Immunology Review

Question 1

What are the primary immune organs or tissues?

Answer 1

o bone marrow (red) – hematopoiesis, B cell development o thymus – T cell development o liver (fetus) - hematopoiesis

Question 2

What are the secondary immune organs or tissues?

Answer 2

o lymph node – B and T cell activation o spleen – adaptive immune response, phagocytosis of opsonized cells o MALT (Mucosal Associated Lymphatic Tissue) o SALT (Skin Associated Lymphatic Tissue) o GALT (Gut Associated Lymphatic Tissue) ƒ Tonsils ƒ Peyer’s patches (ileum) ƒ vermiform appendix o BALT (Bronchus Associated Lymphatic Tissue)

Question 3

Accessory structures in the immune system?

Answer 3

o lymphatic vessels

Question 4

List the immune cells and their functions?

Answer 4

o B lymphocytes – differentiate into plasma cells, antibody production o T lymphocytes – differentiate into cytotoxic T cells (CTLs) and helper T cells (TH) o Natural Killer (NK) cells – immune surveillance, destroy virally infected cells and tumor cells o Dendritic cells – capture, process, and present antigen to T cells o Macrophages – phagocytose and digest antigens o Mast cells – stimulate allergies and inflammatory response o Granulocytes (primarily neutrophils and eosinophils) – many functions

Question 5

Describe the innate immune system?

Answer 5

Question 6

Key features of the innate immune system?

Answer 6

1. Host protection comes from inflammation and antiviral defense.
2. Host response to a pathogen is stereotypical.
3. The host recognizes specialized characteristics of pathogens and damaged cells.
4. The innate immune system does not attack host cells.

Question 7

What are the physical barriers of the innate immune system?

Answer 7

x Tight junctions

x Mucins

x Cilia

x Gut peristalsis

x Normal microflora

Question 8

What are the chemical barriers of the innate immune system?

Answer 8

Acidic pH prevents microbial growth o Skin, stomach, urine, vagina, bile

x Antimicrobial peptides (defensins, cathelicidins) are toxic to microbes and recruit leukocytes o Secreted by epithelial cells in skin, GI tract, respiratory tract

x Lysozyme hydrolyzes peptidoglycan in bacterial cell wall o Secreted by epithelial cells of mucous membranes, moist epithelial linings and many exocrine glands (in tears, saliva, breast milk, GI, GU tracts) o Also found within lysosomes of monocytes, neutrophils, macrophages, and hepatocytes

x Lactoferrin binds free Fe2+ to inhibit bacterial growth o Production and location similar to lysozyme

x Apolactoferrin ( w/o Fe2+) - blocks viral entry by binding lipoproteins, a viral attachment receptor, on epithelial cells

x Surfactants (Surfactant protein A = SPA) bind directly to bacteria, viruses, and fungi to increase their phagocytosis o Secreted by respiratory epithelium, concentrated in alveoli

x Antibodies (Immunoglobulins, Ig) lead to destruction of microbes through multiple mechanisms o Produced by B lymphocytes (plasma cells) o Located in serum, tears, mucus, breast milk, interstitial fluid

x Plasma proteins are constitutively secreted by hepatocytes

Question 9

Explain the plasma proteins secreted by hepatocytes?

Answer 9

o Acute phase reactants bind to bacterial membranes and membranes of apoptotic cells to activate the complement pathway and opsonize (induce phagocytosis) ƒ Examples include C-reactive protein (CRP) and serum amyloid P (SAP) ƒ Levels increase rapidly during infection in response to cytokines

o Mannose-binding lectin (MBL) activates complement pathway and opsonizes ƒ Binds to surface of bacteria, viruses, fungi, and protozoa

o Complement proteins opsonize, recruit phagocytic cells, and are able to cause direct lysis (not always beneficial) by binding directly or indirectly (through CRP, SAP, MBL, or antibodies) to surface of cells or pathogens ƒ Include C1, C2, C3, C4, C5, C6, C7, C8, C9 (and more…)

Question 10

What are the cells of the innate immune system?

Answer 10

x Mast cells

x Macrophages

x Dendritic cells

x NK cells

x Granulocytes

Question 11

Explain dendritic cells?

Answer 11

cells of the innate immune system which can capture, process, and present antigens. These cells are professional antigen presenting cells (APCs) capable of producing MHC I and MHC II molecules and can therefor present intracellular and extracellular pathogens respectively, usually to a T cell. The ability of a dendritic cell to activate both CD4+ T cells and CD8+ T cells is called cross-presentation. They are an important link between the innate and the adaptive immune systems.

Question 12

Explain natural killer cells?

Answer 12

cells of the innate immune system responsible for destruction of virally infected or tumor cells. They constantly survey host cells for abnormalities (immune surveillance). Upon activation, they release their granules containing perforin and granzymes to assist in destruction of the target cell. NK cells also participate in Antibody-Dependent Cellular Cytotoxicity (ADCC), a mechanism of target cell death with the assistance of IgG).

Question 13

what is the complement system? what are the three branches?

Answer 13

The complement proteins get activated through a series of events known as the complement pathway, complement cascade, or complement fixation. This occurs when a complement protein binds (directly or indirectly) to the cell or pathogen surface.

Classical IgG, IgM, SAP, CRP binding to the pathogen

Alternative C3b covalently binding to the pathogen

Lectin Mannose-binding lectin binding to mannose on the pathogen

Question 14

Once C3 is recruited to the pathogen what happens? Two options? If thats not enough what happens?

Answer 14

Once C3 is recruited to the pathogen, it must be cleaved into C3a and C3b, which is accomplished by the formation of the C3 convertase.

If this is not enough to clear the pathogen, there is still one other defense mechanism available involving the complement system – formation of the membrane attack complex (MAC). To assemble the MAC, C5 must first be recruited to the pathogen where it can be cleaved into C5a and C5b by the C5 convertase.

Question 15

What does C5b do?

Answer 15

C5b initiates the late steps of complement activation and the formation of the Membrane Attack Complex (MAC)

Question 16

If options #1, #2, or the MAC do not eliminate the pathogen what happens?

Answer 16

x Extracellular pathogens, such as many bacteria, can be captured and phagocytosed by macrophages, dendritic cells, neutrophils, or eosinophils, or can cause activation of Mast cells.

x Intracellular pathogens, such as viruses, can be eliminated by Natural Killer cells (NK cells) whose job it is to destroy the infected host cell or, cytokines which make the host cell environment unfavorable for pathogen reproduction. Please note: Intracellular pathogens can also be destroyed by cytotoxic T cells of the adaptive immune system.

Question 17

What are PAMPs? Where are PAMP receptors encoded? What are some examples?

Answer 17

Some pathogens can be recognized by cells or plasma proteins because they express key components on their surface which human cells do not express. Generally, these are called Pathogen-Associated Molecular Patterns or, PAMPs. Some examples of PAMPs include: LPS, peptidoglycan, dsRNA, techoic acid, and flagellin. Of importance to note, PAMPs are only found on pathogens, and are not on host (human) cells. This makes PAMPs of particular interest as therapeutic targets. Similarly, host cells such as phagocytic cells, epithelial cells, hepatocytes, and leukocytes have PAMP receptors which are encoded in the germline called Pattern Recognition Receptors (PRRs). Examples of PRRs include TLR, lectin, and NOD-like receptor, and are located in the plasma membrane, cytosol, AND endosomal membrane. This is particularly beneficial since some PAMPs are not available for binding until a pathogen is destroyed during phagocytosis.

Question 18

PAMP receptor signaling assists in controlling what? how?

Answer 18

PAMP receptor signaling assists in controlling intracellular infections by the secretion of antiviral proteins called type I interferons:

o IFN-α - produced by epithelial cells, B cells, macrophages, dendritic cells

o IFN-β - produced by fibroblasts

Question 19

What cells have receptors for type 1 interferons? Binding of these results in?

Answer 19

Interestingly, most cells have receptors for type I interferons and can therefore respond to these ligands. Binding of either IFN-α or IFN-β activates signal transduction pathways that result in production of enzymes that inhibit protein synthesis and degrade viral mRNA inducing an anti-viral state. These virally infected cells can therefore be eliminated by NK cells or phagocytosed and destroyed by a dendritic cell or a macrophage.

Question 20

How do we clear extracellular pathogens?

Answer 20

To clear extracellular pathogens, we stimulate an inflammatory response. Please recall, an inflammatory response is essentially an increase in leukocytes within tissues (infected or noninfected).

Question 21

What are the four signs of inflammation?

Answer 21

redness (rumor), swelling (tumor), heat (calor), and pain (dolor)

Question 22

What are mast cells?

Answer 22

These are non-phagocytic, fixed (resident) cells found primarily within the lamina propria and submucosa of the respiratory and digestive systems, serous membranes, mesentery, dermal papillary layer, and the hypodermis. Even though mast cells cannot phagocytose, they can release pre-formed granules by exocytosis to stimulate an inflammatory response.

Question 23

What are mast cells activated by? Mast cells are the key mediator of?

Answer 23

x C3a, C4a, C5a binding to complement receptors in plasma membrane

x DAMPs and PAMPs binding to their respective receptors

x Substance P (pain neurotransmitter released by nociceptors)

x Opiates that block neurokinin receptors which substance P binds to

x Allergens binding to IgE already present on the mast cell surface

NOTE: mast cells are the key mediator of the allergic response (Immediate hypersensitivity)

Question 24

What are the contents of the mast cells pre-fromed granules?

Answer 24

Histamine, Serotonin, Heparin and other proteoglycans, Neutral proteases like tryptase, Prostaglandins, Leukotrines

Question 25

What does Histamine do?

Answer 25

o Causes local vasodilation by activating nitric oxide (NO) production in endothelial cells – NO relaxes arteriole smooth muscle and prevents platelets from attaching to endothelium → slows blood flow, blood pools (REDNESS, HEAT) and swells tissue capillaries, pushing endothelial cells apart → increased capillary permeability → plasma leaks into tissues (SWELLING) leads to pain

o Cause local smooth muscle contraction (bronchospasm, increased gut peristalsis)

o Neutrophil chemoattractant

Question 26

What does Serotonin do?

Answer 26

o Causes local vasodilation in a similar fashion like histamine

o Stimulates nociceptors – substance P released leads to PAIN (and more mast cell degranulation – positive feedback loop)

Question 27

What does heparin and the other proteoglycans do?

Answer 27

o Temporarily prevent fibrin from forming (thrombin is inactivated)

Question 28

What do the neurtal proteases do?

Answer 28

o Cleaves C3 → C3a produced → C3a stimulates more mast cell degranulation → (another positive feedback loop)

o Cleaves fibronectin and type IV collagen – degrade basal lamina of capillary beds ƒ Increased capillary permeability (SWELLING) ƒ Attracts fibroblasts (wound healing, scar tissue formation) ƒ Activates coagulation cascade → blood clot formed to inhibit infection

Question 29

What do prostaglandins and leukotrines do?

Answer 29

x Prolong effects initiated by histamine and serotonin x Chemoattractants for leukocytes

Question 30

mast cells activate signaling pathways that stimulate cytokine production such as:

Answer 30

x TNF-α – increases cell adhesion molecules on endothelial cells

x IL-1 – increases cell adhesion molecules on endothelial cells

x IL-4 – eosinophil chemoattractant

x Chemokines – leukocyte recruitment and activation

Question 31

What are macrophages? what are their functions?

Answer 31

These resident phagocytic cells are found throughout connective tissue, organs, as well as lymphoid tissue. Recall, some macrophages are monocytes that have left the blood vessels and differentiated into a cell capable of phagocytosing. As such, macrophages have 4 major functions:

1) . Phagocytosis – removes microbes, dead/dying tissue and cells, and tissue debris from blood, lymph, and connective tissues. Stimulates the respiratory burst to destroy the ingested pathogen/cell (note: this does not kill the macrophage).
ii) Production and secretion of cytokines and chemokines that can: x Stimulate and enhance innate inflammatory responses x Stimulate NK cell activity x Modify B and T lymphocyte activity
iii) Present antigens to T cells. Macrophages (and dendritic cells) are the MAJOR cellular link between innate immune defenses and adaptive immune defenses.
iv) Manage wound repair by stimulating angiogenesis and fibrosis.

Question 32

What are neutrophils?

Answer 32

Before they can eliminate bacteria, neutrophils must leave the blood vessels by extravasation and enter the connective tissues where it can phagocytose and destroy bacteria. Recall that neutrophils contain granules that assist in the destruction of the bacteria. Like macrophages, neutrophils also release ROS as they migrate through tissues, leaving behind tissue damage when neutrophil concentration is high. However, unlike macrophages, the ROS produced in phagolysosomes of neutrophils is lethal for both the phagocytosed pathogens AND for the neutrophils. This leads to the formation of pus.
Pus = dead pathogens + dead neutrophils

Question 33

What are eosinophils?

Answer 33

Similar to neutrophils, eosinophils are capable of binding endothelium, migrating out of the blood vessel and into inflamed tissue, and can phagocytose antigen-antibody complexes. Recall that eosinophils are recruited by IL-4, which is secreted by mast cells, thus they play an important role in asthma, but also in the destruction of helminthes. This is not the only similarity that eosinophils share with mast cells… 
Eosinophil activation (degranulation) – antibodies bind to Fc receptors on eosinophils upon a primary exposure to an antigen. At this time, eosinophils do not release their granules. Upon subsequent exposure of the same antigen, the antigen (in this case, an allergen), binds to the antibody (IgE) attached to the eosinophils and induces the eosinophil degranulation. In addition, eosinophils have a receptor for the cytokine IL-5 (IL-5 receptor), which must be engaged before the granules can be released.

Question 34

What are the granular compnents of eosinophils?

Answer 34

x Major Basic Protein – induces mast cell degranulation AND digests sulfated proteoglycans like heparin and other connective tissue molecules, parasite cuticles, the “shell” around parasite eggs, protozoa cysts, and fungal cell walls…very important for immune response to parasites!

x Acid phosphatase, elastase – degrade tissues such as the thick epidermis of helminthes, yeast, and fungi x Eosinophil peroxidase (EPO) – catalyst of eosinophilic respiratory burst

x Eosinophilic cationic proteins = ribonucleases – digest RNA, ribosomes (antiviral)

Question 35

Eosinophils versus mast cells?

Answer 35

Eosinophils can also produce the same lipid mediators and cytokines as mast cells. However, unlike mast cells, eosinophils can: 1. phagocytose, including organisms like bacteria and yeast 2. release antihistimines (arylsulfatase) to provide a negative feedback for mast cells as a part of their control during the late phase of inflammation

Question 36

What is the adaptive immune system?

Answer 36

Generally, an adaptive immune response takes longer to produce than the innate immune response because the innate cells (ie. a dendritic cell or a macrophage) must first capture the antigen, travel through the body using the blood or lymph, and enter the secondary lymphatic organs where they can “show”, or present, the antigen to a T cell. There are two primary cell types of the adaptive immune system:

x B cells

x T cells

Similar to the PRRs on innate immune system cells, the cells of the adaptive immune system also have specialized receptors that can recognize specific ligands. The T cell specific receptor is the T cell receptor (TCR) and the B cell specific receptor is the antibody (Ab, or immunoglobulin, Ig). The major difference, however, between these receptors is that PRRs recognize PAMPs which are only found on pathogens such as bacteria and are usually much larger sequences, whereas the TCR and Ab are very specific in the molecules that they recognize. Additionally, TCR and Ab can recognize self antigen and foreign antigen. The result of recognition and activation of the host immune system against a self-antigen is autoimmunity – a condition in which the host immune system begins to attack its own cells.

Question 37

What are the two categories of T cells?

Answer 37

There are two major classifications of T cells: helper T cells (TH) and cytotoxic T cells (CTLs). These cells are also commonly referred to as CD4+ and CD8+ T cells, respectively. To stimulate the effector functions of these T cells, the antigen must present the peptide in either an MHC I or MHC II molecule. Recall, each of these molecules is produced by the transcription and translation of HLA genes, an important consideration in transplants. Additionally, these MHC molecules are used to present intracellular and extracellular peptides, respectively.

Question 38

Explain antibodies?

Answer 38

Recall, B cells can differentiate into plasma cells which are antibody secreting cells. There are 5 antibody isotypes all of which perform different effector functions: IgA, IgD, IgE, IgG, and IgM. Of particular importance to the respiratory system is the isotype, IgA. Approximately two thirds of total Ig in an individual is IgA. It is concentrated in secretions such as mucus, tears, and breast milk. While IgD is not secreted, and IgG and IgE are only secreted as monomers, IgA and IgM can form polymers with the assistance of the J chain polypeptide. In order for IgA to provide any protective function (it’s only function is the ability to neutralize pathogens and prevent them from attaching to and colonizing the epithelium, or gaining entry into the host body), it must be transported across the epithelium (by transcytosis) and into the lumen where it is most likely to encounter a pathogen.

The basal side of epithelial cells in the gastrointestinal tract, the respiratory tract, tear ducts, and mammary glands express the poly Ig receptor which is responsible for binding to the J chain and activating transcytosis. On the apical side of the cell, an enzyme cleaves the poly Ig receptor, releasing the secretory component (a small portion of the poly Ig receptor component responsible for increasing the antibody half-life), which remains attached to the polymeric IgA or IgM into the mucus, tears, or breast milk on the luminal side.

Question 39

Explain a Type 1 hypersensitivity?

Answer 39

Please recall that hypersensitivity responses are generally unwanted or uncontrolled cellular responses to an antigen that is not harmful to the human host. The immune response produced against the antigen, however, can be harmful and result in tissue damage. Below are pathologies of immediate and late phase mast cell or eosinophil activation.

Recall that many immediate hypersensitivity reactions are a result of activating mast cells and/or eosinophils by cross-linking IgE bound to FcεR on the cell surface. Diagnosis of an allergy, such as one against the allergens hay fever or ragweed, can be done by the use of a scratch test.

In addition, one immunotherapy treatment which has been shown to be effective in some patients with allergies is the use of allergy shots. Here, the patient is administered small amounts of allergen, increasing in dosage, over an extended period of time in an attempt to desensitize the patient to the allergen.

Question 40

What is the hygeine hypothesis?

Answer 40

Increased exposure to pathogens early in life decreases the likelihood of developing allergies. Supporting evidence - children less likely to develop allergies are: - in daycare - multiple siblings - in 3rd world countries - kids that eat dirt

Question 41

Explain a type 2 hypersensitivity?

Answer 41

This is a rare, autoimmune disease which affects primarily males in their teens and twenties. Symptoms initially begin with hemoptysis but progress to kidney involvement manifesting in glomerular dysfunction. Some possible treatments include plasmapheresis and immunosuppressive therapy.

Question 42

What are Toll-like receptors defects?

Answer 42

Innate immune system defect involving the respiratory system:

Toll-Like Receptor (TLR) Defects Recall that activation of TLR pathways leads to the production of cytokines and chemokines including IL-1, IL-6, TNF… all have local and systemic effects in containing infection, generating fever and induction of acute phase innate responses, including production of Creactive protein. Loss or defective function of any of the TLRs will lead to a defect in innate responses, across a range of severities. The best characterized mutation is that which results in TLR-2 deficiency. In this case, patients have an increased susceptibility to Gram positive bacterial infections, Streptococcus pneumoniae meningitis.

Defects in TLR signaling pathway (X linked mutations of NFĸB documented) can result in:

x inappropriate activation of inflammation leadding to autoimmune arthritis, asthma, septic shock, lung fibrosis, atherosclerosis

x persistent inhibition of activation leading to recurrent skin infections in infancy, recurrent respiratory tract infections, diarrhea, failure to thrive (FTT)

Question 43

What is Bruton-type Agammaglobinemia?

Answer 43

Adaptive immune defect involving the respiratory system

Bruton-type Agammaglobulinemia X—linked disorder results from a mutations in a tyrosine kinase specific to B cells (Btk) that result in loss of the signal for B cells to differentiate to plasma cells.
Males develop multiple, recurrent bacterial infections of respiratory tract and skin starting a few months after birth…treatment involves prophylactic antibiotics and IVIG (intravenous immunoglobulin) infusions…death in childhood occurs from respiratory failure due to complications of repeated lung infections.

Question 44

Three types of bacterial killed or inactivated vaccines?

Answer 44

Toxoid – inactivated toxin (may not stop spread of bacteria, but stops mode of pathogenicity)

Killed - whole bacteria (can stop spread and pathogenicity of bacteria)

Capsule or protein subunit – use the most immunogenic antigens from the pathogen (ex: cell wall components)

Question 45

Types of viral killed or inactivated vaccines?

Answer 45

Inactivated – whole virus is chemically treated to inactivate
Subunit – immunogenic components of virus, may be combined to form virus-like particle (VLP; able to stimulate immune response, infect host cells, but unable to reproduce)

Question 46

What are the advantages to killed or inactivated vaccines?

Answer 46

x safe for most individuals (except if allergic reaction occurs)

x longer shelf-life

Question 47

Disadvantages to killed or inactivated vaccines?

Answer 47

x short term immunity (need boosters)

x may not activate T cells

x does not result in IgA production

x large doses needed

x may require adjuvant

Question 48

What are live vaccines?

Answer 48

Live vaccines contain attenuated, or less virulent, bacteria or viruses, however, the pathogen retains the ability to replicate slowly. They are produced by chemical, physical, or biological alterations of the pathogen and are often selected based on their:

x temperature sensitivity (selected on inability to replicate at 37oC)

x inability to replicate in human cells (cultured/grown in non-human cells)

x inability to migrate to “target” tissue (introduced into tissue not optimal for growth)

Question 49

Advantages to live vaccines?

Answer 49

x long term immunity

x activates B and T cells

x can stimulate IgG and IgA production

x small doses needed

x adjuvant not required

Question 50

Disadvantages to live vaccines?

Answer 50

x dangerous for pregnant or immunosuppressed individuals

x may revert to virulent form

x shorter shelf-life

x rare risk of severe reaction

x may be limited by antibodies already present in patient

Question 51

What is the hapten carrier effect?

Answer 51

. Hapten-carrier effect: T-dependent B cells usually respond to the same antigen as helper T cells they present antigen peptides to, but there is an exception. If a small, chemical (hapten) is attached to a large protein (carrier), the hapten-carrier complex can activate a haptenspecific antibody response and a carrier-specific TH cell response. This can lead to the production of memory B cells with high affinity IgG, IgA, or IgE specific for a non-protein antigen.