Antibodies interact complement C1 Activates protein

Leads to activation of all complex proteins

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

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

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

Figure 15.8

Long Double-Stranded RNA (dsRNA)

Induction of alpha and beta interferons› Cells express

iAVPs› Leads to

apoptosis

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

Role of Neutrophiles› First responders› Granules contain antimicrobial

chemicals› NETs-neutrophile extracellular traps

Contain DNA and anti microbial chemicals Trap bacteria and destroy them with

chemicals

› Short lived but lots in reserve

Inflammation occurs in response to tissue damage

Four cardinal signs› Heat› Pain› Redness› Swelling› Loss of function

Fifth sign that can also be present

Factors that initiate inflammatory response› Microbial products trigger toll-like receptors

of macrophages Causes release of pro-inflammatory cytokines

› Microbial cell surface can trigger complement

› Tissue damage results in enzymatic cascade Cascades initiate 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 Results in increased blood

flow Increased blood flow

responsible for cardinal signs of 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 cells is 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 severe Inflammation around brain and spinal cord

can lead to meningitis

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

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