Ch. 7 innate immunity : inflammation and wound healing

What are the bodys three major lines of defense

1. physical and biochemial barriers

2. innate immune response

3. adaptive immunity

innate immunity

• bodys immediate, nonspecific defense against infection and tissue injury

• present from birth

• acts rapidly

• nonspecific

• does NOT have immunologic memory

innate = immediate + nonspecific + no memory

adaptive immunity

• specific immune response that develops after exposure to an antigen

Involves

• b lymphocytes

• t lymphocytes

• antibodies

• immunologic memory

examples of physical barriers (first line of defense)

• skin

• mucus membranes

• epithelial cells

• tight junctions between epithelial cells

• mechanical removal of organism

biochemical barriers

chemicals secreted by epithelial surfaces that kill microorganisms or inhibit their growth

• antimicrobial substances

• enzymes

• fatty acids

• low- pH environment

epithelial cells in innate immunity

• form a wall

• produce antimicrobial substances

• help recognize pathogens

• release substances that recruit/activate immune cells

mechanical processes protect against infection

• they physically remove microorganisms before they can invade tissues

Examples

• respiratory tract: mucus + cilia

• GI tract: peristalsis

• Urinary tract: urine flow

• Eyes: tears

Cells important in innate immunity

• neutrophils

• macrophages

• Mast cells

• natural killer cells

• dendritic cells

protective substances found in tears and saliva

lysozyme and other antimicrobial substances help destroy or inhibit microorganisms

three major protective functions of the normal microbiome

1. produces enzymes that faciliate digestion

2. produces antimicrobial substances

3. competes with pathogens for nutrients and attachment sites

why can antibiotics lead to opportunistic infections

antibiotics can destroy parts of the normal microbiome , reducing competition and allowing resistant/opportunistic organs to multiply

major components/events of inflammation

1. recognition of injury/infection

2. recruitment of inflammatory cells

3. removal of the offending agent/damaged tissue

4. regulation/termination of the response

5. tissue repair

Recognize → Recruit → Remove → Resolve → Repair

purpose of acute inflammation

1. prevent infection/further tissue damage

2. Limit and control the inflammatory response

3. Interact with adaptive immunity

4. prepare the area for healing

body response of acute inflammatory response

• vascular response

• cellular response

• systemic response

what happens during vascular response

• vasodilation → increase blood flow

• increased vascular permeability → fluid/proteins leave vessels and enter tissue

what causes pain during inflammation

inflammatory mediators stimulate sensory nerve endings

• bradykinin

What does mast-cell degranulation release during inflammation

• histamine

• leukotrienes

• prostaglandins

• cytokines

what does histamine do during inflammation

• vasodilation

• increase vascular permeability

histamine = vessels dilate + get leaky

what are cytokines

signaling proteins that allow immune cells to communicate and coordinate the inflammatory response

3 plasma protein systems that are important in inflammation

1. complement system

2. clotting system

3. kinin system

CCK

What is the complement system

A group of plasma proteins that circulate inactive and becomes activated in a cascade during infection/inflammation

they help:

• destroy pathogens

• promote inflammation

• enhance phagocytosis

3 ways complement system can be activated

1. classical pathway

2. lectin pathway

3. alternative pathway

What complement component is central to all 3 complement pathways

C3

C3

Opsonization-

C3b coats the pathogen, making it easier for phagocytes to recognize and engulf it

“b” for binds the bug

opsonization

coating that phagocytes can recognize and engulf it more easily

which complement components are important anaphylatoxins

C3a and C5a → they promote inflammation

what complement components form the membrane attack complex (MAC)

C5b-C9

they assemble on pathogens membrane and create a pore

MAC = C5b-C9

Major effects of complement activation

• opsonization →C3b

• inflammation/anaphylatoxins → C3a and C5a

• chemotaxis → C5a

• Cell lysis/MAC → C5b-C9

clotting system participation in inflammation

Tissue injury activates the coagulation cascade

Fibrinogen → fibrin

fibrin →stop bleeding, trap microorganisms, limit spread of infection

what is chemotaxis

directed movement of inflammatory cells towards an area of infection or tissue injury in response to chemical signals

C5a

two major clotting pathways

• intrinsic pathway → activated by factors within the blood/vessel

• extrinsic pathway → activated by tissue factor from damaged tissue

what does thrombin do

fibrinogen → fibrin (structural mesh of blood clot)

How do innate immune cells recognize pathogens

They have pattern-recognition receptors (PRRs) that recognize common molecular patterns associated with pathogens or damaged cells

PAMPs

Pathogen-associated molecular patterns

DAMPs

damage-associated molecular patterns

molecules released/ exposed by injured or dying host cells that activate inflammation

What do pattern-recognition receptors recognize (PRRs)

PRRs recognize PAMPs →pathogen AND DAMPs → damaged cells

They activate NF-kB

Toll-like receptors (TLRs)

major type of pattern-recognition receptor (PRR) used by innate immune cells to recognize microbial components

activation triggers intracellular signaling that promotes inflammation and cytokine production —>NF-kB

what cells have PRR

macrophages

neutrophils

dendritic cells

after an innate immune cell recognizes a PAMP or DAMP

PAMP/DAMP → binds PRR → intracellular signaling → activation of inflammatory genes → release of cytokines/mediators → inflammation

NOD-like receptors (NLRs)

located primarily in the cytoplasm

recognize danger inside the cell

mast cells

tissue-resident immune cells that are major activators of inflammation

bags of inflammatory chemicals waiting to be released

mast cell degranulation

stored inside mast cell granules → histamine

which histamine receptor is most important in acute inflammation

H1 receptor → vasodilation, increased vascular permeability, bronchoconstriction, smooth muscle effects

What does H2 histamine receptor do

gastic acid secretion

prostaglandins

lipid derived inflammatory mediator contributing to vasodilation, pain and fever

leukotrienes

bronchoconstriction, increase vascular permeability, leukocyte recruitment/chemotaxis

which mediators are synthesized after mast cell activation from arachidonic acid

prostaglandins and leukotrienes

what are the two major arachidonic acid pathways

1. COX pathway (Cyclooxygenase) → produces prostaglandins

2. LOX pathway (5- lipoxygenase) → produces leukotrienes

PGE2

during inflammation : vasodilation, increase vascular permeability, pain, fever

LTB4

recruits inflammatory cells - especially neutrophils toward the site of inflammation

LTC4, LTD4, LTE4 ?

promote bronchoconstriction and increase vascular permeability

asthma and allergic inflammation

how do NSAIDs decrease inflammation

NSAIDs inhibit : COX → less prostaglandin production → decrease inflammation, pain and fever

macrophages during inflammation

• phagocytose microorganisms and damaged tissue

• release proinflammatory cytokines

• help activate other immune cells

• participate in tissue repair/ wound healing

major proinflammatory cytokines released by macrophages

TNF + IL-1 + IL-6

TNF-a

promotes

• inflammation

• endothelial activation

• leukocyte recruitment

• fever/system inflammatory responses

IL-1

contributes to

IL-1= inflammation + fever

IL - 6

inflammation → IL-6 → liver → increase CRP

dendritic cells

specialized antigen-presenting cells (APCs)

they:

1. capture antigen in tissues

2. travel to lymph nodes

3. present antigen to T lymphocytes

they help initiate the adaptive immune response

leukocytes during inflammation

margination → rolling → adhesion → diapedesis → chemotaxis

margination

leukocyte moves from center of blood flow toward the endothelial wall

what is leukocyte rolling

loosely attach and roll along the endothelial surface

largely mediated by selectins

what causes firm leukocytes adhesion to the endothelium

integrins →allow leukocytes to firmly attach before leaving the vessel

what is diapedesis

movement of leukocytes through the endothelial wall and out of the blood vessel into tissue

also called transmigration

what is chemotaxis

directed movement of leukocytes toward increasing concentration of chemical attractants at the site of injury/infection.

What is the sequence of acute inflammation from vessel change to leukocyte arrival

• tissue injury

• inflammatory mediators released

• vasodilation

• increase blood flow → redness and warmth

• increase vascular permeability

• fluid/protein enters tissue → edema

• leukocyte recruitment

• margination → rolling→ adhesion → diapedesis → chemotaxis

• Leukocyte reach the injury

first leukocyte to arrive during acute inflammation

neutrophil

function of neutrophil

• migrate to site

• phagocytose microorganism

• kill using enzymes and reactive substances

what arrives after neutrophil

monocyte →macrophages

steps of phagocytosis

1. recognition

2. engulfment

3. formation of phagosome

4. fusion with lysosome → phagolysosome

5. killing

role of eosinophils in inflammation

allergic reactions

parasitic infections

role of mast cells in inflammation

release inflammatory mediators → histamine

basophils during inflammation

similar to mast cells and release inflammatory mediators

role of natural killer (NK) cells:

destroy

• virus-infected cells

• tumor cells

what is granulomatous inflammation

a form of chronic inflammation where macrophages accumlate and organize around an agent that is difficult to eliminate

forms a granuloma

what does a left shift mean

an increased number of immature neutrophils (bands) in the bloodstream

4 phases of wound healing

1. hemostasis

2. inflammation

3. proliferation/new tissue formation

4. remodeling and maturation

Phase 1: hemostatsis

• body stops the bleeding

• vasoconstriction → platelet activation → fibrin clot

events of proliferative phase

• angtiogensis

• fibroblast proliferation

• collagen production

• granulation tissue formation

• re-epithelialization

• wound contraction

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