Anatomy Immune system

Immune System

Protects us from infectious agents and harmful substances

• provide immunity

Two types of immunity

Innate and Adaptive

Innate Immunity

Skin and mucosal + Nonspecific internal defenses ([7]Cells, Chemicals, and Physiologic responses)

• present at the time of birth (do not need prior exposure)

Adaptive immunity

T-lymphocytes (cell-mediated immunity) and B-lymphocytes (humoral immunity + plasma cells (synthesize and release antibodies))

What is the purpose of innate immunity?

Responds nonspecfically to a range of harmful substances

What is the first line of defense for Innate Immunity?

skin and mucosal membrane

What is the second line of defense for Innate Immunity?

internal processes

• neutrophils, macrophages, dendritic cells, eosinophils, basophils, mast cells, and non-killer cells

Phagocytic cells

Neutrophil, macrophage, and dendritic cells

• engulf infectious agents

• Phagosome: membrane lined sac housing bacteria

• Lysosome: membrane bound intracellular vesicle containing lysosomal enzymes → breaking down and destroying the bacterial after destruction occurs

• Phagolysosomes: contains both the bacteria and lysosomal enzymes

Proinflammatory chemical-secreting cells

Basophils and mast cells

• promotes inflammation

• Basophils release histamine (vasodilation + increases capillary permeability), heparin (enhances blood flow + anticoagulant), and eicosanoids (increases inflammation)

Apoptosis-initiating cells

NK cells (releases perforin and granzyme)

• kills unwanted or unhealthy cells like virally infected cells or tumor cells

• The virus needs to invade the host cell in order to replicate/must take over the host cell because it cannot replicate on its own

  • It does this by inserting its own DNA into the DNA of the cell and takes over the coding of the host cells or replicate

• Perforin- causes perforation or pore on the cellular membrane

• This allows the granzyme to enter → causes apoptosis (breaks down intracellular components

Parasite-destroying cells

Eosinophils

• releases cytotoxic chemicals (destroys the outer protective covering of the parasite which is known as the cuticle)

  • Once the cuticle is destroyed, the parasite’s ability to control its internal environment has been ceased

Interferon (IFN)

Nonspecific and viral protein

helps prevent viral neighboring cells that haven’t quiet yet been infected

• releases IFN alpha + beta + gamma

  • Alpha and beta get released from the viral infected cells and travels to normal cells

• NK cell causes apoptosis within virally infected cells

• IN gamma from the NK cell promotes macrophages and phagocytizes the infected cell

Complement system

group of over 30 plasma proteins that work along with antibodies

• synthesized by liver and releases in inactive form (enzyme cascade activates them)

What are the two complement activation pathways?

Classical pathway and Alternative pathway

Classical pathway

Antibody attaches to foreign substance and then complement binds to antibody (this is what activates other complement proteins)

Alternative pathway

Complement binds to polysaccharides of bacterial or fungal cell wall (takes out the middleman > antigen complex is not needed for activation)

Opsonization

complement protein (opsonin = CODED) binds to pathogen and enhances likelihood of phagocytosis of pathogenic cell (makes bacteria more readily recognizable = making it easier to be phagocytosed)

Inflammation

enhanced by complement, activated mast cells and basophils, and attracts neutrophils and macrophages

Cytolysis

complement triggers destruction of target cells and form membrane attack complex (MAC) that creates a channel in target cell’s membrane (group of complement fragments will band together to join complexes = MAC)

• attach to bacteria + able to break through cell membrane + fluid rushes in and pressure breaks down the cell

Elimination of immune complexes

complement links antigen-antibody complexes to erythrocytes and cells move to liver and spleen where complexes are stripped off

• Activated complement protein attach to the antibody on one side and receptors on the erythrocytes — macrophages will phagocytose the immune complex with the bacteria and erythrocyte will continue —- RBC transport mechanism for the elimination of immune complexes and bacteria

Process of inflammation

• tissue damage

1. Release of inflammatory and chemotactic factors (mast cells + basophil = responds to something that is not normal/wanted)

2. Vascular changes: vasodilation of arterioles (increased blood flow), increase in capillary permeability (more flow of immune cells), and display of CAMS (proteins that are present within the lining of endothelial cells)

3. Recruitment of immune cells: margination (“pull over”, leukocytes and platelets can’t stay in/move out of the blood flow), diapedesis (white blood cells can pass through capillary walls and into interstitial tissue), and chemotaxis (neutrophils migrate from capillary to site of tissue damage due to the chemical gradient)

4. Delivery of plasma proteins (allows excess fluid to escape)

• Lymphatic capillary “cleans up the excess” → more fluid within the tissues and will be picked up by the lymphatic capillary as well

Signs of inflammation

Redness- increased blood flow

Swelling- increases fluid loss from capillaries

Heat- increased blood flow and metabolic activity

Pain- stimulation of pain receptors

Loss of function

Fever (pyrexia)

abnormal body temperature elevation

• results from the release of pyrogens from immune cells or infectious agents

100.4ºF — 38ºC

• Prostaglandins: causes thermoregulation set point to increase → generates heat in order to bring body to this new set point

Ex: fever — shiver — peripheral vessels constrict — additional blanket

Events of a fever (mainly where it takes place and what gets released)

1. Pyrogens circulate through blood and target hypothalamus

2. Hypothalamus releases prostaglandin E₂

3. Hypothalamus raises temperature set point leading to fever

• when body temperature is elevated, the virus will not be able to be as detrimental

Benefits of a fever

• Inhibits reproduction of bacteria and viruses

• Promotes interferon activity

• Increases activity of adaptive immunity

• Accelerates tissue repair

• Increases CAMs on endothelium of capillaries in lymph nodes

• Adaptive immunity involves lymphocytes to attack foreign agents; due to the increased metabolic activity, proliferation of lymphocytes will occur

• Accelerates tissue repair — produce more adhesion molecules on surface = more immune cells marginating and exiting capillaries → more immune cells will be in circulation of the lymph filtering out unwanted substances

What is the purpose of adaptive immunity?

Involves specific lymphocyte responses to an antigen

• contact with antigen causes lymphocyte proliferation

Plasma cells release antibodies so B-lymphocyte forms plasma cells when stimulated

Which response time is quicker; innate or adaptive immunity?

Innate Immunity

What are the two branched os adaptive immunity?

Cell-mediated immunity (T-lymphocytes; effective against antigen within cells and requires antigen-presenting cell) and Humoral immunity (B-lymphocytes, plasma cells, and antibodies; effective against antigen outside cells and does NOT require antigen-presenting cell)

Antigen

substance that binds a T-lymphocyte or antibody

usually a protein or large polysaccharide

Example of antigen:

• capsid- protein protective layer of viruses

• Bacterial toxins- as they replicate, they release toxins which are recognizable

Antigenic determinant (a.k.a epitope)

Specific site on antigen recognized by immune system

• each as different shape and multiple determinants

Specific region on an antigen that is bound to by an antibody

Immunogen

Not only something that is recognizable, but also provokes an immune response

antigen that induces an immune response

Immunogenicity

ability to trigger response (how rapid and vigorous is the response)

• increases with antigen’s degree of foreignness, size, complexity, or quantity

Haptens

small foreign molecules that induce immune response when attached to a carrier molecule in host (hypersensitivity reactions)

• an antigen, but is not an immunogenicity bc it is too small to create an immune response

• Can be recognized and bound to

What type of contact do B-lymphocytes make with antigens?

Direct contact

What type of contact do T-lymphocytes make with antigens?

Indirect → antigen is processed and presented by another cell type

T-lymphocyte subtype

Cytotoxic T-lymphocytes

• release chemicals that destroy other cells

• CD8 allows for proper alignment of antigen presenting cell to the t-cell receptor

Helper T-lymphocytes

• assist in cell-mediated, humoral, and innate immunity

• Contain T-cell receptors embedded within their membranes

• Each one of these receptors is identical and has an attachment point for specific antigens

• CD4 protein aids in allowing proper alignment of the antigen presenting cell to the TCR

Antigen presentation

cells display antigen on plasma membrane so T-cells can recognize it

• To recognize cells are present…all nucleated cells of the body and antigen-presenting cells (APC’s)

Attach antigen to MHC

MHC- major histocompatibility complex

Bound together and always embedded in the membrane

These antigens that are going to be presented must be attached to the MHC complex in order to be recognized and bounded

T-Lymphocytes with MHC molecules

Helper → CD4 → MHC Class II

Cytotoxic → CD8 → MHC Class I

Class I and II- Immune cells, dendritic cells, macrophages, and B-lymphocytes

Only class I- epithelial cell

Three main events in life of lymphocytes

1. Formation and maturation of lymphocytes

• Primary lymphatic structures (red bone marrow + thymus)

• Recognize one specific foreign antigen

2. Activation of lymphocytes

• Secondary lymphatic structures is the location where lymphocytes are exposed to antigens/site of lymphocyte activation

3. Effector response: action of lymphocytes to eliminate antigen

• T-lymphocytes migrate to site of infection

• B-lymphocytes stay in secondary structures (plasma cells)

• Lymphocytes that are replicated will resemble the OG one and contains the same receptors to attack the specific antigen

Formation of Lymphocytes

B-cells become fully functional/mature in bone marrow

• Red bone marrow = responsible for production

T-lymphocytes are released from the bone marrow as pre-t-lymphocytes and travel to the thymus to complete maturation (gain their specific receptors)

• Both of these cells after maturing are naive immunocompetent cells and have not been exposed to their specific antigens

Activation of Lymphocytes and Effector Response

Secondary lymphatic structures house B- & T-lymphocytes

The activated lymphocytes will travel to the site of infection

• Helper T-lymphocytes release cytokines to enhance immune response

• Cytotoxic T-lymphocytes destroy infected cells via apoptosis

• B-lymphocytes form plasma cells which produce antibodies

Antigen challenge

First encounter between antigen and lymphocytes (Usually occurs in secondary lymphatic structures)

• due to broad distribution of secondary lymphatic structures, it is inevitable that our bodies will have antigen challenge

Clonal selection

Forming clones in response to an antigen

• all formed cells have same TCR or BCR that matches specific antigen

• A given lymphocyte is being specific end from the entire population bc of its superficial receptor for a given antigen → that type of lymphocyte is going to replicate

Activation T-lymphocytes

1. First signal: CD4 binds with MHC class II molecule APC; TCR interacts with antigen within MHC class II molecule

Physical attachment of the helper t-cell to the antigen coreceptor binds to the MHC on the antigen → that union provides the proper alignment so now the t-cell can bind to the antigen

2. Second signal: Other receptors interact and the helper T-lymphocyte releases IL-2, which binds with the helper T-lymphocyte

3. Activated helper T-lymphocyte proliferates and differentiates to form a clone of activated and memory helper T-lymphocytes

Binding of the t-cell to the antigen causes the helper to-cell to release a specific type of cytokines known as interleukin 2

IL-2 binds to the interleukin binding receptor on the surface of the helper t-cell → causes the proliferation of helper t-cells to enhance immune response memory helper t-cells will respond quickly to the pathogen that they have been previously exposed to beforee the pathogen can replicate and affect the body

Activation of Cytotoxic T-lymphocyte

1. First signal: CD8 binds with MHC class I molecule of infected cell; TCR interacts with antigen within MHC class I molecule

2. Second signal: IL-2 released from activated helper T-lymphocyte activates the cytotoxic T-lymphocyte

IL-2 is being released from helper t-cells and will activate the cytotoxic cell as well as enhancing the immune response

Activation of B-lymphocyte

1. First signal: Free antigen binds to BCR; B-lymphocyte engulfs and presents antigen to activated helper T-lymphocyte

B-lymphocyte have the ability to bind directly to the antigen and does not need the antigen presenting on the surface

1. Second signal: IL-4 released from activated helper T-lymphocyte stimulates B-lymphocyte

IL-4 is the specific type of cytokines known released for B-lymphocytes. B-lymphocytes will proliferate to form plasma cells that have these antibodies attached to them.

Some B-lymphocytes will not for plasma cells → they will remain as memory B-lymphocytes instead.

Effector response

Mechanism used by lymphocytes to help eliminate antigen

Each lymphocyte has its own type

Effector response for helper T-lymphocyte

Release IL-2, IL-4, and other cytokines

After exposure To antigen → activated and memory helper T-cells migrate to infection site

Help activate B-lymphocyte

Stimulate activity of innate immune system cells

Regulate and enhance cells of adaptive and innate immunity (does not destroy infected cells themselves)

Effector response for cytotoxic T-lymphocyte

Destroy unhealthy cels by apoptosis

Attachment of the cytotoxic t-lymphocyte to the antigen causes the release of perforin and granzymes → same chemicals released by NK cells

Perforin attaches to the membrane of the abnormal cell and perforates the membrane allowing granzymes to enter the cell

Granzymes can break down a nucleus, destroy the function of organelles, etc., leading to apoptosis of the abnormal cell

Effector response for plasma cells (differentiated B-lymphocyte)

Produce antibodies

Most activated B-lymphocytes become plasma cells

Plasma cells release antibodies

Antibodies circulate through lymph and blood until encountering antigen

Antibody titer

Circulating blood concentration of antibody against a specific antigen

Antibodies

Immunoglobulin proteins produced against a particular antigen

• Gamma globulins = antibodies

• Not directly causing the removal of the antigen but they “tag” pathogens for destruction by immune cells

• No antigen presenting cell on the surface is necessary for the binding of antibodies

Antibody structure

Light chain- shorter and lower MW (lower part of floating arm)

Light and heavy chain are bound together by disulfide bond

Hinge region- the arms of the antibodies are able to adjust their angle in order to properly bind to the specific antigen

Functional regions- variable and constant region

Constant region- every single antibody within a single class will have identical constant region

Variable region- every single antibody will have a difference variable region; give antibodies their specificity; where the antigen-binding site is located

Binding of antigen-binding site of an antibody with antigen causes

Neutralization, agglutination, precipitation

• they are grouped together because it is antigen-binding site that is involved

Neutralization

Antibody covers biologically active portion of microbe or toxin

• binding of the antibodies covers up the biologically active parts of the cell, which causes the blockage of pathogens to attach the cell and take it over

Agglutination

antibody cross-links cells (CLUMPING)

• allows phagocytosis to be done more efficiently → multiple bacteria cells are clumped together

Precipitation

Antibody cross-links circulating particles forming an insoluble antigen-antibody complex

• can’t be invaded by bacteria

Exposed Fc portion following antigen binding by antibody promotes

Complement fixation, opsonization, activation of NK cells

• grouped together because the action is taking place at the Fc region of the antibody

Complement fixation

Fc region of antibody binds complement proteins; complement is activated

• Fc region is able to bind to complement proteins; triggers cascade effect

Opsonization

Fc region of antibody binds to receptors of phagocytic cells, triggering phagocytosis

• means it is covered in something

• Allows phagocytosis to occur more efficiently; there are Fc receptors found on phagocytes and receptors which bind to the Fc region of antibodies, allowing phagocytosis

Activation of NK cells

Fc region of antibody binds to of an NK cell, triggering release of cytotoxic release of cytotoxic chemicals

• these NK cells release perforin and granzymes to break down affected cells and cause apoptosis to occur

Where are IgG Imunoglobulins found?

Found in body fluids including blood, lymph, cerebrospinal fluid, serous fluid, peritoneal fluid, breast milk

• able to participate in all 6 effector responses

What is the action of IgG?

Neutralization, agglutination, precipitation, complement activation, opsonization, NK activation

Percent of IgG

75-85%

IgM

Has 10 binding sites which makes it best at agglutination

IgE

In response to parasitism chemotactically draws eosinophils to the site of the parasite; eosinophils releases the contents of its granules and breaks down the functioning parasite

• in response to allergies, IgE antibodies attach to the antigen via its binding site; the Fc binds to a Fc receptor on a mast cell or basophil cause it to release the contents of its granules → this release causes many inflammatory responses such as itchy eyes, bronchoconstriction, etc.

IgA

areas exposed to environment; best at neutralization

IgE

Allergy & parasitism; degranulation of basophils & mast cells; chemotactic for eosinophils

Effector Response (Cell-mediated immunity)

Activated helper T-lymphocyte releases cytokines to stimulate activity of B=lymphocytes, and regulates cells of innate immunity.

Activated cytotoxic T-lymphocytes release cytotoxic molecules (perforin and granzymes) causing apoptosis of foreign or abnormal cells

Effector Response (Humoral immunity)

Fab region of antibody binds to antigen to cause several consequences including neutralization of microbial cells and particles; agglutination of cells and precipitation of particles

Fc region of antibody serves as point of interaction with several structures including complement to cause complement activation, binding of phagocytic cells to cause phagocytosis of an unwanted substance or cell and binding of NK cells to induce apoptosis of an unwanted cell

Immunologic Memory: Memory

Memory results from formation of a long-lived army of lymphocytes upon immune activation

Immunologic Memory: Activation

Activation leads to formation of many memory cells against specific antigen

• initial exposure of an antibody to its specific antigen which leads to the cloning of many identical cells; some are utilized to fight the antigen at the time of exposure while others are utilized as memory cells to decrease the effect that this antigen has if it enters the body at a later date

Immunologic Memory: Adaptive immunity

Adaptive immunity activation requires contact between lymphocyte and antigen

• lag time between first exposure of the host and direct contact with the lymphocyte (leg time is quicker [less time for antibodies to show up after exposure] ad the response is of greater magnitude infection is removed before a person is even able to show symptoms

Secondary response

Pathogen typically eliminated before disease symptoms develop

Vaccines provoke the production of memory cells

Antibody titer

A measure of immunologic memory/antibody concentration

Primary Response

Secondary Response

Active Immunity

Production of memory cells due to contact with antigen

Active immunity: naturally acquired

Direct exposure to antigen

Active immunity: Artificially acquired

Antigen exposure from vaccine

Passive immunity

No production of memory cells; antibodies from another person or animal

Passive immunity: naturally acquired

Transfer is mother to child across the placenta or in breast milk

Passive immunity: artificially acquired

Transfer of serum containing antibody from another person or animal