Innate Immune System Physiology- Gonsalves

3 lines of defense of the immune system

1. Innate or Nonspecific System

2. Adaptive or Specific System

3. Functional System

The first 2 lines of defense are

nonspecific

The first line of defense of the innate is

external body membranes like the the skin and the mucus membranes (external line of defense)

What does the first line of defense do?

Prevents physical entry of microorganisms

What is the second line of defense?

internal defenses- phagocytes, antimicrobial proteins, inflammation (internal innate)

(Throws many uncustomized generic responses at pathogens)

The _________ is activated by __________ signals when the external defenses are penetrated

second line of defense(internal innate), chemical

The functional system

1. Has organs that are involved in the immune response but also involves trillions of individual immune cells.

2. The immune system confers immunity which is resistance to disease.

Job of the immune system

protect the body against pathogens

Function of the innate system

1. Combat pathogens

2. Be in a state of readiness and respond to protect the body from ALL foreign substances starting within minutes of invasion

Pathogen

disease causing microorganism

How the skin protects the body?

1. Heavily keratinized epithelial membrane acts as a physical barrier (dead skin cells form a layer and then slough off)

2. Resistant to most weak acids/bases, bacterial enzymes and toxins

3. Secretions are acidic and inhibit bacterial growth (ph 3-5)

4. Sebum also contains chemicals that are toxic to bacteria

Mucus membranes

line all body cavities that open to the exterior including the digestive, respiratory, urinary, and reproductive tracts

All the ways the innate (nonspecific) first line of defense protects from pathogens?

1. The epidermis

2. Sebaceous oil glands

3. Sweat

4. Hair

5. Mucous

6. Cilia

7. Gastric acidity

The stomach secretes __________ and _______________ which kill microorganisms

HCl, protein-digesting enzymes (mucous external membrane defense)

__________ and _________ __________ contains lysozyme, an enzyme that ___________ bacteria

Saliva, lacrimal fluid, destroys (mucous membrane external defense)

This traps microorganisms that enter the digestive and respiratory passageways

Sticky mucous

Structural modifications of the mucous membranes

Tiny mucus-coated hairs and ciliated mucosa of the respiratory tract trap and sweep particles away from the lower respiratory passageways.

Internal Innate is nonspecific and consists of:

1.Phagocytes, natural killer cells, antimicrobial proteins

2. Fever inducement

3. Inflammatory response- macrophages, mast cells and all WBCs (leukocytes)

Phagocytes

cells capable of engulfing or "eating" and absorbing bacteria and other small cells and particles.

Main way they protect is through phagocytosis

Phagocytosis

A type of endocytosis in which a cell engulfs large particles or whole cells

The main phagocyte

macrophages (they love to "gobble gobble")

Macrophages characteristics

1. derived from monoctyes that leave the blood stream, enter the tissue and enlarge

2. Can roam the tissues in search of cellular debris or "foreign invaders" similar to alveolar macrophages of the lungs

3. Can be fixed - stay at strategic locations such as liver resident Kupffer cells

Neutrophil Characteristics

1. Most abundant of WBCs

2. May become phagocytic upon exposure to infectious material

3. Secrete defensins

4. Can release oxidizing and bleach-like chemicals that destroy cells, including themselves

5. Can cause normal tissues to become cancerous with prolonged activity

6. Lifespan = 0.5-1 day

Why can neutrophils cause normal tissue to become cancerous with prolonged activity?

The chemicals they release damage tissues, leading to these tissues needing to be repaired. If the tissue has to be continually repaired mistakes can be made which cause cancer.

Defensins

antimicrobial peptides that inhibit microbial growth (antibiotic like chemicals) they are produced not only by phagocytic (mainly neutrophils) cells and lymphocytes, but also by the epithelial cell lining of the gastrointestinal and genitourinary tracts, the tracheobronchial tree, and keratinocytes.

Fixed macrophages include:

Histocytes (connective tissue)

Kuppfner cells (liver)

Alveolar cells (lungs)

Microglia (nervous)

Eosinophil involvement in phagocytosis

1. Weak phagocytes but are important against parasitic worms

2. Non-professional phagocytes and dont primarily use phagocytosis but they do kill cells by discharging the destructive contents of cytoplasmic granules.

Mast cells

1. Main job is to release histamine, involved in allergies becasue if they were activated too much = allergic reaction.

2. They have some phagocytic capabilities but are not "professional" phagocytes

Phagocytes

1. Macrophages- main phagocyte

2. Neutrophils- may become phagocytic, but limited to it and can kill in many other ways

3. Eosinophils- weak phagocyte, mostly kill through chemical release

4. Mast Cells- have some phagocytic capabilities, main function is to release histamine

Phagocytosis requires ameoba- like digestion:

1. Phagocyte engulfs the particle using flowing cytoplasmic extensions

2. The particle is enclosed in a membrane-like vacuole called a phagosome

3. A lysosome fuses with the phagosome to form a phagolysosome

4. Indigestible waste is removed by exocytosis

Ameoba-like digestion requires

adherence of the particle to the phagocyte

Opsonization (B cells)

The coating of of foreign particles complement proteins and antibodies which increases adherence

(The coating of pathogens with antibodies in order to increase their susceptibility to ingestion by phagocytes.)

Opsonins

used to overcome the repellent force between the negative cell walls and promote uptake of the pathogen by the macrophage.

How is adherence of the particle to the phagocyte increased?

1. Carbohydrate signatures

2. Opsonization

_________________ has a capsule that makes adherence difficult. ____________ would help with adherence.

Pneumococcus, opsonization

What happens when a pathogen survives lysosomal enzymes and begins to multiply within the vacuole of the phagocyte?

Respiratory bursts can be activated by the adaptive immune system and release chemicals that produce free radicals like nitric oxide, which can kill cells.

Nature Killer Cells are located in the

blood and lymph

Nature Killer Cells can kill and lyse

cancer cells and virus infected cells

Natural Killer cells belong to the group large ___________ __________

granular lymphocytes

Nature Killer Cells Characteristics can recognize __________ ___________ but are fairly _________________

surface sugars, nonspecific

These cells are not phagocytic but release cytolytic chemicals called perforins that kill our cells too.

Nature Killer Cells

Perforins

protein, released by killer cells of the immune system, which destroys targeted cells by creating lesions like pores in their membranes. Once the pores are there, fluid rushes in and causes the cell to cytolysis/

Killer cells can also secrete chemicals that ___________ the inflammatory response

enhance

Nature Killer cells are part of the

Second line of defense- Second Innate

Inflammation is a ______________ feedback loop

positive

What triggers inflammation?

tissue injuries like physical trauma, heat, irritating chemicals, infection by viruses, fungi, and bacteria

Inflammation is a ______________ _______________ response to a "bunch of things"

generic, nonspecific

Why is pain useful?

1. Helps us to heal because we are more likely to rest the injured area

Functions of Inflammation

1. Prevents spreading of damaged agents

2. Disposes of cell debris and pathogens

3. Sets the stage for repair processes

Cardinal Signs of inflammation

redness, heat, swelling, pain, and sometimes impairment of function

Inflammatory mediators:

histamine, kinins, prostaglandins, cytokines, complement

Where can inflammatory mediators come from?

injured tissue cells, phagocytes, lymphocytes, mast cells, and blood proteins

Histamines are released by

mast cells

Prostaglandins are released by

damaged cells, made from the cell membranes of these broken cells

Braddykinins are triggered

to be released when any vascular tissue is damaged

inflammation begins with the ____________ of chemicals called inflammatory _______________ into the ____________________ fluid.

release, chemicals, mediators, extracellular

Main Inflammatory mediators

histamine, prostaglandins

Histamine and prostaglandins cause

Vasodilation which increases permeability of blood vessels and hyperemia = congestion within the blood that is responsible for redness and heat in the skin

Inflammatory mediators also cause

Increased permeability of the local capillaries

-exudates flow from the bloodstream into tissue spaces

- local edema occurs and pain is triggered

Exudates

fluid containing proteins like clotting factors, antibodies and pus that filter from cells or capillaries and ooze into lesions or areas of inflammation

Why is edema beneficial?

1. Helps to dilute harmful substances that may be present

2. Brings large quantities of oxygen and nutrients needed fro repair

3. Allows entry of clotting proteins which forms fibrin mesh that prevents the spread of harmful agents

Beta-defensins

small proteins that function in antimicrobial defense by penetrating a microbe's cell membrane and cause microbial death in a manner similar to that of antibiotics.

(antibiotics that our body makes)

Inflammation increases the production of ____________ ____________ which are antibiotic like chemicals.

beta-defensins

Phagocytic Mobilization (when there is injury)

1. Mast cells are already present in the tissue and are therefore the first responders

2. Next are the neutrophils = expendable

3. Macrophages

Leukocytosis

increase in the number of white blood cells

For Leukocytosis to take place 3 events must take place

1. Margination

2. Diapedesis

3. Chemotaxis

Leukocytosis is like a superhero team assembling to fight off an infection: first, the white blood cells gather on the blood vessel walls (margination), then they squeeze out of the vessels (diapedesis), and finally, they follow chemical signals to the site of infection (chemotaxis).

Injured cells release chemicals called _____________ _______________ to promote the release of _______________ from the red bone marrow.

leukocytosis-inducing factors, neutrophils

Margination

inflamed endothelial cells sprout cell adhesion molecules (CAMs) called selectins. As neutrophils encounter these CAMs, they slow and roll along the surface, eventually achieving an initial foothold. When activated by inflammatory chemicals, CAMs on neutrophils bind tightly to endothelial cells of the capillary wall.

The neutrophils then begin clinging to the inner walls (margins) of the capillaries and postcapillary venules.

Margination only happens where the _____________ is because of selectins.

Injury

Diapedesis

the process of neutrophils emigrating through the capillary walls to the site of inflammation. Only happens where the site of the injury is

Chemotaxis

the attraction of neutrophils and other white blood cells to the site of injury due to inflammatory chemicals called chemotactic agents.

Monocytes become ___________ about __________ hours after entering the tissues.

Macrophages, 8-12

Macrophages are _____________ at sites of ____________ inflammation.

fixed, chronic

What is Pus?

a mixture of dead or dying neutrophils, broken-down tissues cells, and living and dead pathogens

_____________ sacs of pus walled of by ___________ ___________

Abscesses, collagen fibers

What are Infection Granulomas?

Tumor-like growths containing macrophages infected by pathogens "hiding" within them. Healthy macrophages surround the infected cell and a fibrous capsule forms.

Formation of a Granuloma

There is an inflammatory trigger. Macrophages are recruited to the site of inflammation and activated as part of the innate immune response. If the recruited and activated macrophage is unable to remove the inflammatory stimulus efficiently, a further immune response may be triggered. Additional macrophages are recruited to the site, and a chronic inflammatory reaction develops. The macrophages form a tight aggregate around the inflammatory stimulus and outer fibrous capsule is formed.

Antimicrobial proteins

attack microorganisms directly or inhibit their ability to reproduce

Interferon

proteins that can induce a nonspecific resistance to viral infection by several mechanisms, including the inhibition of protein synthesis, inactivation of viral RNA, and enhancement of phagocytic and cytotoxic mechanisms.

Interferon Characteristics:

1. Not Virus specific

2. Activates macrophages and mobilizes natural killer cells

3. Plays an anti-cancer role

4. Small proteins that interfere with with viral protection

Types of interferons (a type of cytokine):

1. Alpha comes from most other leukocytes

2. Alpha is used to treat genital warts and can combat Hep C

3. Beta comes from fibroblasts

4. Gamma comes from lymphocytes

Complement system of the innate immune

group of at least 20 plasma proteins that destroy foreign substances by lysis when activated

The complement system ____________ the inflammatory response

amplifies

What is inflammation?

damage that occurs to vascularized tissue.

Inflamation is ___________ in the short term and __________ in the long term

good, bad

Types of cytokines

interleukins, interferons, growth factors, tumor necrosis factor, chemokines

(Cytokines are like different types of messengers in your body, each with their own unique role - interleukins help immune cells communicate, interferons fight viruses, growth factors promote cell growth, tumor necrosis factor kills cancer cells, and chemokines attract immune cells to infection sites.)

The complement system has 2 pathways

A classical and an alternative pathway. These both lead to the activation of C3, one of the complement proteins. C3 is cleaved into two subunits which can cause inflammation and opsonization.

What is MAC?

Membrane Attack Complex which inserts into the membrane of the target cell and inhibits the cell's ability to eject Ca++ and causes lysis.

How are fevers beneficial?

Speeds up the metabolic rate of tissue cells, causes the liver and spleen to uptake iron and zinc, which bacteria require in large amounts. Decreases the ability of pathogens to reproduce.

Body temperature is controlled by the ________ __________ and is set to ____________

hypothalamic neurons, 36.2 celsius

Fever occurs when __________ reset the neurons ___________

pyrogens, higher

Pyrogens

chemicals secreted by leukocytes and macrophages exposed to foreign matter that cause fever

Carbohydrate signatures

Increase cell adherence to the pathogen. Lectin receptors on the phagocyte (pattern recognition receptors) bind to pathogen-associated molecular patterns (PAMPS) founnd on the surface of the pathogens.

Types of Macrophages

wandering and fixed

Wandering macrophages

actively seeking pathogens

widely distributed in loose connective tissue. These are monocytes

fixed macrophages

sit in the tissues and don't move

Difference between neutrophils and macrophages

Neutrophils generally attack bacteria and engulf and destroy. Macrophages do this too but can also pull off parts of the pathogens, usually proteins, and present them on the surface of their cell for the adaptive immune system(antigen presenting cells, APCs)

Carbohydrate Signatures

Lectins associated with the receptors on the phagocyte (pattern recognition receptors) that bind to pathogen-associated molecular patterns (PAMPs) found on the surface of pathogens.