The Lymphatic System pt.2 : Lect. 19-20

Inflammatory Response

Resident leukocytes: mast cells, dendritic cells and macrophages sound the alarm when tissue is damaged from trauma or infection.

—> initiates the inflammatory response which makes it easier for many elements (leukocytes, proteins, platelets) in the blood to be recruited to the site

Functions:

1. Prevents the spread of damaging agents to nearby tissues

2. Disposal of cell debris and pathogens

3. Sets the stage for repair processes

4. Alerts the Adaptive Immune System

4 major events of an Inflammatory Response:

1. Inflammatory chemicals are released from damaged or stressed tissue cells (+ toll-like PRRs) and resident immune cells (& other immune cells that arrives)

2. Arterioles dilate and capillaries become more permeable in response to inflammatory chemicals causing redness, heat and swelling

3. Phagocyte mobilization. Phagocytes from the blood move to the site of injury/infection

4. Phagocytes arrive at the site of injury and consume pathogens (phagocytosis) and cell debris

Chemical Signals released (5):

1. Histamine (from mast cells)

2. Cytokines (from tissue cells and macrophages)

3. Bradykinin (from damaged Blood vessels)

4. Prostaglandins (from damaged tissue cells)

5. Compliment proteins

Histamine

Released by resident mast cells & basophils in response to mechanical injury, presence of certain microbes & chemicals released by neutrophils

Effects:

1. Vasodilation of local arterioles, increased permeability of local capillaries (fluid moves into the tissues)

2. Also causes bronchial constriction (smooth muscle) & mucus production —> becomes evident during allergic reactions

Cytokines

Small proteins that act as chemical messengers, that calls for the innate and adaptive immune systems

• Resident macrophages or dendritic cells present in skin & mucous membranes tissues are usually the first immune cells to encounter microbes when these barriers have been broken

• —> Recognize PAMPs on microbes = initiates phagocytosis & release of cytokines to promote the inflam. resp. (binding of PAMP to a toll-like PRR initiates a transduction cascade —> cytokines)

Bradykinin

A plasma protein released when there is damage to the endothelial lining of blood vessels

Effects:

• Vasodilation

• Increased capillary permeability

• Induces chemotaxis by leukocytes

• Stimulates nociceptors (pain receptors) = causing individual to protect an injured area

*Blood vessel injury triggers: inflam. resp. & blood-clotting cascade

Prostaglandins

Formed and released by damaged tissue cells

Effects:

• Vasodilation

• Increased capillary permeability

• Induces chemotaxis by leukocytes

• Stimulates nociceptors (pain receptors) = causes individual to protect an injured area

Increased vascular permeability leads to edema

The surge of protein-rich fluids into the tissue space serves several functions:

1. Dilutes harmful substances that may be present

2. Brings in large amounts of oxygen and nutrients needed for repair

3. Allows the entry of clotting proteins which form a gel-like fibrin mesh in the tissue space. This effectively isolates the injured area and prevents the spread of bacteria and harmful agents into surrounding tissues. It also forms a scaffolding for permanent repair

Increased Vascular Permeability Promotes Immune Function

When blood flow is increased d/t vasodilation & cap. permeability, important immune proteins called compliment proteins and immune cells like neutrophils & monocytes can exit the blood and enter the affected tissue

Phagocyte Mobilization (4 steps)

Chemical signals released:

• Attract neutrophils and then monocytes to the site

• Activate bone marrow to produce the appropriate innate immune cells: neutro, mono, baso, eosino

Mobilization of phagocytes occurs in 4 steps:

1. Leukocytosis – more leukocytes enter blood from bone marrow

2. Margination - accumulation and adhesion of leukocytes to capillary walls

3. Diapedesis – the migration of leukocytes through vessel walls

4. Chemotaxis – leukocytes follow chemical trail to site of injury/infection

Timeline of inflamm. response

• Immediate — resident mast cells, dendritic cells and/or macrophages

• 6-24 hours later — neutrophil numbers will increase in blood, many will enter the damaged tissue and begin phagocytosis. Neutrophils lifespan is short

• Within 24-48 hours — macrophages derived from circulating monocytes predominate at the injury

Abscess

A walled-off localized collection of pus

• Emigration of neutrophils, along with tissue destruction may lead to abscesses

• Commonly produced by pyogenic (pus-producing) bacteria (e.g. Staphylococci)

• Treatment: lancing the abscess (cutting in and draining it) & antibiotics

Cellulitis

When pus forming bacteria spread into surrounding tissues

• Pus and the microorganism that produced it cause the reaction in the surrounding tissues

• These spreading infections are serious life-threatening events. Must be treated by vigorous:

1. elimination of the infectious agent (usually with antibiotics)

2. incision and drainage of the lesion

Interferons

Antimicrobial proteins produced to block further infection of body cells by viruses

• Viruses inject their DNA (or RNA) into a body cell where it takes over the cell’s machinery to make more copies of itself

• A virus infected cell will die

• However, before that happens the presence of viral DNA switches on interferon genes in the cell’s nucleus

• They are transcribed and translated into interferon proteins which are released by that cell

• Released interferon proteins bind to receptors on uninfected cells = stimulates them to produce antiviral proteins

• If a virus tries to invade, the antiviral proteins will block it from reproducing

• Therefore, interferons give resistance to our healthy cells against viral attack

*They cannot help a cell that is already infected with virus

Complement System

A group of at least 20 plasma proteins that normally circulate in the blood in an inactive state. They provide a major mechanism for destroying foreign substances in the body

Activated helps by:

1. Acting as inflammatory chemicals

2. Promoting phagocytosis by:

• Acting as chemotactic factors to attract phagocytes

• Acting as opsonins

3. Lysing and killing certain bacteria

4. Enhancing the effectiveness of both innate and adaptive immune responses

3 Pathways leading to Complement Activation:

1. Classical complement cascade begins with the formation of an antibody-antigen complex (antibody bound to an epitope on a pathogen). The 1st compliment protein binds to the antibody-antigen complex which triggers the compliment cascade. (Adaptive Immunity)

2. Lectin pathway: Lectin Proteins (a type of PRR, pattern recognition receptor) attach to a PAMP on surface of pathogen. 1st compliment protein will then bind and start the compliment cascade. (Innate Immunity)

3. The Alternative complement cascade begins with one of the complement proteins binding directly on the surface of a microbe. (Innate Immunity)

Classical Complement Pathway

Primarily activated by either an IgG or IgM antibody binding to an epitope (specific part - tag) on a pathogen

IgG and IgM are classes of antibody molecules

• Antigen binding sites on antibodies have shapes that are complementary to specific epitopes - portions of proteins found on the surface of microbes

• The stem region of the antibody can activate the Classical Complement Pathway by providing a site for the 1st compliment protein in the pathway to bind to

• When the first of the Complement proteins is triggered by an antibody interlocked with a pathogen’s epitope it sets in motion a cascade of reactions

• Each compliment component is activated in turn, acting upon the next in a precise sequence of carefully regulated steps known as the “Complement cascade”

These 2 pathways do not involve antibodies, they are both part of the innate immune system

Lectin Pathway: Involves a class of pattern recognition receptors (PRRs) called lectins which attach to carbohydrate PAMPs on the surface of microbes. This initiates the complement cascade.

Alternative Pathway: The 1st protein in the complement cascade binds to the surface of the microbe directly

All pathways lead to the splitting…

of a key protein C3

• C3 splits into C3a and C3b

• C3a enhances inflammation

• C3b acts in 2 ways: Opsonization & MAC

C3b Activates MAC

C3b triggers the complement cascade (made from a group of proteins that assemble together) which results in the formation of a protein complex known as the Membrane Attack Complex (MAC)

MAC will self-assemble in the plasma membrane of a target cell (e.g. a bacterium) and form a pore. These pores allow the passage of water into the cell and eventually cell lysis

Besides lysis, what else does the complement system do?

1. Enhance phagocytosis (through opsonization)

2. Act as chemotactic factors (attract phagocytes to the site)

3. Stimulate mast cells and basophils to release histamine which amplifies the inflammatory response