Chapter 17 Innate Nonspecific Host Defenses

susceptibility

lack of resistance to a disease

Immunity

ability to ward off diseases

Innate immune system

defenses against any pathogen present since birth

Adaptive immunity

immunity or resistance to a specific pathogen that develops over time with exposure of pathogens

• development of antibodies

Physical barriers that make up the first line of defense

• skin (dermis and epidermis)

• mucous membranes (mucus)

• ciliary escalator

• lacrimal apparatus (secretions help remove microbes)

skin

body’s largest organ that consists of

• epidermis: made up of tightly packed cells that sloughs off to remove microbes

• dermis: connective CT

Mucous membranes

susceptible to spirochete pathogens (treponema pallidumz)

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Mucus

traps microbes that are produced by goblet cells

ciliary escalator

transports microbes trapped in mucus away from lungs using cilia

Lacrimal gland

produces tears that help wash away microbes from the surface of the eye

• part of first line of defense

Tears and mucus

contain lysozymes that break apart bacterial cell wall

B. pertussis targets respiratory system and damages

cilia

B. pertusis uses virulence factors

• filamentous hemagglutinin

• fimbriae

• pertacin

that allow it to bind to cilated cells

PTx is an

A-B exotoxin that stimulates adenylate cyclase which

• reduces phagocytic activity

• increases histamine release

PTx toxin stimulates adenylate cyclase which increases

cAMP in immune cells, weakening their ability to fight off infection

Histamine releaxe causes

vasodilation which makes blood vessels leaky leading to inflammation

• controlled by PTx

B. pertussis (pathogen) controls the

fever → kills our cells

cytokines are

signaling molecules

• Interleckins

• TNF - tumor neurosis factor

Chemical barriers in first line of defense

• sebum - inhibits bacterial growth

• lysozyme - break down cell walls by destroying chemical bonds

• gastric juice - has low pH that kills most pathogens

• vaginal secretion - prevents yeast infections

resident microbiota

normal, non-harmful microbes that live in the human body

Vaginal canal normal microbiota produce

pH that is not suitable for Candida albicans

Commensal microbiota

microbes benefits without harming host

Probiotics with prebiotics for example LAB prevent

Salmonella enterica growth during antibiotic treatment

Fever is elevated body temperature triggered by

IL-1 from phagocytes, enhancing T-cell production, and interferon activity

Phagocytosis

involves neutrophils, macrophages and dendritic cells that engulf pathogens

Inflammation brings immune cells to infection sites via

vasodilation and permeability increases

• Triggered by

  • Histamine

  • Kinins

  • Prostaglandins

  • Leukotrienes

Neutrophils

• can leave blood, enter tissue, and destroy microbes

• essential in early infection

Macrophages

• clean up damaged tissues

• increase in later infection

Natural killer (NK) cells

target infected host cells and tumor cells

Lymphatic system

drains interstitial fluid, filters lymph through nodes containing B-cells and T-cells

• Nodes trap microbes for phagocytosis

Phagocytic cells

• Neutrophils: lots of numbers

• Macrophages: the marines

• Dendritic cells:placed in epidermis

• B-cells: create antibody

• T-cells: activate B-cells

B-cells and T-cells are found in

lymph nodes + nodules

Cytotoxic T-cells (CTL’s) and NK’s target

virally infected cells and cancer cells

Eosinophils contain

granzymes + perforins that create pores in pathogen membranes

• increase during parasitic infection

Mast cells/ basophils are

granulocytes that contain vasodilators

Vasodilators include

• histamine

• kinins

• prostaglandin

• leukotrienes

Macrophages start as

monocytes: immature macrophage

• has no phagocytic activity

• mature by leaving blood + entering into tissue

Inflammation molecular pathway

1. Wound creates a portal of entry in the epidermis

2. Dead/dying cells damaged by wound release chemotactic cytokines

3. Dendritic cells near wound detect that pathogens that are entering and release additional cytokines

4. Cytokines from both dying cells and dendritic cells activate mast cells and basophils

5. Mast cells and basophils degranulate which causes release of VASODILATORS

   1. HISTAMINE

   2. PROSTAGLANDIN

   3. LEUKOTRINE

   4. KINNINS

6. Vasodilators make blood vessels permeable allowing plasma to flow from blood vessel into tissue causing interstitial fluid

7. Monocytes move closer to vessel walls (marginatation)

8. Monocytes squeeze through blood vessel walls and enter the tissue (diapedesis) → wandering monocyte

9. Excess interstitial fluids along with any pathogen drains into lymphatic capillaries and becomes lymph fluid

10. Lymph fluid will travel through the lymph nodes and nodules that contain T-cells, B-cells, and FIXED macrophages

11. It then goes into subclavian vein where it is returned to the blood PATHOGEN free

Fluid exchanges between lymphatic system and blood

Blood plasma leaks into interstitial spaces, enters the lymphatic capillaries, and flows through lymph nodes. Lymph returns to blood through the subclavian vein

PAMP’s (Pathogen Associated Molecular Patterns)

Molecules on pathogens that trigger immune responses by being recognized as foreign

TLR’s (Toll-Like Receptors)

detect and bind to PAMP’s, initiating signaling pathways that activate immune response

• Flagella

• NAM-NAG

• Mycolic acid

• LPS

• GP120

PAMP and TLR process (phagocytosis)

…

Phagocytosis process

1. Phagocytes recognize pathogens

2. Phagocyte surrounds pathogen with its membrane, forming a pocket around it

3. Phagosome gets created that contains pathogen

4. Phagosome fuses with lysosome to form phagolyssome

5. Enzymes in phagolysosome break down pathogen into smaller pieces

6. Excoystosis

Bacteria in a biofilm community are more difficult to

phagocytose than free floating bacterial cells because they are more difficult to be pulled off

Oxidative burst

Neutrophil releases H2O2 (hydrogen peroxide) which causes free radicals → can bind to DNA and cause mutations

• Pathogen will come in and it’s DNA is mutated so much that it dies

Complement proteins are ready to go as soon as

inflammation occurs

• another way to attack proteins

• found in serum of blood.

3 ways to turn on complement proteins

1. Alternative pathway (fastest)

2. Lectin pathway (2nd fastest)

3. Classical activation (slowest)

Alternative pathway (fastest)

uses protein factors

1. Protein factors bind to the glycolipids of the pathogen

2. Complement protein bind to protein factors and causes activation cascade

3. Complement protein is active and can do it’s jobs

   1. Opsonization

   2. Inflammation

   3. Cytolysis

Lectin pathway

Phagocytic cell phagocytoses pathogen

Release waste → lymphatic capillary → circulatory system → makes lectin → circulatory system → vasodilated blood vessels →

1. Lectin binds to manose

2. Complement protein binds to lectin

3. Complement protein causes activation cascade

4. Activated complement protein can now do 3 jobs

   1. Opsonization

   2. Cytolysis

   3. Inflammation

Classical activation

Relies on antibodies (7-10 days)

1. Pathogen has antibody’s that bind to the antigen/PAMP

2. Complement protein binds to the FC region of the antibody

3. Complement protein causes activation cascade

4. Activated complement protein can now do it’s 3 jobs

   1. Opsonization

   2. Cytolysis

   3. Inflammation

Once compliment protein is activated by one of the 3 methods it can do all 3 of its jobs

1. Opsonization

2. Cytolysis

3. Inflammation

they all happen at the same time and help WBC attack pathogens

Opsonization

Creates a handle to grab pathogen

1. Activated complement protein will bind to the pathogen on the surface of the phagocytic cells

2. Complement receptor binds activated complement protein and grabs a hold of pathogen

Mast cells/ basophils are

granulocytes

Inflammation

1. Mast cellls/basophils have complement receptor on surface

2. Complement receptor binds to activated compliment protein

3. This causes mast cells/basophils to degranulate releasing vasodilators (histamine, kinins, leukotrienes, prostaglandins)

4. This causes blood vessels to become permeable

5. Leads to inflammation

Cytolysis

1. Activated complement protein forms pore called MAC (membrane attack complex) in the plasma membrane of the pathogen

2. Since all cells are hypotonic water will be drawn inside pathogen

3. Cell will lyse

Some bacteria can evade complement

• If pathogen has capsule, glycolipids are not exposed → complement cannot be activated

• No pore → no cytolysis

• If pathogen has protease → it will chew up activated compliment protein

Interferons are

cytokines

• alpha, beta, gama

How interferons work

1. Viral infected cells will release interferons alpha and beta to protect neighboring viral uninfected cells

2. This causes viral uninfected cell to do transcription → translation → makes enzymes called AVP (antiviral proteins)

3. AVP are RNAses therefore they chew up the RNA genomes of the viral infection (Ex. +ssRNA genome of HIV)

4. They will get chewed up and it will prevent infection

Gamma interferons

activate macrophages and promote the killing of bacteria and tumor cell

Transferins

• made my hepatocytes (liver) and found in serum of blood (soluble proteins)

• Work by binding to iron → prevents pathogen from binding → prevents growth

• always present in circulatory system

AMP’s are

released when CLR bind to PAMPs

• causes pores → water rushes in → pathogen dies

• have not shown ability for pathogen to become resistant to it because AMP are different from host-to-host therefore pathogen can’t evolve

Innate response

cytokines recruit phagocytes and cause inflammation

Adaptive response

Cytokines activate B and T cells to produce antibodies and attack specific pathogens

Role of inflammation in innate immunity

helps isolate pathogen, recruits immune cells, and facilities tissue repair

Antimicrobial peptides

Produced in response to TLR activation and disrupt bacterial cell

• can also enhance macrophage and neutrophil activity

Innate vs Specific Adaptive responses

• innate: phagocytes respond to any pathogen without specificity

• adaptive: B and T cells respond to specific pathogens