Lecture 3 - Innate Immunity

What is innate immunity?

The first line of defense against infection

Ready to eliminate pathogens immediately upon invasion, an immune mechanism exits even before infection occurs

Innate immunity is primarily mediated by...

Physical, chemical, and microbial barriers, and by innate immune cells

What are characteristics of bacteria and fungi?

Between 1-10 micrometers

Can grow independently

What are characteristics of viruses?

Between 10-50 nanometers

Require a host cell for repliocation

What is the general size of human cells?

10 micrometers

What is the general size of parasites?

Above 100 micrometers

What is canine pyoderma?

A skin infection most often caused by Staphylococcus pseudintermedius

Occurs when the skin barrier is compromised and bacteria overgrow

What is dermatophytosis?

Ringworm

Fungal infection, usually caused by Microsporum canis, that affects the hair, skin or nails

What is canine papillomatosis?

Caused by infection with canine papillomavirus, which induces benign growths (warts) on the skin or mucous membranes

What is myxomatosis?

In rabbits

Caused by the myxoma virus, transmitted mainly by biting insects or direct contact

Severe skin swelling and nodules

What are examples of physical barriers?

Skin (epidermis)

Mucosa (epithelium)

What are examples of chemical barriers?

Low pH

Enzymes (lysozymes)

Antimicrobial peptides (defensins)

What is an example of a microbial barrier?

Commensals

What are the 4 signs of an inflammatory response?

Redness

Heat

Swelling

Pain

Inflammatory responses are triggered by...

Innate immunity

Explain the mechanism of the inflammatory response.

Pathogen passes through the skin and binds to a PRR on macrophage

This causes release of inflammatory cytokines

This causes vasodilation and increased vascular permeability

What does vasodilation cause?

Increased blood flow, resulting in redness and heat

What is increased vascular permeability?

Endothelial cells lining blood vessels loosen their connections

What does increased vascular permeability cause?

Blood components and leukocytes leak out from dilated blood vessels which causes swelling and pain

What are inflammatory cytokines?

Small secreted proteins that act on cells

What are PAMPs?

Pathogen-associated molecular patterns

Molecules conserved within a class of microbes but absent in the host

What are the 2 categories of PRRs (pattern recognition receptors)? What type of cells have them?

Signaling receptor: cytokine production

Phagocytic receptor: phagocytosis

Innate immune cells

What are the 4 types of PRRs?

Toll-like receptors (TLR)

C-type lectin receptors

NOD-like receptors

RIG-like receptors

What are characteristics of TLRs?

On the cell surface/endosomes

Signaling receptor

Recognizes PAMPs of bacteria and viruses

What are characteristics of C-type lectin receptors?

On the cell surface/endosomes

Phagocytic receptor

Recognizes PAMPs of bacteria and fungi

What are characteristics of NOD-like receptors?

Within the cytoplasm

Signaling receptor

Recognizes PAMP of intracellular bacteria

What are characteristics of RIG-like receptors?

Within the cytoplasm

Signaling receptor

Recognizes PAMP of intracellular viruses

Signaling receptors can be located...

On the cell surface, in endosomes, or in the cytoplasm

What are endosomes?

Membrane-bound vesicles in eukaryotic cells that sort and transport internalized molecules

Macrophages express a variety of ___ on their surface

Phagocytic receptors

Bacterial/fungal infections are mostly...

Extracellular

Some may live and grow inside host cells

__ have a higher phagocytic capacity than __

Neutrophils

Macrophages

What do macrophages do in response to bacteria?

Phagocytic receptor is activated, induces phagocytosis and killing

Signaling receptor is activated, releases cytokines (TNF-a) and chemokine (CXCL8)

Vascular permeability increases

Recruits neutrophils to the infection site

What innate immune cells have phagocytic receptors?

Macrophages

Neutrophils

Dendritic cells

What innate immune cells have signaling receptors?

Macrophages

Neutrophils, eosinophils, basophils

Dendritic cells

NK cells

Mast cells

What are representative inflammatory cytokines produced by macrophages?

TNF-a (tumor necrosis factor a)

IL-1B

IL-6

IL-12

CXCL8 (chemokine)

IL-8

What is the function of TNF-a?

Increases vascular permeability

Activates vascular endothelial cells

What is the function of IL-1B?

Activates vascular endothelial cells

Activates lymphocytes

What is the function of IL-6?

Activates lymphocytes

Make heat and raise tissue temperature

What is the function of IL-12?

Induce IFN-y producing CD4 Th1 cells and cytotoxic CD8 T cells

What is the function of CXCL8 and IL-8?

Recruit neutrophils from the blood to the infected tissue

How do leukocytes migrate to sites of inflammation?

1. Leukocytes roll on vascular endothelial cells

2. Chemokines cause leukocytes to adhere firmly to the endothelial cells

3. Leukocytes cross the blood vessel wall and migrate to the site of inflammation

Bacterial phagocytosis is enhanced by...

Opsonin

What can act as opsonin?

Complement components

Antibodies

What are characteristics of viral infections?

Intracellular infection, then infect other cells

Once a virus enters a cell, it can no longer be phagocytose by neutrophils or macrophages

What are the steps in eliminating a virus from the body?

Virus resistance with type 1 interferon (2 days)

Elimination of virus infected cells by NK cells (3 days)

Activation of adaptive immunity by dendritic cells, T cell killing of infected cells (7 days)

What cell types produce interferons?

Macrophages, fibroblasts, epithelial cells, endothelial cells and lymphocytes produce type 1 interferons (IFN a/B)

How do NK cells kill viruses?

NK cells kill virus infected cells that lack MHC by releasing cytotoxic granules with perforin and granzyme B

What is the function of MHC?

Present antigens

Where are MHC class 1 and 2 expressed?

Class 1: all somatic cells

Class 2: APCs such as dendritic cells, macrophages, B cells

What are the steps the adaptive immune system takes to kill viruses if the innate immune system fails?

1. Dendritic cell phagocytoses viruses

2. Dendritic cells become activated and migrate to lymph nodes via afferent lymphatic vessels

3. Present antigens to naive T cells

4. Naive T cells differentiate into activated T cells, which travel via the blood to the infection site

5. CD8 T cells kill virus infected cells via cytotoxic granules containing perform and granzyme B

What are the most effective antigen presenting cells to the least? Why?

Dendritic cells, macrophages, B cells

They reside at pathogens entry sites (skin, airways, gut) and they can migrate from tissues to lymph nodes

What 3 signals are required for T cell activation?

1. Antigen presentation

2. Costimulatory molecule stimulation

3. Cytokine receptor signaling

What receptors are found on T cells that are important for activation, proliferation, and differentiation?

T cell receptor

CD28

Cytokine receptor

What are characteristics of the innate immune response?

Immediate, minutes to hours

Non specific, <100 receptors

No memory, always the same response

What are characteristics of the adaptive immune response?

Slow, days to weeks

Highly specific, > 10^9 receptors

Has memory, improve during response