1. Innate Immune Response
Chapter 15

2. What am I?

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. Cells of the Immune System

11. Granulocytes Contain cytoplasmic graduals Divided into three types
Neutrophils
Basophils
Eosinophils

12. 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)

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Figure 15.7

23. 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

24. 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

25. 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

26. Figure 15.8

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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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