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Chapter 14 - Innate Immunity
1. [14-01] Describe Classical, Lectin, Alternative pathways of the compliment system activation – Lecture 5, Slide 5 –
Classical pathway of Compliment system activation: Host antibody binds with microbial antigen (works only after prior exposure). Antibody recruits C1 protein à C1 activates C2 & C4 by cutting them in ½ = C2a + C2b + C4a + C4b → C2a & C4b form C3 convertase → C3 = C3a + C3b
Classical pathway of Compliment system activation: Host antibody binds with microbial antigen (works only after prior exposure). Antibody recruits C1 protein à C1 activates C2 & C4 by cutting them in ½ = C2a + C2b + C4a + C4b → C2a & C4b form C3 convertase → C3 = C3a + C3b
Lectin pathway of compliment system activation[*]: Host Mannose-binding (M-B) lectins bind w/ microbial mannose-containing surface carb. M-B lectins activate C2 & C4 by cutting them in ½ = C2a + C2b + C4a + C4b à C2a & C4b form C3 convertase à C3 = C3a + C3b
Alternative pathway of compliment system activation[†]: Host C3b recruits B, D, and P factors bind to Lipopolysaccharide (LPS). Endotoxins, polysaccharides or cell wall bind C3b[‡] à recruits factors B, D, P (properdin) à B, D, P factors form C3 convertase à C3 = C3a + C3b
2. [14-02] Describe Opsonization, Inflammation, Formation of membrane attack complex as outcomes of the compliment system activation – Lecture 5, Slide 6 –
Opsonization: C3b binds to surface of bacterial cells, acts as a mark for phagocytic cells.
Inflammation: C3b and factor P form complex that splits C5 à C5a + C5b, C5a attracts macrophages and neutrophils to site of infection, C3a binds to mast cells causing degranulation and massive histamine release à Vasodilation helps WBCs migrate from blood stream into tissue.
Formation of membrane attack complex: C3b and factor P form complex that splits C5 à C5a + C5b, C5b binds to cytoplasmic membrane of bacterial cells recruits proteins C6, C7, C8, C9 (9copies) à Form large pores that cause lysis and death of bacteria.
Opsonization: C3b binds to surface of bacterial cells, acts as a mark for phagocytic cells.
Inflammation: C3b and factor P form complex that splits C5 à C5a + C5b, C5a attracts macrophages and neutrophils to site of infection, C3a binds to mast cells causing degranulation and massive histamine release à Vasodilation helps WBCs migrate from blood stream into tissue.
Formation of membrane attack complex: C3b and factor P form complex that splits C5 à C5a + C5b, C5b binds to cytoplasmic membrane of bacterial cells recruits proteins C6, C7, C8, C9 (9copies) à Form large pores that cause lysis and death of bacteria.
3. [14-03] Describe the mechanisms of evasion of compliment system by bacteria. Name species and their virulence factors involved – Lecture 5, Slide 7 –
Digestion of C5a: Prevents attraction of phagocytic cells to site of infection, reduced inflammation. (EX: C5a peptidase from Streptococcus pyogenes).
Inactivation of C5b: Prevents formation of membrane attack complex in bacterial cell, no pores form. (EX: Lipopolysaccharide complexes of Neisseria gonorrhoeae, Bordetella pertussis, Haemophilus influenza).
Inactivation of C3 convertase: Prevents the activation of compliment system, no opsonization, inflammation, or membrane attack complex. (EX: M protein of Streptococcus pyogenes binds to compliment regulatory protein (factor H), to inactive C3-convertase.
Digestion of C5a: Prevents attraction of phagocytic cells to site of infection, reduced inflammation. (EX: C5a peptidase from Streptococcus pyogenes).
Inactivation of C5b: Prevents formation of membrane attack complex in bacterial cell, no pores form. (EX: Lipopolysaccharide complexes of Neisseria gonorrhoeae, Bordetella pertussis, Haemophilus influenza).
Inactivation of C3 convertase: Prevents the activation of compliment system, no opsonization, inflammation, or membrane attack complex. (EX: M protein of Streptococcus pyogenes binds to compliment regulatory protein (factor H), to inactive C3-convertase.
4. [14-04] Describe the killing of microbes by phagocytic cells – Lecture 5, Slide 10 –
Two step process: Phagocytosis + Digestion.
Two step process: Phagocytosis + Digestion.
· Phagocytosis
1 – Opsonization: Microbe is targeted by opsonins or antibodies on its surface.
2 – Binding of opsonized microbe to phagocytic cell: For microbes marked by C3b, C3b receptors involved in binding. For microbes marked by antibodies, Fc receptors involved in binding.
3 – Ingestion of microbe and formation of phagosome: Microbe taken into the cell with formation of vesicle called phagosome.
1 – Opsonization: Microbe is targeted by opsonins or antibodies on its surface.
2 – Binding of opsonized microbe to phagocytic cell: For microbes marked by C3b, C3b receptors involved in binding. For microbes marked by antibodies, Fc receptors involved in binding.
3 – Ingestion of microbe and formation of phagosome: Microbe taken into the cell with formation of vesicle called phagosome.
· Digestion
4 – Formation of phagolysosome: Phagosome fuses with lysosome containing hydrolytic enzymes.
5 – Digestion: Microbe is disintegrated by enzymatic action, w/ some nutrient absorbed by cell.
6 – Excretion of residual bodies: Non-digested remnants removed from phagocytic cell
* Microbes can also be killed by H2O2 produced by activated phagocytic cells.
4 – Formation of phagolysosome: Phagosome fuses with lysosome containing hydrolytic enzymes.
5 – Digestion: Microbe is disintegrated by enzymatic action, w/ some nutrient absorbed by cell.
6 – Excretion of residual bodies: Non-digested remnants removed from phagocytic cell
* Microbes can also be killed by H2O2 produced by activated phagocytic cells.
5. [14-05] Describe the mechanisms of microbial evasion of phagocytosis: Killing of phagocyte at the distance; Prevention of Phagocyte’s adhesion to microbe; Prevention of phagolysosome formation. Name bacteria and their virulence factors involved – Lecture 5, Slide 13 –
Microbial counter to phagocytic cells:
Microbial counter to phagocytic cells:
· Killing phagocytes at a distance – Bacterial secreted toxin binds to phagocytic cells to kill them (for the examples below: destroying by forming pores in plasma membrane).
o Staphylococcus aureus (Leukocidins)
o Streptococcus pyogenes (Streptolysin O, Streptolysin S)
o Streptococcus pneumoniae (Pneumolysin)
· Prevention of phagocytic adhesion to microbe – Prevents phagocytic binding to microbe.
o Staphylococcus aureus (Biofilm, coagulase, Protein A, IgA protease, Capsule)
o Streptococcus pyogenes (Biofilm, Protein G, M protein, Capsule)
o Streptococcus pneumoniae (IgA protease, Capsule)
· Escaping phagosome, followed by killing macrophage – Microbe is ingested, but destroys phagocytic cell inside out.
o Shigella spp. (Components of cell wall, Shiga toxin)
· Prevention of phagolysosome formation – Prevents digestion microbe’s inside phagocytic cell.
o Listeria monocytogenes (Components of cell wall)
o Mycobacterium tuberculosis (Components of cell wall)
o HIV (Components of virus envelope)
v Biofilms = Bacteria embedded in extracellular material à Prevents contact between bacteria and phagocytes.
v Capsule = Gelatinous outer material of microbes à Prevents C3b and antibody contact + receptor contact.
v Protein A & G, Coagulase = Covering bacteria by host proteins à Proteins A & G bind IgG inverted, coagulase precipitates human fibrin
v IgA protease, M protein = Interfering with opsonization of bacteria à IgA protease digests IgA antibodies, M protein prevents C3 convertase
6. [14-06] Describe fever development caused by infection of Gram-negative bacteria. What are benefits of fever development? – Lecture 5, Slide 14 –
Gram-negative bacteria ingested by macrophage à Formed phagosome fuses with lysosome and bacteria is destroyed à Endotoxin released from bacterial cell wall à Triggers production of interleukin 1 by macrophage à Interleukin 1 secreted by macrophage enters blood stream à Interleukin 1 travels to hypothalamus à Hypothalamus produces prostaglandin à Prostaglandin causes fever.
Benefits of fever:
· Reduction in bacterial growth due to high body temperature.
· Increased activity of T helper and T cytotoxic cells on host.
· Increased production of antimicrobial substances by host.
7. [14-06] Protection of human cell by interferon against viral infection – Lecture 5, Slide 17
Interferons: Antiviral proteins produced by virus-infected host cells that prevent spread of virus infection to neighboring cells.
Interferons: Antiviral proteins produced by virus-infected host cells that prevent spread of virus infection to neighboring cells.
1st virus enters host cells and starts replication à Infected cell produces interferons à Interferons taken up by neighboring cell à Triggers production of antiviral proteins (AVP) in neighboring cells à Virus enters alerted cell, antiviral proteins prevent viral replication à Viral spread is limited.
Chapter 15 - Adaptive Immunity
8. [15-01] Distinguish Antigen, Epitope, Hapten, Antibody. – Lecture 5, slide 18 –
Antigen: Any compound that can induce the antibody production in the host.
Epitope: Part of the antigen that can be recognized by a specific antibody.
Antibody: Protein produced by immune system in response to appearance of foreign antigens in host.
Hapten: Small molecule that is NOT immunogenic. It becomes immunogenic only if it forms complex with carrier molecule.
Antigen: Any compound that can induce the antibody production in the host.
Epitope: Part of the antigen that can be recognized by a specific antibody.
Antibody: Protein produced by immune system in response to appearance of foreign antigens in host.
Hapten: Small molecule that is NOT immunogenic. It becomes immunogenic only if it forms complex with carrier molecule.
9. [15-02] Describe the structure of antibody – Lecture 5, Slide 19 –
Y-Shaped protein produced by immune system (mainly plasma B cells) in response to appearance of foreign antigen. Composed of 4 polypeptides = 2 light & 2 heavy chains that hold together 4 disulfide bonds.
Has 3 domains (parts)[§]:
Y-Shaped protein produced by immune system (mainly plasma B cells) in response to appearance of foreign antigen. Composed of 4 polypeptides = 2 light & 2 heavy chains that hold together 4 disulfide bonds.
Has 3 domains (parts)[§]:
· Fa domain: (upmost portion of the Y) Variable region with antigen binding groove, where epitope can fit tightly, in lock and key manner.
· Fb domain: (Just above the junction of the Y) Holds light and heavy chains together.
· Fc domain: (Stem of Y) Responsible for various immune reactions leading to elimination of microbes, and abnormal cells. Can trigger compliment activation, phagocytosis, attack by natural killer.
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Fa – Variable region specificity of antibody
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Fb – Holds light and heavy chains together
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Fc – Responsible for various immune reactions
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11. Describe antibody-dependent cellular toxicity as protective mechanism resulting from antibody-antigen binding – Lecture 5, Slide 20 –
Fa portion of antibody binds to the antigens on the microbe or infected cell. The exposed Fc portion of the antibody is recognized by the Fc receptor of a natural killer cell that then attacks the microbe/infected cell.
When antibody binds to large pathogen too big to be ingested normally, recognized by Fc receptors of natural killer cells. Natural killers attacked antibody labeled cell by delivering toxic substances that either lyse or trigger apoptosis.
Fa portion of antibody binds to the antigens on the microbe or infected cell. The exposed Fc portion of the antibody is recognized by the Fc receptor of a natural killer cell that then attacks the microbe/infected cell.
When antibody binds to large pathogen too big to be ingested normally, recognized by Fc receptors of natural killer cells. Natural killers attacked antibody labeled cell by delivering toxic substances that either lyse or trigger apoptosis.
12. [15-04] Describe neutralization reaction as protective mechanism resulting from antibody-antigen binding – Lecture 5, Slide 20 –
Binding of antibody to viral particles/soluble toxins that renders them biologically inactive. Antibodies interfere with the antigen-receptor connections of viruses and toxins.
Binding of antibody to viral particles/soluble toxins that renders them biologically inactive. Antibodies interfere with the antigen-receptor connections of viruses and toxins.
13. [15-05] Compare IgM, IgG, IgA, IgD and IgE classes of antibody – Lecture 5, Slide 21 –
IgM: 1st antibody produced in response to first exposure to microbe. Pentamer capable of cross-linking microbes (can agglutinate) and able to activate complement system. Only antibody produced by fetus.
IgG: (85% - Majority) 2nd antibody produced in response to first exposure to microbe, during class-switching from IgM à IgG. Antibody of memory that will be produce on 2nd exposure, that can leave blood stream and enter tissues. Activates complement system. Only antibody that can cross placenta.
IgA: Secretory antibody that can NOT activate complement system, but can cross-link (agglutinate) microbes. Dimer found in blood, lymph, breast milk, saliva, tears, and mucous membrane.
IgD: Localized, monomeric antibody on surface of B cell. Does NOT activate compliment system, BUT plays role in activation of naïve B cells.
IgE: Localized, monomeric antibody on surface of mast cells and basophils. Does NOT activate compliment system, BUT plays role in inflammation reactions and allergic reactions.
IgM: 1st antibody produced in response to first exposure to microbe. Pentamer capable of cross-linking microbes (can agglutinate) and able to activate complement system. Only antibody produced by fetus.
IgG: (85% - Majority) 2nd antibody produced in response to first exposure to microbe, during class-switching from IgM à IgG. Antibody of memory that will be produce on 2nd exposure, that can leave blood stream and enter tissues. Activates complement system. Only antibody that can cross placenta.
IgA: Secretory antibody that can NOT activate complement system, but can cross-link (agglutinate) microbes. Dimer found in blood, lymph, breast milk, saliva, tears, and mucous membrane.
IgD: Localized, monomeric antibody on surface of B cell. Does NOT activate compliment system, BUT plays role in activation of naïve B cells.
IgE: Localized, monomeric antibody on surface of mast cells and basophils. Does NOT activate compliment system, BUT plays role in inflammation reactions and allergic reactions.
14. [Self-insert Question] Describe B cell development from naïve B cells to effector cells via clonal deletion, selection, and expansion (Lecture 5, Slide 22)
Naïve B cells produced in bone marrow, each B cell has receptor for antibodies produced by the cell. à Clonal deletion: Selective killing of naïve B cells that can produce antibodies against its own antigens.[**] à Clonal selection & expansion: Once select naïve B cells exposed to antigen, activated à chosen for proliferation à Each proliferated descendant becomes an effector cell (all descendants of activated B cell, memory/plasma cells).
Plasma cells: Activated B cell that has STOPPED cell division and is actively producing the specific antibody.
Memory cells: Activated B cell that persists in host for years and are responsible for prompt + strong secondary immune response.
Naïve B cells produced in bone marrow, each B cell has receptor for antibodies produced by the cell. à Clonal deletion: Selective killing of naïve B cells that can produce antibodies against its own antigens.[**] à Clonal selection & expansion: Once select naïve B cells exposed to antigen, activated à chosen for proliferation à Each proliferated descendant becomes an effector cell (all descendants of activated B cell, memory/plasma cells).
Plasma cells: Activated B cell that has STOPPED cell division and is actively producing the specific antibody.
Memory cells: Activated B cell that persists in host for years and are responsible for prompt + strong secondary immune response.
15. [15-08] Describe T-cell dependent B-cell activation – Lecture 5, Slide 23 –
B cell activation with T-helper cells:
B cell activation with T-helper cells:
1) Naïve B cell has B cell receptor and MHCII on its surface
2) B cell receptor binds to antigen
3) Bounded antigen is taken into the cell
4) Within cell, antigen is shredded to fragments
5) Fragments are loaded onto MHCII complexes on surface of B cells
6) T-helper cell recognizes antigen-MHCII complex with receptors and CD4 protein
7) T-helper cell binds to B cell and delivers interleukin 4 à activates B cell
8) B cell undergoes proliferation à Forms plasma cells and memory cells
16. [15-09] Compare the properties and functions of T helper cells, T cytotoxic cells, Natural killers – Lecture 5, Slides 27-28 –
T helper cells (hTc): CD4 coreceptor and T-cell receptor (TCR) used to bind to cells with antigen-MCHII complex, activation of cells via delivery of interleukins (IL-2 induces activation and cell division for cytotoxic T cells, IL-4 for B cells, IL-2 for marcophages).
T cytotoxic cells (cTc): CD8 coreceptor and T-cell receptor (TCR) used to bind to cells with antigen-MCHI complex, kills cells with perforin (forms aq pores in plasma membrane) and granzyme (protease that induces apoptosis).
Natural killers (NT): Common origin with B and T cells, BUT lack antigen specificity (NO receptors for antigens). Do have a Fc receptor à can recognize cells labeled by IgG à can recognize and destroy cells with NO MHC on surface membrane.
T helper cells (hTc): CD4 coreceptor and T-cell receptor (TCR) used to bind to cells with antigen-MCHII complex, activation of cells via delivery of interleukins (IL-2 induces activation and cell division for cytotoxic T cells, IL-4 for B cells, IL-2 for marcophages).
T cytotoxic cells (cTc): CD8 coreceptor and T-cell receptor (TCR) used to bind to cells with antigen-MCHI complex, kills cells with perforin (forms aq pores in plasma membrane) and granzyme (protease that induces apoptosis).
Natural killers (NT): Common origin with B and T cells, BUT lack antigen specificity (NO receptors for antigens). Do have a Fc receptor à can recognize cells labeled by IgG à can recognize and destroy cells with NO MHC on surface membrane.
[*] Works only if bacteria have mannose-containing carbohydrates.
[†] Works only if bacteria have lipopolysaccharide complexes on its surface (e.g. Gram-negative bacteria).
[‡] C3b is present already in small amounts throughout tissues.
[§] Fa – variable depending on specific target, Fb & Fc are species specific
[**] Occurs during fetal development, important in preventing autoimmune issues.
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