Innate Immunity

What are the the two main types of external barriers?

Epithelial barriers and Antimicrobial proteins/peptides

What some of the epithelial barriers?

Skin and the Epithelial lining of the digestive tract, respiratory tract, urogenital tract, and ducts of glands, including secretions

What secretions are included in the epithelial barriers?

Mucus, HCl, Sweat, Tears, and Saliva

What are the antimicrobial proteins/peptides?

Lysozyme, Defensins, and Surfactants

Where are lysozymes secreted from?

Secreted in tears, saliva, and is in the respiratory tract

What is the function of Lysozymes?

Directly kill bacteria

Where are defensins secreted from?

Lots of epithelial cells secrete them

What are the functions of defensins?

Kill bacteria and attack virus

Where are surfactants secreted from?

Respiratory tract

What is the function of surfactants?

They modify microbes to prevent entry through epithelial layers

What do PRRs recognize?

PAMPs and damage associated molecular patterns (DAMPs)

What are the PRR classes? Which is the most well known?

toll-like receptors (TLRs), most well known

Lectin receptors

Scavenger receptors

Opsonization receptors

Cytosolic innate receptors

What is the function of toll-like receptors?

Binding results in activation of many genes

What are the toll-like receptors?

Sit outside the membrane and are TLR2 and TLR4

What is the function of lectin receptors?

initiate phagocytosis

What are the lectin receptors?

DC-SIGN, Dectin-1, Dectin-2 Fc gamma R, CD206

What is the function of Savenger receptors?

initiate phagocytosis

What are the scavenger receptors?

SR-A

What is the function of Opsonization receptors?

initiate phagocytosis

What are the opsonin receptors?

CR3

What is the function of Cytosolic innate receptors?

within the cytosol of the cell

recognize intracellular PAMPs (intracellular pathogens are viruses)

inhibit viral replication

What does PRR signaling induce?

Expression of different proteins

antimicrobial proteins, Type 1 interferons, proinflammatory cytokines, chemokines, and enzymes

What is an example of antimicrobial proteins?

Defensins

What are some examples of Type 1 interferons and the function(s)?

IFN - alpha and IFN - beta, they prevent viral replication

What are some examples of proinflammatory cytokines and the function(s)?

IL-1, IL-6, TNF - alpha

Increase vascular permeability, and allow for recruitment of cells to the site of infection

What are some examples of chemokines and the function(s)?

IL-8/CXCL8

Recruit immune cells to the site of infection

What are the functions of enzymes?

Allows for the synthesis of antimicrobial compounds and allow for synthesis of mediators of inflammatory response

What is the first step of phagocytosis?

PAMP binds to PRR

What is the second step of phagocytosis?

Results in polymerization of actin microfilaments which extends the cell membrane

What is the third step of phagocytosis?

Pathogen is engulfed in a phagosome

What is the fourth step of phagocytosis?

-Phagosome fuses with the lysosome which contains antimicrobial compounds

         - Phagosome fuses with cytoplasmic granules in neutrophils

What is the fifth step of phagocytosis?

Pathogen is killed and digested

What is the sixth step of phagocytosis?

Digested pieces of pathogen are released by the cell

What are the two ways phagocytosis is initiated?

•PAMP recognition by a PRR

•Opsonins

What is an opsonin?

Soluble protein that binds to pathogen surface and marks it for phagocytosis

How do opsonins initiate phagocytosis?

-The opsonin will bind to a PRR and initiate phagocytosis

-Antibodies, complement proteins

What do lysosomes/cytoplasmic granules contain?

-Antimicrobial proteins – defensins

-Low pH compounds

-Enzymes – lysozyme

-Compounds that mediate oxidative damage

        - reactive oxygen species (ROS)

        - reactive nitrogen species (RNS)

What are the hallmarks of inflammation?

-Pain

-Redness

-Swelling

-Heat

-Loss of function

What is swelling due to?

Increased vascular permeability that results in fluid and cells leaving bloodstream

What is redness and heat due to?

Increased blood flow to the site of infection

What is pain/loss of function due to?

Damage to health tissue

What is the first step of an inflammatory response after the pathogen invades healthy tissue?

PRR recognition of PAMPs by resident macrophages and dendritic cells

What is the second step of an inflammatory response after the pathogen invades healthy tissue?

Phagocytosis by resident macrophages and dendritic cells

What is the third step of an inflammatory response after the pathogen invades healthy tissue?

Release of proinflammatory cytokines (IL-1, IL-6, TNF – alpha) , proinflammatory mediators (Prostaglandins), and chemokines (IL-8) by resident macrophages and dendritic cells

What is the fourth step of an inflammatory response after the pathogen invades healthy tissue?

Blood flow and vascular permeability increases in response

What is the fifth step of an inflammatory response after the pathogen invades healthy tissue?

Fluid enters tissue delivering antimicrobial molecules

What is the sixth step of an inflammatory response after the pathogen invades healthy tissue?

Neutrophils are recruited by IL-8

What is the seventh step of an inflammatory response after the pathogen invades healthy tissue?

Neutrophils perform phagocytosis

What is the eighth step of an inflammatory response after the pathogen invades healthy tissue?

Monocytes are recruited by CCL2

What is the ninth step of an inflammatory response after the pathogen invades healthy tissue?

Monocytes differentiate into macrophages

What is the tenth step of an inflammatory response after the pathogen invades healthy tissue?

Newly differentiated macrophages perform phagocytosis

What is the eleventh step of an inflammatory response after the pathogen invades healthy tissue?

Professional APCs activate the adaptive immune system

What do macrophages secrete?

IL-1, IL-6, TNF-alpha, IL-8, and IL-12

IL-1, IL-6, and TNF - alpha have?

They can have systematic effects a main one being fever

When secreted by macrophages IL-1 and TNF-alpha have what functions?

Increases vascular permeability and induces fever

When secreted by macrophages IL-6 has what functions?

Induces release of acute-phase proteins and induces fever

When secreted by macrophages IL-8 has what function?

Recruits neutrophiles

When secreted by macrophages IL-12 has what function?

Recruits and activates natural killer cells

What is the acute phase of infection?

The phase preceding recovery or death

What does the acute phase of infection result in?

Systemic effects of inflammatory response

What is the acute phase of infection caused by?

By proinflammatory cytokines: IL-1, IL-6, TNF – alpha

What are the acute phase response effects?

1. Proinflammatory cytokines act on bone marrow to stimulate production of white blood cells

2. Proinflammatory cytokines act on the brain and induce fever (proinflammatory cytokines are considered pyrogens)

       induce fever which increases chemotaxis of neutrophils and increases survival of immune cells

3. Increase production of sleep-inducing molecules which allows for redirection of resources to immune system

4. Act on hunger centers to decrease appetite

              - Decreases nutrient availability for pathogens

5. Proinflammatory cytokines act on skeletal muscle to catabolism of protein

              - increases amino acid availability for production of proteins by immune cells and liver

6. Proinflammatory cytokines act on the liver to produce acute phase proteins: will see a decrease in muscle weight but a major increase in liver weight because of this and Some are complement proteins, opsonins, and iron binding proteins

What iron binding proteins does the body produce during the acute phase?

Liver produces transferrin and haptoglobin which bind iron making it unavailable for pathogens

What do pathogens produce to counter the transferrin and haptoglobin the liver produces in the acute phase?

Produce siderophores that remove iron from transferrin and haptoglobin

What does the liver produce in response to siderophores produced by the pathogen in the acute phase?

Liver produces lipocalin 2 which binds to siderophores and limits their ability to function