Lecture 1: Innate Immune System

Innate Immunity

Early Recognition:

• First line of host defense (skin, mucosal barrier, blood brain barrier, chemical barriers

• Detects microbes and initiates mechanisms to remove threats

• Distant characteristics:

1. Local effect

2. Nonspecific

3. Lacks memory

4. Works quickly

5. Pre-programmed

• Protective Proteins: Keratin, Interferons, Complement

• Protective cells: Neutrophils and Macrophages

• Protective processes: Fever and Inflammation

External Barriers:

• Acid mantle: Inhibit bacterial growth

• Dermicidin: Antibacterial peptide in sweat

• Defensins and Cathelicidins: Destroy bacteria, viruses and fungi. These are enhanced by Vitamin D

Mucous Membranes:

• Chemical barriers and Physical barriers

• Sticky consistency

• Lysozyme (mucus, tears, saliva): Destroys bacterial cell walls

• Hyaluronic acid: In a healthy state, large, intact hyaluronic acid molecules act like a tough structural glue in your mucus membranes. It physically traps bacteria and viruses so your body can flush them out, while sending an "all clear, anti-inflammatory" signal to keep your immune system calm

• Hyaluronidase: The enzyme that chops up hyaluronic acid, and it plays a dual role depending on who is using it. Your own body releases hyaluronidase at an injury site to intentionally break down the hyaluronic shield. This creates the "distress flare" fragments needed to activate your immune defenses and allows healing immune cells to easily move through the tissue to reach the wound

Cells of the Innate Immune System

Granulocytes:

• Neutrophiles (60-70% of leukocytes):

1. Granules contain hydrolytic enzymes or defensins (antimicrobials)

2. Pattern Recognition Receptors on surface

3. Phagocytic: “bacteria slayers”

4. Highly Regulated-to prevent unwanted damage to host cells

5. Degranulation: When bacteria are detected in immediate area, lysosomes migrate to the cell surface and discharge enzymes into the tissue fluid, and releases antimicrobials to kill bacteria

6. Phagocytosis: Engulfing microbes with pseudopods and destroying with lysosomal enzymes

7. Neutrophil Extracellular Traps (NETs): Release of chromatin to neutralize and kill bacteria, fungi, viruses and parasites and prevent dissemination of bacteria (too many?-can cause blood clots and tissue damage!)

• Eosinophils (2-4% of leukocytes):

1. Red to crimson (acidophilic) coarse, lysosome-like granules

2. Stand guard against parasites, allergens and other foes

3. Secrete superoxide, H2O2 and neurotoxins

4. Kill parasites such as tapeworms and roundworms

5. Phagocytized and degrade antigen-antibody complexes, allergens and inflammatory chemicals

6. Found in the mucous membranes

7. Can degranulate

• Basophils (<0.5% of leukocytes)

1. Large, purplish-black (basophilic) granules contain histamine

2. Secrete chemicals to aid in mobility and action of other leukocytes

3. Secrete histamine (vasodilator) - increased blood flow; heparin (anticoagulant) - mobility of WBC’s prevents clotting; leukotrienes - activate and attract neutrophils and eosinophils

4. Mast cells are very similar - found in tissues rather than in bloodstream

5. Eosinophils promote the action of basophils and mast cells

Agranulocytes:

• Monocytes (3-8% of leukocytes):

1. Differentiate into macrophages (large phagocytic cells found in tissues)

2. Found in connective tissue (some specialized microglia-nervous system; alveolar macrophages-lungs; hepatic macrophages-liver)

3. Phagocytize pathogens, dead neutrophils and debris of dead cells

4. Present antigens to activate other cells of the immune system

• Dendritic Cells:

1. Antigen presenting cells

2. Found in cells in contact with external antigens (gastrointestinal mucosa, skin epithelia)

3. Travel to lymph nodes

• Lymphocytes (25-33% of leukocytes)

1. Increase during infections and immune responses

2. Broadly: destroy cancer cells, present antigens to activate other cells of the immune system, secrete antibodies, serve in memory

3. Three types of lymphocytes: Natural killer cells, T cells, B cells

4. All can travel in and out of tissues and the bloodstream

Natural Killer Cells (Lymphocyte)

• Continually patrol the body for pathogens and diseased cells

• Target cells infected with viruses, cells of transplanted organs and tissues, and cancer cells

• NK cells bind, release perforins, create a hole in the membrane of the invading cell

• Also secretes granzymes to destroy target cell’s enzymes and induce apoptosis

Antimicrobial Proteins

• Can inhibit microbial reproduction and provide short-term, non-specific resistance to pathogenic bacteria and viruses (dermicidin, cathelicidin)

• Interferons: Little benefit to cell that secretes them; messenger to alert neighboring cells of danger

• Complement System: 30 or more globulins that contribute to both innate and adaptive immunity. Contributes to pathogen destruction through: inflammation, immune clearance, phagocytosis and cytolysis

Interferons

When certain cells are infected, they secrete interferons

Complement System

Group of >30 globulin proteins that contribute to immunity. Plasma proteins

Innate Immunity: Pattern Recognition Receptors

• Activation of these receptors—triggers intracellular pathways that results in production of cytokines, chemokines and cell-surface molecules

• Molecular security cameras—broad ability to detect

• (cytokines—proteins secreted by cells that interact with specific receptors on other cells and induce a functional response)

• Broadly what do they recognize?

• Bacterial cell wall components (LPS, peptidoglycan), viral RNA/DNA, or fungal carbohydrates.

• Specifically PRRs recognize:

1. Pathogen-Associated Molecular Patterns (PAMPs): Essential conserved microbial components

2. Damage-Associated Molecular Patterns (DAMPs): Markers of tissue damage or death on host cells

Major Classes of Pattern Recognition Receptors

• Toll-like receptors (TLRs): Detect microbial lipids, proteins, nucleic acids (found on cell surfaces & endosomes).

• NOD-like receptors (NLRs): Cytoplasmic sensors for bacterial products and cell stress; some form inflammasomes.

• RIG-I-like receptors (RLRs): Detect viral RNA inside cells, triggering interferon production.

• C-type lectin receptors (CLRs): Bind fungal and bacterial carbohydrates.

• AIM2-like receptors (ALRs): Detect cytosolic DNA

Inflammation

• Local defensive response to tissue injury—trauma or infection

• Purposes:

1. Limit spread of pathogens

2. Remove debris of damaged tissue

3. Initiate tissue repair

• 4 Signs of Inflammation:

1. Redness

2. Swelling

3. Heat

4. Pain

• Mobilization of defenses (Signal cytokine released by damaged tissues) —> Containment and Destruction of Pathogens (Fibrinogen) —> Tissue Cleanup and Repair (Monocytes—macrophages)