Blood and the Immune System II

Innate Immune System

Nonspecific defenses, 1st line of defense (physical and chemical surface barriers), 2nd line of defense (internal cellular and chemical defense - if pathogen penetrates barriers)

Adaptive Immune System

Specific defenses, 3rd line of defense (immune response - if pathogen survives non specific, internal defenses)

Leukopoiesis

A process where uncommitted stem cells in the bone marrow produce progenitor cells for blood cells and platelets. Platelets develop to megakaryocyte stage and are released in circulation. Neutrophils, monocytes, and basophils are progenitor cells found in circulation, while lymphocytes are derived from their own lineage

Basophils and Mast cells

Cells with a lobed nucleus and blue staining. They play a role in inflammatory reactions and allergies, releasing anticoagulant heparin and histamine. Basophils are found in circulation, making up less than 1% of WBC, while mast cells are found in tissues

Neutrophils

Have a segmented nucleus with 2-5 lobes and are the most abundant leukocyte. They function as early first responders to infections and phagocytose bacteria

Neutrophil Extravasation

1. roll along endothelial wall

2. are tethered, captured and activated

3. crawl to exit sites (endothelial cell junctions)

4. exit sites open due to signals between leukocytes and endothelial cellsis the process by which neutrophils leave the bloodstream and migrate to sites of infection or inflammation.

Eosinophils

Have a bilobed nucleus and cytoplasmic granules stain bright red. Make up about 1.3% of WBC and serve as defence against parasites in the GI tract, lungs, urinary, and genital epithelia. They attach to large, antibody-coated parasites and release substances to damage or kill them

Agranulocytes: Monocytes and Macrophages

Phagocytic primary tissue scavengers found in the bloodstream and tissues. They are 2-3 times larger than RBCs and consume 100 bacteria per lifetime, removing debris from old RBCs and dead neutrophils

What were tissue macrophages originally called

Reticuloendothelial system and were not associated with leukocytes

What is the current name for tissue macrophages and their parent monocytes in blood

Mononucelar phagocyte system or MPS.

Monocytes

Make up 3-9% of leukocyte in the blood but only stay there for 8 hours. They enlarge and differentiate into macrophages during their 8 hour commute from blood to tissue

Agranulocytes: Lymphocytes

Only slightly larger than RBCs, make up 25-33% of WBCs, are found in the adult body, which approximately 1 trillion cells. They function in the immune response, including natural killer, T, and B cells

Lymphocytes: Natural Killer Cells

Protect against viral infections and some cancers. They can respond quickly and destroy target cells through cell-cell contract. They can release interferons and cytokines to warn uninfected cells and enhance immune responses mediated by other cell types

Antigen

A molecule, often on the surface of a pathogen, that the immune system recognizes as a specific threat

MHC markers

• proteins expressed on the surface of a cell

• display both self and non-self antigens

• used primarily in the recognition of pathogens in immune responses but also used in self recognition

MHC-I

found on the cell surface of all nucleated cells in the bodies of vertebrates

MHC-II

found mostly on macrophages, B cells and dendritic cells (APCs)

Lymphocytes: T cells

Have receptors for antigens that APCs can present to activate. When a helper T cell (CD4) encounters an APC with a foreign antigen fragment, it secretes cytokines to enhance the immune response. Initial priming occurs in lymph tissues like the spleen, lymph nodes, tonsils and gut

What happens during Step 1: Threat

An invader enters the body

What do macrophages do in Step 2: Detection

They engulf and digest the invader and present its antigen on their surface using a self (MHC) marker

How is a helper T cell activated

A macrophage presents the antigen to the helper T cell and secretes a chemical to activate it

What happens to the helper T cell during Step 3: Alert

It divides and becomes an effector helper T cells

What does the effector helper activate

A. cell-mediated response: activates naive cytotoxic T cells

B. antibody-mediated response: activates naive B cell

What does the naive cytotoxic T cell do in Step 5

Divides into effector cytotoxic T cell and memory cytotoxic T cell

What do effector cytotoxic T (CD8) cells do

Target infected cells, bind to MHC-I, and kill cells using perforin and granzymes

What is the role of memory T cells

Remain in the body for long term surveillance and quicker response upon re-exposure

What do plasma cells (effector B cells) do

Secrete antibodies that neutralize toxins, trigger complement release and attract macrophages

Do B cells directly engage pathogens

No antibodies attack the antigens

What happens with memory B cells

They stay in the body for long term surveillance and rapidly produce plasma cells and more memory cells if re-exposed

What does the naive B cell do in Step 5

Divides into plasma cells (effector B cell) and memory B cells

Clonal Selection Theory

States that B cells, which are genetically identical, inherit the ability to produce specific antibodies. These cells are naive and can only produce one type of antibody. Exposure to their antigen stimulates cell division, resulting in a large population of identical B cell clones

Primary reponse

First exposure to antigen, slower and weaker response, produces mostly IgM antibodies

Secondary Response

Lymphocyte clones and memory cells result in faster and stronger response. Produces IgG antibodies

Antibodies target pathogenic bacteria

Does not destroy them, just marks them as targets for immunological attack. pathogen may be attacked by innate immune cells (macrophages, neutrophils) or by complement (blood protein defense system)

What are the 3 pathways of the Complement Pathway

1. Classical pathway (high level activity triggered by antibody)

2. Alternative pathway (low level, continuous activity)

3. Lectin pathway

Classical and lectin pathways are very similar

What is the end result of the Complement Pathway

1. Massive amplification of response

2. Formation of cell-killing membrane attack complex (MAC)

What complement proteins are involved in 1. Recognition

C1

What complement proteins are involved in 2. Activation

C4, C2, C3 (in this order)

What complement proteins are involved in 3. Attack

C5, C6, C7, C8, C9

Classical pathway

Starts with antibodies and C1 proteins binding to the surface of the pathogen

Lectin pathway

Starts with lectins binding to mannose residues on the surface of the pathogen

The Complement Cascade

1. activation of C1 (classical pathway)

2. C1 catalyzes hydrolysis of C4 into C4a and C4b

3. C4b binds plasma membrane and is active

4. C3 cleaved into C3a and C3b

5. C3b converts C5 into C5a and C5b

6. C3a and C5a stimulate mast cells to release histamine

7. C5, C6, C7, C8 and C9 inserted into bacterial cell membrane to form a membrane attack complex

Membrane Attack Complex (MAC)

Large pore that kills bacterial cell through osmotic influx of water

What are the 4 key signs of inflammation

1. Redness - blood flow carries defensive cells and chemicals to damaged tissue, removing toxins

2. Heat - increases the metabolic rate of cells in the injured area to speed healing

3. Swelling - fluid containing defensive chemicals, blood clotting factors, oxygen, nutrients and defensive cells seeps into injured area

4. Pain - hampers movement, allowing the injured area to heal

Acute inflammation

Bruises and torn tissue

Chronic inflammation

Disease states such as arthritis, obesity etc

Sepsis

Systemic inflammation causes organ dysfunction, potentially fatal. Symptoms include high fever, rapid pulse/respiratory rate, hypotension, hypoxemia, oliguria, acidosis. Treatment involves antibiotics and IV fluids

Endotoxin and sepsis

Typically caused by bacterial lipopolysaccharide, a component of gram-negative bacteria, which triggers innate immunity and releases inflammatory cytokines when large amounts enter circulation

Fever

Infection leads to fever

Autoimmune diseases

A failure of the immune system to recognize and tolerate self-antigens

Reasons why self-tolerance may fail

Exposure to unknown antigens, alteration of tolerated antigens by foreign haptens, production of antibodies directed against other antigens, cross-reaction of antibodies against foreign antigens, presentation of self-antigens to helper T cells, and insufficient activity of regulatory T lymphocytes, leading to autoimmune diseases

Acquired Immune Deficiency Syndrome (AIDS)

Caused by the human immunodeficiency virus HIV (retrovirus), which infects and destroys helper T cells in the gastrointestinal mucosa, leading to decreased immunity and increased susceptibility to infections and cancer

Antiretroviral therapy (ART)

Used to suppress HIV replication, but it is not a cure, as HIV viral DNA integrates in host DNA, and not all individuals with AIDS have access

What is the first component of Allergies

Abnormal response by B cells: hay fever, asthma and most other allergies caused b IgE immediate hypersensitivity

What is the second component of Allergies

Abnormal responses by T cells: delayed hypersensitivity i.e. hours to days because the reaction is mediated by lymphokines instead of antibodies