chapter 24: the immune system new aim: how does the body defend itself against mo’s? nonspecific...

Chapter 24: The Immune SystemNEW AIM: How does the body defend itself against MO’s?

Nonspecific (innate)

vs.

Specific (adaptive/acquired) Immunity


1. skin

I. Nonspecific (innate) vs. Specific (adaptive) Immunity

A. Nonspecific immunityi. 1st line of defenseii. Does not distinguish one pathogen from another

- dead, stratified epithelium blocks MO’s- acids secreted from skin glands- Lysozyme

* Enzyme that breaks down bacterial cell wall* Found in sweat, saliva, tears

iii. Components


1. skin

I. Nonspecific (innate) vs. Specific (adaptive) Immunity


iii. Components

- desquamation of skin* Your skin is stratified epithelium (many layers). Only the bottom layers are alive and doing mitosis. The top (outer) layers are constantly falling off along with anything attached to it like bacteria or viruses.


2. Beating cilia/mucus of respiratory system

I. Nonspecific vs. Specific Immunity


3. Stomach acid4. Hairs of nostrils

iii. Components


5. Nonspecific defense cells



iii. Components

- cells that confront microbes that get past skin, digestive and resp. surfaces

a. Monocytes (become macrophages = big eaters) and neutrophils•Collectively called phagocytes (cyte = cell; phago = phagocytosis) – cells that phagocytose

b. Natural killer cells (do not confuse with killer T-cells)* Attack viral infected body cells


6. Proteins


A. Nonspecific immunity

iii. Components

- interferons

Fig. 24.1

The infected cell is done for and will become a viral producing factory. However, it will secrete a protein called interferon, which will warn neighboring cells that a virus is in town.


6. Proteins



iii. Components

- complement proteins

Fig. 24.11

Complement proteins are always in your blood in an inactive form. They are activated by antibodies bound to a foreign cell (cancer cell, bacterium, etc...). When activated, they make a hole in the membrane causing the cell to lyse – nutrients, organelles, etc... diffuse out.


7. Inflammatory response (local)



iii. Components

- triggered by ANY tissue damage

Fig. 24.2





iii. Components

1. Rubor (redness) - due to vasodilation2. Edema (swelling) – enhanced leakiness of blood vessesl 3. calor (warmth) – both due to enhances leakiness of blood vessels

Fig. 24.2

Results in:

histamine





iii. Components

- triggered by ANY tissue damage- Rubor, edema, calor

- Pus

- Coagulation cascade seals off area so bacteria can’t get into the blood…

The dead warriors (white blood cells and bacteria) after the battle…

A pimple is a bacterial infection of a skin pore, pus is what is left after the battle.


8. Inflammatory response (systemic – entire system)



iii. Components

a. MO’s in blood and/orb. toxins from bacteria in blood (recall exo- and endotoxins – ch27)

c. Body’s Response - increase WBC count

- increase body temp. = fever (this is a normal response)

- triggered by toxins or chemicals released by WBC’s

- Higher temps stimulates phagocytes, gives your WBC’s and advantage while at the same time inhibits bacterial growth


8. Inflammatory response (systemic – entire system)



iii. Components

d. Septic shock (when the systemic response goes bad)

Septic shock is caused by cytokines (cell signaling molecules secreted by one cell to talk to another – like hormones, but not secreted into blood) and by the toxins produced by some bacteria.

These substances cause the blood vessels to widen (vasodilate), which results in a drop in blood pressure.

Consequently, blood flow to vital organs—particularly the kidneys and brain—is reduced. This reduction in blood flow occurs despite the body's attempts to compensate by increasing both the heart rate and the volume of blood pumped.

Eventually, the toxins and the increased work of pumping weaken the heart, resulting in a decreased output of blood and even poorer blood flow to vital organs. The walls of the blood vessels may leak, allowing fluid to escape from the bloodstream into tissues and causing swelling. Leakage and swelling can develop in the lungs, causing difficulty breathing (respiratory distress).


9. Lymphatic system


A. Nonspecific immunityiii. Components

a. Involved in both nonspecific and specific immunityb. Lymph vessels, lymph nodes, tonsils and adenoids, appendix, spleen, bone marrow, thymus

c. Lymph - fluid carried by vessels- similar to IF, less O2 and nutrients


9. Lymphatic system



iii. Components

d. functionsi. return IF to circ. system

- vessels resemble veins- valves, skeletal muscles propel lymph

- vessels are dead-ended

ii. fight infection- in lymph nodes and other lymph organs- lymph nodes

- packed with macrophages and lymphocytes- lymphocytes involved in specific immunity


9. Lymphatic system


Fig. 24.3

9. Lymphatic system


9. Lymphatic system



iii. Components

Fig. 24.3


9. Lymphatic system



iii. Components

Fig. 24.3

-Spleen- destruction of old RBC’s

- rich in B and T cells for fighting infection- “large lymph node” for blood- filters pathogens out of blood


9. Lymphatic system



iii. Components

Fig. 24.3

- Appendix

- Thought to be vestigial

- Possibly a shrunken cecum since we no longer rely on hard to digest plant material

- New studies suggest it harbors and protects bacteria helpful to the colon.

- Contain WBC’s and may be important in fighting infection

- If an infection occurs in the colon, the bacteria living there will be destroyed. Those in the appendix can repopulate the colon.


9. Lymphatic system



iii. Components

Fig. 24.3

- Appendcitis

- Infection of the appendix- Caused by an obstruction of the opening to the appendix

- Fills with mucus and swells

- Blood flow disrupted, cells begin to die (necrosis = dying cells), walls begin to breakdown and if it breaks, bacteria will enter your body cavity.

Infected appendixAppendectomy – removal of the appendix


9. Lymphatic system



iii. Components

Fig. 24.3

- Tonsils and Adenoids

- Trap bacteria/viruses as they enter through nose and mouth



B. Specific immunity (The Immune System)

i. More effective than nonspecificii. Used when nonspec. fails or in combination

iii. antigen

a. Foreign molecule that elicits immune response

b. Surface molecule of virus, bacteria, mold spores, cancer cells, pollen, transplant, etc…

Why must it be a surface molecule?

The same reason that when a person is wanted by the FBI they show a picture of their face and not of their heart. The surface of the cells is the part that other cells and antibodies will “see”.




iv. Lymphocytes (B and T cells)a. Spend time in lymph tissueb. Produce the specific immune responsec. Originate in bone marrow

- 2 fates1. Mature in bone marrow = B-cell

2. Leave bone marrow and circulate to thymus, mature there and become a T-cell




iv. Lymphocytes (B and T cells)

Fig. 24.5

1. B cells elicit humoral immunity

2. T cells elicit Cell-Mediated immunity

Humoral implies humors or “fluids”. This response will involve antibodies (proteins), which will be dissolved in the fluids of the body – secretions like saliva and breast milk, the blood plasma, interstitial fluid, lymph fluid, etc… - to recognize foreign substances (antigens)

In this case cells will be directly involved in recognizing foreign substances (antigens)

Chapter 24: The Immune SystemAIM: How does the body defend itself against MO’s?



v. Humoral immunity

Fig. 24.6

a. B-cells make and secrete antibodies (a protein) into blood

b. We have millions of B-cells and each one produces a different antibody, which will bind to a different antigen (one B-cell, one antigen).

Antibody structure (quarternary structure)

(Epitope)




v. Humoral immunity

Fig. 24.6


The antigenic determinant (epitope) is the specific part of the antigen that the antibody binds to via hydrogen/ionic/hydrophobic interactions.

b. We have million of B-cells and each one produces a different antibody, which will bind to a different antigen (one B-cell, one antigen).




v. Humoral immunity

Fig. 24.6

How can there be millions of B-cells each expressing a unique antibody if we only have 30,000 or so genes?? Wouldn’t we need 1,000,000’s of genes, one for each antibody?




v. Humoral immunity

Fig. 24.6


There are many genes coding for each segment (V, D or J) of the variable region. The genes will undergo recombination in a given B-cell and a unique combination of VDJ will result in both chains (light chain doesn’t have a D segment).

1. V(D)J recombination




v. Humoral immunity

Fig. 24.6


When a B-cell is activated it begins to rapidly divide.

2. Somatic hypermutation

The VDJ regions have an abnormally high rate of mutation (1 nucleotide change per variable gene [VDL] per division) during S-phase resulting in a slight variations in all daughter cells – genetic diversity followed by natural selection!!




There are five major types of antibodies (IgG, IgM, IgA, IgD and IgE – or G-MADE), each has a slightly different function in the body. For example: IgG - found in the blood and interstitial fluid and can cross the placenta giving immunity to the fetus

IgA - found in external secretions like saliva and breast milk.

Another name for an antibody is an immunoglobulin or Ig for short.




The five antibody (immunoglobulin) types of mammals…




v. Humoral immunity

Fig. 24.5


c. B-cells display the antibody they make (~100,000 of them) on their surface as an antigen receptor and wait in the lymph system and spleen for an antigen that will bind the antibody it makes…

b. We have million of B-cells and each one produces a different antibody, which will bind to a different antigen (one B-cell, one antigen).



B. Specific immunity (The Immune System) - OVERVIEW

Memory T-cells are also made form T-cells activated by Helper T-cells. For a future encounter with the same antigen carrying pathogen.




v. Humoral immunityd. Clonal selection

- The single activated B-cell will undergo mitosis resulting in the formation of plasma cells (antibody secreting cells) and memory B cells…

- Why are plasma cells shown with a lot of ER?

Fig. 24.9 Now what do these antibodies do?

- If the antigen does come along one day, it will bind to the B-cell’s antibody and activate the B-cell.

(Activation actually requires a second signal by a helper T-cell that we will discuss shortly)

They are secreting incredible amounts of protein (antibodies) and the ER/Golgi are required to do this – recall endomembrane system.




v. Humoral immunity

Antibodies bind to antigens (surface molecules), flagging them for phagocytosis by phagocytes or activating complement.

Fig. 24.11http://catalog.nucleusinc.com/generateexhibit.php?ID=15529&ExhibitKeywordsRaw=&TL=1&A=2

What about those memory B-cells?

Know all the terms like neutralization, agglutination, precipitation…

http://catalog.nucleusinc.com/generateexhibit.php?ID=15529&ExhibitKeywordsRaw=&TL=1&A=2




v. Humoral immunity

Fig. 24.9

1. Memory B-cells are soldiers that will wait in reserve for the return of the same antigen.

2.These cells with memory T-cells are what gives you immunity.

STORY: You are infected with the virus Varicella zoster, which causes chicken pox. A B-cell will recognize the virus somewhere in your spleen or lymph nodes and be activated with the help of a helper-T cell (discussed shortly). The B-cell will undergo mitosis forming plasma and memory B-cells, which all make the same antibody (it is mitosis so they are all ALMOST genetically identical clones). Plasma cells will make and secrete antibodies to fight the current virus, while many, many memory B-cells will sit in lymph nodes and the spleen for the rest of your life possibly, with the same antibody on their surface awaiting the return of the virus/antigen. Initially there was only a handful of B-cells activated, the second response will activate 10,000’s!!




v. Humoral immunity

Fig. 24.9

Why not make Memory B-cells for all 100+ million antibodies?

A. You do not have enough room in your lymph and spleen and B. You would spend a huge amount of ATP to do this. You would need to eat incredible amounts of food to maintain such a system.



B. Specific immunity (The Immune System)vi. Cell-mediated immunity

a. B-cells fight the battle outside our cells, but what about when the pathogen has gotten in like a virus that has turned your cell into a virus producing factory?

- T-cells fight this one

b. We have million of T-cells in our lymph nodes and spleen and each one produces a slightly different antigen receptor called a T-cell receptor (this is the “antibody” of the T-cell although it well never secrete it).




Fig. 24.13

c. STORY

1. It all starts when some kind microorganism (microbe) gets engulfed by a macrophage (a mature monocyte) of the innate immune system.

The macrophage needs to warn the specific immune system as to what is going on!!

The phagocytosed microbe will be in a vesicle which will fuse with a lysosome thereby partially digesting the microbe.

2 and 3. The pieces of the microbe will then bind to MHC-II receptors of the macrophage and be displayed on the surface – the macrophage is now called an Antigen Presenting Cell (APC).

(MHC-II)




Fig. 24.13

c. STORY

4. You have millions of Helper T-cells, each one making a slightly different T-cell receptor (analogous to B-cells each making a different antibody receptor).

A helper T-Cell (the same ones that HIV infects), with a matching T-cell receptor to the displayed antigen will bind to the antigen/MHC-II receptor of the APC.

(MHC-II)

(MHC-II)




Fig. 24.13

c. STORY

5. The APC will secrete interleukin-1, a cytokine (a protein that acts as a signal to instruct cells what to do), which will bind to interleukin receptors on the Helper T-Cell.

Interleukin-1 (IL-1) Interleukin-2 (IL-2)

Interleukin:

Inter – between; leukos - whiteA signal between white blood cells. 5

The combination of IL-1 and the MHC-II complex activates the Helper T-Cell, and the specific immune system has been notified!

Time to find out what the Helper T-Cell does…




Fig. 24.13

c. STORY

6. The helper T-cell will secrete interleukin-2, also a cytokine, which will bind to receptors on the T-cell itself, cytotoxic (toxic to cells) T-cells, and B-cells, both of which that have been partially activated by the SAME antigen (remember earlier that I said a B-cell would not fully activate with a helper-T cell)


6

5IL-2 stimulates the same Helper T-cell that secreted it to undergo mitosis…

IL-2 will activate the B and cytotoxic T cells, which have been partially activated already by the SAME antigen – antigen binds to antibodies on B-cell surface or MHC-II on Cyto T-cell surface.

Cytotoxic T-Cell is also called a Killer T-Cell




Fig. 24.13





Fig. 24.13

c. STORY

**All of these lymphatic cells (B and T cells) need two signals to be active:


6

5

1. The antigen

-An APC displays the antigen bounds to MHC-II (the antigen/MHC-II complex), which will bind to the T-celI receptor of a Helper T-cell - Binds directly to T-cell receptor of a Cytotoxic T-cell that recognizes that antigen.

- Binds directly to an antibody on the surface of a B-cell.




Fig. 24.13

c. STORY



6

5

1. The antigen

What if the T-cell or B-cell does not have an T-cell receptor or antibody, respectively, that can bind to the antigen?

Nothing, that cell will not be selected.




Fig. 24.13

c. STORY



6

5

2. Interleukins

IL-1 from the APC will activate the partially activated Helper T-cell.

IL-2 from the Helper T-cell will activate the already partially activated Cytotoxic T-cells and B-cells as well as itself

Now what will the activated Cytotoxic T-cells do?




Fig. 24.13

c. STORY

The cytotoxic T-cells will now bind to infected cells displaying the SAME antigen on MHC-I (MHC-ONE) receptors.

APC’s display antigen using MHC-II, while infected cells use MHC-I.

Cytotoxic T-cells secrete the protein perforin onto any cell with the proper MHC-I/antigen complex. Perforin puts holes in the cell membrane causing the cell to lyse...




Memory T-cells are also made from T-cells activated by Helper T-cells. For a future encounter with the same antigen carrying pathogen.




Recap: It all begins when a microbe is phagocytosed by a macrophage or an antigen from the microbe binds to the antibody receptor of a B-cell. The macrophage becomes an APC when it displays pieces of the microbe attached to MHC-II on its surface. The Helper T-cell with a T-cell receptor that matches the antigen binds and it activated by interleukin-1 released by the APC. The Helper T will in turn secrete IL-2 and activate itself to undergo mitosis as well as cytotoxic T-cells that have also been partially activated by antigen binding to their T-cell receptors and B-cells that have already been partially activated by antigen binding to their antibody receptors. The cyto T-cells will undergo mitosis to make memory T-cells and other cyto T-cells that will bind to the same antigen displayed on MHC-I receptors of infected cells and lyse those cells using the protein perforin, which puts holes in the membrane. B-cells will undergo mitosis to make plasma cells and memory B-cells. The plasma cells will secrete antibodies, which will bind to antigen and mark objects with this antigen for death (phagocytosis by macrophages). Memory B and T cells hang in the lymph nodes and spleen awaiting the return of the antigen…



B. Specific immunity (The Immune System)vii. Memory cells

Fig. 24.8

a. Memory B and T-cells are reservists for next time that specific antigen shows up:

Primary immune response

Secondary immune response

The first time the lymphocytes see the antigen. Antibodies are made, but relatively slowly due to the small number of B-cells activated and only a relatively small number of antibodies are made compared to the second time the lymphocytes see the antigen for the same reason.

The secondary response results upon re-exposure to the antigen. You have millions of memory B-cells. Most of them will be activated and antibodies are made quickly and in large number thanks to the large number of cells. You do not get sick. It must be the same antigen. Any mutation that changes the structure of the antigen will not elicit the secondary response.



B. Specific immunity (The Immune System)viii. Active vs. passive immunity

a. Active

1. Body produces own antibodies (plasma cells)2. Permanent for the most part (memory cells)

b. Passive1. Fetus gets antibodies from mom (doesn’t produce its own).

- conveys immunity

2. Antibody shots

3. Not permanent. Explain.Protein are not highly stable like DNA and will only last a short amount of time before they lose their structure (denature) and must be recycled. You are only protected for as long as the antibodies (immunoglobulins) last. There is no way to replace them…

Researchers are currently attempting to generate antibodies that will stick to cancer cells. How would this help us?



B. Specific immunity (The Immune System)viii. Active vs. passive immunity

a. Active

How can we use active immunity to our advantage?

Vaccines…train the immune system to recognize antigens in a safe way…this can be done by injecting bacterial/viral antigens into us…




Smallpox - infectious disease unique to humans, - caused by either two virus variants: Variola major and Variola minor - Localizes in small blood vessels of skin, mouth and throat. - V. major - mortality rate of 30–35%. - Long-term complications of V. major infection

- characteristic scars on face: occurred in 65-85% of survivors- Blindness resulting from corneal ulceration and scarring: 2-5%

- Emerged about 10,000 BC- killed ~400,000 Europeans each year during the 18th century - responsible for a third of all blindness- Between 20 and 60% of all those infected—and over 82% of infected children—died from the disease

-20th century, - 300–500 million deaths- 1967, the World Health Organization (WHO) estimated that 15 million people contracted the disease and that two million died in that year.- 1979 - small pox is gone



B. Specific immunity (The Immune System)ix. Vaccines

a. First vaccine - small pox - 1797

1. Edward Jenner

3. Took pus from cowpox pustule and inserted it into an incision on a boy

4. Boy could not get small pox (he was immune)

2. Two related diseases: cow pox and small pox



B. Specific immunity (The Immune System)ix. Vaccines

b. Inject a harmless variant of disease causing microbe

1. Body responds to antigens2. Memory cells produced

3. Immune system primed for the “real thing”

4. That’s easy…so where is the HIV vaccine?

HIV is a retrovirus. Viral particles that use reverse transcriptase and prone to making more errors in their DNA that a virus using DNA polymerase. This results in a quickly changing virus…the antigens change quicker than out immune systems can keep up with. It is like a criminal that can shape-shift (change what they look like…become anyone).



C. Overview

Non-specificSpecific



D. Autoimmune diseasesi. Immune system turns against the body

1. systemic lupus erythromatosus (lupus or SLE)

- Chronic autoimmune disease – lymphocytes attack connective tissue

- Causes inflammation

- Nine times more likely in women than men

- Unpredictable with periods of illness alternating with remission

- There is no cure, symptoms are treated

- Can be fatal, but fatalities are now rare with medical technology

Butterfly rash

- Precise cause is not known – genetic with environmental triggers like UV light




2. Rheumatoid Arthritis

- Chronic systemic inflammatory disorder that mainly affects the joints

- 1% of worlds population affected by this, women 3X more likely than men

- Onset typically between 40 and 50 years of age

- Problems in addition to joints can occur like inflammation of lung tissue and tissue surrounding the heart

- Precise cause is unknown

- Treated of symptoms with physical therapy and anti-inflammatory drugs

- No cure, lifespan reduced 5 to 10 years (estimated)




- Immune system attacks β (beta)-cells of the pancreas, which secrete insulin

- No insulin = no blood sugar regulation:

3. Insulin dependent (Type 1 early onset) diabetes

1. You eat a candy bar

2. Absorb monosaccharides into blood at jejunum

3. Blood sugar increases – sensed by proteins on the surface of beta cells in the pancreas

4. Beta cells secrete the hormone insulin (a protein) into the blood

5. Insulin circulates in the blood and binds to insulin receptors on the surface of muscle and liver cells.

6. Muscle and liver cells respond by sending glucose transporters to the cell surface causing the uptake of glucose in the blood, which will be stored as glycogen in the liver and muscle cells.

- Treatment is insulin injections




- Immune system attacks schwann cells

4. Multiple sclerosis (MS)

- Schwann cells are nervous system cells that wrap around and insulate neurons forming what is called the myelin sheath because the cells are filled with myelin – a mixture of 80% lipid and 20% protein.

- Without these cells, electrical signals will leak and the signal will not make it to where it needs to go…

- 5 to 10 years lifespan reduction, but suicide is a major concern



E. Immunodeficiency diseasesi. Lack one or more components of immune system

1. Severe combined immunodeficiency (SCID)- Aka “Boy in the bubble syndrome”

- Disorder in which both B and T cells are crippled due to defects in several possible genes

- The defective genes typically code for interleukin receptors.

- Most common treatment is bone marrow transplant

- “Bubble” is a sterile (microbe-free) chamber



E. Immunodeficiency diseasesi. Lack one or more components of immune system

2. HIV – human immunodeficiency virus

- Reminder – infects and destroys CD4+ Helper T-cells

- No Helper T-cells, no activation of Cytotoxic T-cells and B-cells

- AIDS does not kill patient, a secondary infection or cancer typically does due to a compromised immune system.

- Treatment: Drug cocktails that inhibit multiple enzymes at once to get the many variants and avoid artificial selection due to rapid mutation of the virus.



F. Allergiesi. Overreaction to environmental antigens (allergens)

1. Allergen = surface protein of pollen, salivary proteins of dogs/cats, hair of animals, etc…2. Histamine binds cellular histamine receptors resulting in allergy symptoms

3. How do you think antihistamines work?

Histamine



F. Allergiesii. Anaphylactic shock

- hypersensitivity to an allergen (ex. Bee sting)- sudden release of histamine by mast cells

- rapid dilation of blood vessels (swelling) / constriction of bronchioles

- rapid drop of blood pressure (shock)

- Emergency treatment = epinephrine (adrenaline)- hormone that counters anaphylactic shock

- counters airway constriction (dilates airway) - increases cardiac output to counter drop in BP

Epi-pen = epinephrine pen

chapter 24: the immune system new aim: how does the body defend itself against mo’s? nonspecific...

Documents

nonspecific immunity

nonspecific defense

immune system new aim

specific adaptive immunity

components cells

line of defense

phagocytosis cells

neighboring cells