CH 7: Innate Immunity

Inflammation and wound healing

Immunity

types of immunity

• innate resistance

• adaptive immunity

innate resistance

natural barriers and the inflammatory response

lines of defense

• first line

• second line

• third line

first line

natural barriers: physical, mechanical and biochemical

• we are born with

• body’s surfaces to prevent damage from envrironment

second line

inflammation: activated to protect from further injury & promote healing

third line

adaptive (acquired) immunity

first line

physical and mechanical barriers

• protect against damage & infection

• compose epithelial cells in the skin & membrane GI, genital urinary tract

• skin and low temp/pH of skin

• linings of the GI, genitourinary, and respiratory tracts

• highly interconnected junctions

• sloughing off of cells

• coughing and sneezing

• “washing”

• vomiting

• urinating

• mucus and cilia

first line of defense II

biochemical barriers

antimicrobial peptides → group of proteins

normal microbiome

biochemical barriers

synthesize and secrete substances to trap or destroy microorganisms

antibacterial peptides in mucus, perspiration (sweat), saliva, tears, and earwax

antimicrobial peptides

cathelicidins, defensins (a defensins in neutrophils and B defensins), and collectins (lungs)

• granules from some cells

• release to protect from some bacteria

normal microbiome

body surfaces colonized spectrum of normal microorganism

inhibits colonization by pathogens; releases chemicals that prevent infection

vaginal: Lactobacillus

intestinal: ammonia and phenols → chemicals inhibit colonization of patho microorganisms

• relationship → communcile (one benefit w/o affecting another)

• bacteria contributes to the human body in a protection against pathogenic microorganisms

• microbiome → produce chemicals → amonia

• microorganisms in microbiome normal → won’t cause any disease, keep balance in the surfaces

second line of defense

inflammatory response

• causes: infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes and radiation

• cellular and chemical components

• nonspecific: Takes place in approximately the

  same way, regardless of the type

  of stimulus or whether exposure

  to the same stimulus has

  occurred in the past

• rapidly initiated

• no memory cells

second line of defense II

inflammatory response

• cardinal signs: redness, heat, swelling, pain, loss of function

• vascular response: blood vessel dilation, increased permeability and leakage, white blood cells (WBC) adherence to the inner walls of the vessels, and migration through the vessels (diapedesis)

• happens in any vascular or trauma

• can be: infection, O2 deprivation, trauma

second line of defense III

inflammatory response

• once in the tissues, the cells and chemicals associated with the inflammatory response:

  • prevent and limit infection and further damage

  • limit and control the inflammatory process

  • interact with components of adaptive immune system

  • prepare the area of injury for healing

plasma protein systems

provide a biochemical barrier against invading pathogens are

• complement systems

• clotting system

• kinin system

all contain active enzymes (proenzymes)

• sequentially activated-cascade

  • first proenzyme is converted to an active enzyme

  • the activation of the first component of a system results in sequential activation of other components

complement system

together form 10% of plasma proteins

produce several factors destroy pathogens

• can destroy pathogens directly

• activates or collaborates with every other component of the inflammatory response

• pathways

  • classical, lectin, alternative

• functions: anaphylatoxic activity → resulting in mast cell degranulation; leukocyte chemotaxis; opsonization; cell lysis

classical

antibodies and antigens

lectin

mannose-containing bacterial carbs

alternative

gram-neg bacterial and fungal cell wall polysaccharides

plasma protein systems iv

clotting (coagulation) system

• forms a fibrinous mesh at an injured or inflamed site. main substance in fibrinous mesh is insoluble protein called fibrin

• prevents spread of infection

• keeps microorganisms and foreign bodies at the site of inflammation for removal

• forms a clot that stops bleeding

• provides a framework for repair and healing

• pathway: extrinsic and intrinsic

extrinsic pathway

is activated by the tissue factor outside the vascular space

intrinsic

is activated in the vascular space when the vessel wall is damaged

plasma protein systems v

Kinin system

• functions to activate and assist inflammatory cells

• kinin is primarily bradykinin

• causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis

• kininases degrade kinins

plasma protein systems vi

• interactions among the three plasma protein systems are finely regulated to prevent injury to the host tissue and to guarantee activation when needed

• multiple mechanisms are available to either activate or inactivate (regulate) these plasma protein systems

cellular mediators of inflammation

• cellular mediators

• biochemical mediators

cellular mediators

• mast cells,

• granulocytes (neutrophils, eosinophils, basophils

• monocytes and macrophages

• natural killer (NK) cells and lymphocytes

• cellular fragments (platelets)

biochemical mediators

• originate from destroyed or damaged cells

• modulate the localization ad activities of other inflammatory cells

• tissue regeneration or repair (resolution)

cytokines

interleukins (ILs)

• are produced primarily by macrophages andlymphocytes in response to a microorganisms or stimulation by other products of inflammation

• help regulate inflammation

• many types exist

• examples:

  • IL-1

  • IL-6

  • IL-10

• transforming growth factor-beta is an anti-inflammatory cytokine

IL-I

pro-inflammatory cytokine causes fever

IL-6

pro-inflammatory cytokine: helps with healing

IL-10

anti-inflammatory cytokine

cytokines II

interferons (IFNs)

• protect agains viral infections

• are produced and released by virally infected host cells in response to viral double-stranded ribonucleic acid (RNA)

• do not directly kill viruses but prevent them from infecting additional healthy cells

• types: IDN-a and IFN-B, IFN-y

IFN-a and IFN-B

induce the production of antiviral proteins

IFN-y

increases microbicidal activity of macrophages

mast cells

• most important inflammatory response activator

• are a type of white blood cell that play a key role in the body’s immune response, especially in allergic reactions and inflammation

• found in connective tissues → near blood vessels, nerves, skin, lungs, and the lining of the gut

• activation

  • physical injury, chemical agents, immunologic processes

  • chemicals are released in 2 ways: degranulation, synthesis of lipid-derived chemical mediators

Histamine Receptors

• receptors

• HI receptors (pro-inflammatory)

• H2 receptor

HI receptor

• proinflammatory

• is present in smooth muscle cells of the bronchi

• induces bronchoconstriction

H2 receptor

• anti-inflammatory

• is present on parietal cells of the stomach mucosa

• induces the secretion of gastric acid

phagocytes iv

monocytes and macrophages

• monocytes that are produced in the bone marrow, enter circulation, migrate to the inflammatory site, and develop into macrophages

• monocytes are precursors to macrophages in tissues

  • kupffer cells (liver); alveolar macrophages (lungs); and microglia (brain)

macrophages

larger and more active as phagocytes than monocytes, and are important cellular initiators of inflammation; they help in wound healing

phagocytosis

• is the process by which a cell ingests and disposes of foreign material

• is the destruction of microorganisms and cellular debris

• production of adhesion molecules occur

• margination (pavementing) occurs

  • leukocytes adhere to endothelial cells

• diapedesis occurs

  • cell emigrate through the endothelial junctions

  • most important: neutrophils & macrophage

phagocytosis II

steps:

1. opsonization

   • glue between the phagocyte and the target cell by C3B making the foreign cell more susceptible to phagocytosis) recognition, and adherence

2. engulfment

   • small pseudopods surround adherent microorganism

3. phagosome formation

4. fusion with lysosomal granules

   • creates a phagolysosome

5. destruction of the target

   • uses primary and secondary granules

phagocytosis v

natural killer (NK) cells: recognize and eliminates cells that are infected with viruses and cancer cells in the blood

lymphocytes

are the main components of the adaptive immune response

wound healing

biological process involves in tissue repair

• filling in the wound, sealing the wound (epithelialization), shrinking the wound (contraction)

wound healing can follow three general pathways

• regeneration, resolution, repair

• scar tissue

regeneration

most favorable outcome → replacement of damage tissue w/ healthy tissue

resolution

returning injured tissue to the original structure and function → take up to 2 years

repair

replacement of destroyed tissue with scar tissue → composed mainly of collagen

scar tissue

primarily composed of collagen to restore the tensile strength of the tissue

• possibly loss of function

wound healing II

primary intention

secondary intention

primary intention

• wounds that heal under conditions of minimal tissue loss

• original tissue structure and function that have been restored

secondary intention

• wounds that require significantly more tissue replacement

  • open wound

• wounds that cause scar formation

wound healing iv

phase I: inflammation

• Coagulation and infiltration

• Platelets, neutrophils, macrophages

• Fibrin mesh of blood clot acts as scaffold

• Platelets release growth factors

• Neutrophils and macrophages clean the

wound

• Debridement occurs

• Blood vessels and lymph drain away debris.

• Vascular dilation and permeability reverse

wound healing v

phase ii: reconstruction

• Wound begins to heal

• Healing begins 3–4 days after the

injury and continues for 2 weeks

• Fibroblast proliferation occurs.

• Collagen synthesis by fibroblasts.

• Epithelialization—cells from

healthy tissue grow into wound

• Wound contracts through the

actions of myofibroblasts

• Cellular differentiation occurs

wound healing vi

phase iii: remodeling and maturation

• Healed wound is remodeled

• This phase begins several weeks

after injury and may last for 2

years

• Cellular differentiation continues

• Scar tissue forms

• Scar remodeling occurs

dysfunctional wound healing ii

dysfunction during reconstructive phase

• impaired collagen matrix assembly

  • causes: malnutrition

  • keloid scar

  • hypertrophic scar

• impaired epithelialization

  • anti-inflammatory steroids, hypoxemia, and nutritional deficiencies

  • cleaning with povidone-iodine and hydrogen peroxide

• impaired contraction

  • contractures: result from excessive myofibroblast-derived tension