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PHARM 310 > Humoral Immunity and Complement System > Flashcards

Humoral Immunity and Complement System Flashcards

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1
Q

Mechanism of Affinity Maturation of B-Cells, what is the result? (Low)

A

Somatic Hypermutation of Ig genes in rapidly proliferating germinal center B-cells
- Germinal Center B-Cells with low affinity surface Ig

  1. Receptors do not form crosslinks
  2. B-cell does not present antigen to T-cell
  3. B-cell dies by apoptosis
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2
Q

Maternal Antibody Protection
- During Pregnancy

A

During Pregnancy
- IgG is transported from placenta to fetal blood (by FcRn)

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3
Q

Maternal Antibody Protection
- At Birth

A

At Birth
- Baby has passive IgG from mother
- Wanes and is at its lowest from 3-12 months old

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4
Q

Fc(gamma)
- Name
- Structure
- Relative binding strength
- Cell type
- Effect of ligation

A
  • CD64
  • 3 segment alpha and a gamma segment
  • Medium binding strength
  • Mainly macrophages. Also Neutrophils, Eosinophils, Dendritic
  • Manages respiratory burst to induce killing of pathogens
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5
Q

Natural targets of Mast Cell granules

A

Parasites like
- Helminth Worms
- Protozoa

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6
Q

Maternal Antibody Protection
- Breast feeding

A

Breast Feeding
- Dimeric IgA in mother’s milk is transferred into the baby’s gut

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7
Q

What is Humoral Immunity

A

Immunity mediated by macromolecules (Antibodies, Complement Proteins)

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8
Q

Process of Formation of C5 Convertase
(Classical Pathway 2/3)

A
  1. C5 binds to C4bC2bC3b (C5 Convertase) and is cleaved into C5a and C5b
  2. C5b then initiates the assembly of the membrane attack complex
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9
Q

What is the Classical Pathway’s C3 Convertase

A

C4b2a

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10
Q

How fast is Mast Cell granule release

A

Very fast response to antigen as granules are prepackaged and just have to release

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11
Q

How are Complement Proteins amplified

A
  • Formation of the Membrane Attack Complex
  • Opsonization, enhances phagocytosis by macrophages
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12
Q

Complement Activation
- What is the Lectin Pathway

A
  1. Lectin (Collectin) Pathway
    Mannose-Binding Lectin binds CHO on the bacteria’s surface leading to complement activation
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13
Q

Fc(epsilon)
- Name
- Structure
- Relative binding strength
- Cell type
- Effect of ligation

A
  • No name
  • 2 segment alpha, a beta segment, a gamma segment
  • Binds for life, very strong
  • Mainly Mast Cells, Also Eosinophils, Basophils, FDCs
  • Secretion of granules
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14
Q

Fc(alpha)
- Name
- Structure
- Relative binding strength
- Cell type
- Effect of ligation

A
  • CD89
  • 2 segment alpha, and a gamma segment
  • Weak binding strength
  • Macrophage, Eosinophils, Neutrophils
  • Uptake induction of killing
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15
Q

When does Complement System occur (Alternative Pathway)

A

Occurs at onset of infection

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16
Q

Erythrocytes and Complement System Process

A
  1. Small Antigen:Antibody complex forms in circulation and activates complement
  2. Immune complex is coated with covalently bound C3b
  3. CR1 on erythrocyte surface binds to C3b-tagged immune complex
  4. Erythrocyte carries immune complex into the liver or spleen
  5. Immune complex is detached and taken up by macrophage
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17
Q

Process of Opsonization

A
  1. Antibody binds to bacteria
  2. The bacterium with the antibody binds to the Fc receptor on the cell surface
  3. Macrophage membrane surrounds bacterium
  4. Macrophage membrane fuses creating the phagosome (a vesicle containing the bacteria)
  5. Lysosome fuses with phagosome to create the phagolysosome
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18
Q

Anaphylatoxins Process

A
  1. Increased permeability allows for more fluid leaked from blood vessels
    - Brings in antibodies and complements into site of infection
  2. Greater migration of macrophages, neutrophils, and lymphocytes from blood into tissue
    - Activity of macrophages and neutrophils increase
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19
Q

Natural Killer Cell Process

A
  1. Antibody binds to antigens on a cells surface
  2. Fc gamma 3 receptors on NK cell recognize the bound antibody
  3. Fc receptors are crosslinked and release a signal to the NK cell
  4. NK cell kills the target cell by Granzymes inducing apoptosis
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20
Q

What cells are Cell-Mediated Immunity

A

T-Cells and NK Cells
- They use cellular interactions

Summary: Cells that destroy bacteria

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21
Q

Complement System function in Alternative Pathway

A

Used in innate immunity
- Proteins are found in blood and lymph

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22
Q

Complement Activation
- What is the Classical Pathway

A
  1. Classical Pathway
    Acquired immune response from antibody interacting and binding to specific antigen on pathogen surface
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23
Q

What is a memory B-cell

A

Long lived antigen specific B-cells

Are re-activated when re-exposed to the same antigen
- Becomes plasma cells as a secondary immune response

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24
Q

Process of Formation of C3 Convertase
(Alternate Pathway 2/2)

A
  1. Surface bound C3b binds Factor B
  2. Factor D cleaves Factor B into Bb and Ba forming C3bBb (C3 Convertase)
  3. Lots of C3 is then cleaved with C3b binding to the microbial surface
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25
Where are the components of the Complement System synthesized?
All synthesized in the liver
26
Where does B cell activation occur
Secondary Lymphoid Tissue
27
Poly Ig function and process
1. Dimeric IgA binds to poly-Ig receptor on basolateral face of epithelial cell 2. Endocytosis of IgA 3. IgA is transported to the apical face of epithelial cell 4. Receptors is cleaved 5. IgA is bound to the mucus by the secretory piece
28
Mechanism of Affinity Maturation of B-Cells, what is the result? (High)
Somatic Hypermutation of Ig genes in rapidly proliferating germinal center B-cells - Germinal Center B-Cells with high affinity surface Ig 1. Helper T cell helps B-cell receptor to crosslink 2. Also helps sustain B-cell proliferation and differentiation 3. B-cell becomes either a memory B-cell of Plasma cell
29
What cells are responsible for endocytosis opsonization
- Neutrophils - Blood Monocytes - Tissue Macrophages
30
What is ADCC, what cells do this
Antibody-Dependent Cell-mediated Cytotoxicity - Done by NK Cells
31
Component Proteins (Regulators)
- C1 Inhibitors (C1-INH, serpin) - C4-Binding Protein (C4-BP) - Decay Accelerating Factor (DAF) - Complement Receptor 1 (CR1) - Protein-S (Vitronectin)
32
Antibody Effector Functions (IgG)
In the spleen/lymph nodes IgM undergoes isotype switching and affinity maturation to become IgG Actively transported from blood to extracellular tissue space (Lamina Propria) to improve delivery of IgG to tissues
33
What are the endpoints that all the Complement pathways converge to
Complement Fixation and phagocytosis - Formation of C3b and/or Cb4 tagging of pathogen surface Membrane Attack Complex - Perforation of pathogen cell membrane
34
Complement System Activation (Alternative Pathway)
35
Benefits of the Complement System (Classical Pathway)
- Opsonization - Phagocyte chemotaxis and activation - Lysis of bacteria and infected cells - Clearance of immune complexes - Clearance of apoptotic cells
36
Process of Formation of soluble C3 Convertase (Alternate Pathway 1/2)
1. C3 is hydrolyzed and forms iC3/C3(H2O) 2. Factors B binds to iC3 3. Factor D cleaves Factor B into Factor Ba and Factor Bb forming Soluble iC3Bb (Soluble C3 Convertase) 4. Soluble iC3Bb cleaves Factor C into C3a and C3b 5. C3b binds to the surface of the microbe
37
Process of Neutralization
1. Virus binds receptor on cell 2. Receptor mediated endocytosis of virus 3. Acidification of endosome causes virus to fuse with cell, causing entry of viral DNA or 1. Bacteria adhesions binds to surface of the bacteria 2. Bacteria is internalized and propagates Neutralization causes antibody to bind to bacteria and prevent it from binding
38
FcRN function and process
1. IgG is endocytosed from the blood by endothelial cells 2. Acidic pH of vesicle causes IgG to associate with FcRn protecting it from proteolysis 3. When it reaches the basolateral face of the endothelial cell the basic pH of the extracellular fluid causes IgG to disociate from FcRN
39
What are Anaphylatoxins
Acts on blood vessels to increase vascular permeability - C3a, C4a, C5a
40
Early Acting Components of Classical Pathway - Which proteins are serine proteases that activate themself or other complement proteins by cleaving a peptide bond
- C1r - C1s - C2
41
What is the Alternative Pathway's C3 Convertase?
C3bBb
42
Where is Complement Receptor 1 found (6)
- Erythrocytes - Macrophages - Monocytes - Polymorphonuclear Leukocytes - B Cells - FDCs
43
What does the Complement System do? Cell or antibody based mechanism?
Induces cytotoxicity of foreign organisms through both cell-mediated and antibody-based mechanisms
44
What are Natural Killer Cells
Large circulating granular lymphocytes - Main role is innate immunity Recognize and kill human cells coated with antibody - Antibody-dependent cell-mediated cytotoxicity
45
Component Proteins (Factors)
B, D, H, I Properdin (P) - Stabilizes C3bBb on microbial surface
46
What are the two mechanisms of Humoral Immunity
1. Neutralizing antibodies that cover the surface of the pathogen - Prevents binding, growth, or replication 2. Opsonizing antibodies that tag pathogens for destruction. - Promotes phagocytosis by macrophage - Use Fc receptors to tag pathogens
47
Early Acting Components of Classical Pathway - Which proteins covalently attach themself to the pathogens surface and to the antigen:antibody complex
- C4 - C3
48
Mechanism Natural Killer Cells use to kill cells
Secrete Granzymes to trigger apoptosis
49
Function of Membrane Co-factor Protein (MCP)
Alternative Pathway - Disrupts and inactivates C3 Convertase C3bBb on human cell surface Done by removing Bb and Protein I cleaving C3b into iC3b
50
What is the Classical Pathway's C5 Convertase
C4b2a3b
51
Component Proteins (Lectins and Proteases)
Mannose Binding Lectin (MBL) MBL Associated Serine Proteases (MASP-1 and MASP-2)
52
Function of Decay Accelerating Factor (DAF)
Alternative Pathway - Disrupts and inactivates C3 Convertase C3bBb on human cell surface Done by removing Bb
53
Function of Factor H
Alternate Pathway - Inactivates C3 Convertase
54
When is a baby most susceptible to infection
3-12 months old - When the baby has lost most of the mother's IgG
55
Natural Killer Cells vs T/B-Cells
NK Cells do not contain any TCR or surface Ig - Express Fc-gamma III receptors for IgG1 and IgG3
56
What cells are Humoral Immunity
B-Cells and Plasma Cells - They release antibodies which can opsonize pathogen - They release antibodies which can neutralize pathogens Summary: Complement proteins that destroy bacteria
57
Function of Properdin
Alternate Pathway - Stabilizes C3 Convertase on microbial surface and protects it from inactivation by Factor H
58
Complement System Overview Process
1. Complement activation from any of the 3 pathways 2. C3b covalently binds to the pathogen surface 3a. Recruitment of inflammatory cells 3b. Opsonization of pathogens causing uptake and killing by phagocytes 3c. Perforation of pathogen's cell membrane 4. Death of pathogen
59
What inactivates the complement system?
Complement protein is heat inactivated
60
Process of Formation of Membrane Attack Complex (Classical Pathway 3/3)
1. C6 binds to and stabilizes C5b 2. C6 then forms a binding site for C7 3. C7 binds to C5b,6 and exposes a hydrophobic region allowing attachment to cell membrane 4. C8 binds to C5b,6,7 and inserts a hydrophobic region into the cell membrane 5. C9 polymerizes on the C5b,6,7,8 complex 6. Forms a membrane-spanning channel 7. This channel can disrupt the cell's integrity 8. Cell death
61
What is the order of the Complement Protein Cascade
C4, C1, C2, C3, C5, C6, C7, C8, C9
62
Maternal Antibody Protection (Distribution)
Mother's Distribution - IgG is spread throughout the body - IgE is located in epithelial cells across the body - Dimeric IgA is in digestive tract - IgM is located on the heart Baby's Distribution - IgG is received from placenta - IgA is received from breast milk
63
When is the Complement System activated?
During an innate immune response through several mechanisms
64
Intrinsic Properties of B-Cells vs Intrinsic Properties of Plasma Cells
B-Cells have - Surface Ig - Surface MHC Class II Plasma Cells have - High-rate Ig secretions
65
Antibody Effector Functions (IgA)
In the spleen/lymph nodes IgM undergoes isotype switching and affinity maturation to become Dimeric IgA - Has greater volume distribution Protects the mucosal surfaces of the body - Epithelia linings of gastrointestinal - Eyes, Nose, Throat (ENT) Dimeric IgA is made in loose aggregates of lymphocytes underlying the mucosal epithelium Facilitates the antibody production in feces, sputum, tears, and other bodily secretions
66
What is the Complement System made up of?
Group of serum glycoproteins - Complement Proteins which are a group of zymogens (inactive form of enzyme)
67
Inducible Properties of B-Cells vs Inducible Properties of Plasma Cells
B-Cells have - Growth - Somatic Hypermutation - Isotype Switching Plasma Cells do not have any of these properties
68
Detriments of the Complement System
- Inflammation - Anaphylaxis
69
Early Acting Components of Classical Pathway - Which proteins noncovalently bind to antigen:antibody complex
- C1q
70
Process of Formation of C3 Convertase (Classical Pathway 1/3)
1. Activated C1s cleaves C4 into C4a and C4b 2. Some C4b binds covalently to microbial surface (C4a goes off and cause inflammation) 3. Activated C1s cleaves C2 into C2a and C2b 4. C2a binds to surface C4b forming Classical C3 Convertase (C4b2a) 5. C4b2a then binds C3 and cleaves it into C3a and C3b 6. C3b binds covalently microbial convertase
71
Maternal Antibody Protection - After Birth
After Birth - IgM is produced soon after birth - IgG is produced at 6 months after birth
72
Effects of Mast Cell granule release
Increase local blood vessel permeability - Increased mucus, runny nose Molecules and cells and fluid can move into the tissues (swelling)
73
What Immunoglobulins protect the internal tissues
IgM, IgG, and monomeric IgA
74
Antibody Effector Functions (IgM)
First antibody produced Secreted as pentamer by plasma cells in bone marrow, spleen, lymph nodes
75
Property of Fc Receptors in Opsonization
- Are specific for antibody isotype - Can express different kinds of Fc receptors that can bind specific Fc regions on antibodies
76
Early Steps of Classical Pathway Process
1. Pentameric IgM binds to antigens on bacteria surface where IgM adopts a flat staple formation 2. C1 (qrs) binds to a single IgM molecule OR 1. IgG binds to antigens on bacterial surface 2. C1q binds to two or more IgG molecules 3. C4 is cleaved by C1s into C4a and C4b 4. C4b contains an exposed nucleophile 5. C4b is attacked by H20 to form an SH and COOH group 6. Soluble C4b OR 5. C4b is attacked by R-OH or R0NH2 to form S and COR group 6. C4b is bound to pathogen surface, R group binds cell surface
77
What are contained in Mast Cell granules
Histamines and other inflammatory mediators
78
Function of Complement Receptor 1
C3b and C4b tag and fix molecules - RBCs can bind tagged immune complexes and clear them out - Phagocytosis is stimulated
79
B Cell Activation Process
1. Endocytosis and Processing of antigen 2. MHC Class II presents antigen 3. CD40 ligand and IL-2 help trigger B-cell 3. CD4 helper 2 cell triggers B-cell clonal expansion and differentiation into antibody secreting plasma cells
80
Complement Activation - What is the Alternative Pathway
2. Alternative Pathway Innate Immune response from interactions with bacterial cell wall polysaccharides

PHARM 310 (8 decks)

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