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

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

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

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

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