Innate Immune Response Chapter 15

What am I?

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 Antimicrobial substances and Normal Flora pH changes

First Line of Defense 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

First Line of Defense 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

First Line of Defense 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

First Line of Defense 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

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

Cells of the Immune System 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 graduals Divided into three types Neutrophils Basophils Eosinophils

Cells of the Immune System Granulocytes Contain cytoplasmic graduals Neutrophils Most abundant and important in innate response Granules contain chemicals which kill microbes Sometimes called polymorphonuclear neutrophilic leukocytes (PMNs)

Cells of the Immune System 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

Cells of the Immune System 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

Cells of the Immune System 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

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 sends signal to cell Cell responds by initiating some action

Cell Communication 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

Cell Communication 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

Sensor Systems 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

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

Sensor Systems 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

Sensor Systems Classical pathway Alternative 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

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 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

Sensor Systems Long Double-Stranded RNA (dsRNA) Induction of alpha and beta interferons Cells express iAVPs Leads to apoptosis

Phagocytosis Process of phagocytosis Chemotaxis Recognition/attachment 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

Phagocytosis 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 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 Causes release of pro-inflammatory cytokines Microbial cell surface can trigger complement 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 Results 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 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

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