Medical Microbiology I > The Complement System > Flashcards

The Complement System Flashcards

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1
Q

3 lines of protection

A
  • Natural barriers
  • Innate, antigen-nonspecific immune defenses
  • Adaptive, antigen-specific immune responses
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2
Q

Natural barriers

A
  • Skin, mucosal surfaces, acid of the stomach

- Prevent invasion by most microbes

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3
Q

Innate, antigen-nonspecific immune defenses

A
  • Soluble Components

- Cellular Components

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4
Q

Soluble components of innate, antigen-nonspecific immune defenses

A
  • Soluble antimicrobial molecules
  • Defensins
  • Complement components
  • Type 1 interferons
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5
Q

Cellular components of innate, antigen-nonspecific immune defenses

A
  • Phagocytes
  • Monocytes
  • Macrophages
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6
Q

Skin barrier defenses

A
  • Dry environment

- Fatty acids – organisms & sebaeous glands

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7
Q

Mucous membrane barrier defenses

A
  • Ciliated epithelial cells

- Alveolar macrophages

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8
Q

Eye barrier defenses

A
  • Tears

- Lysozyme

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9
Q

Acidic environment barriers

A
  • GI tract - bile

- Bladder, kidneys

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10
Q

Lysozyme function

A
  • Catalyzes hydrolysis of bacterial peptidoglycan
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11
Q

Lysozyme source

A
  • Tears, saliva, nasal secretions, body fluids, lysosomal granules
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12
Q

List of soluble factor examples

A
  • Lysozyme
  • Lactoferrin, transferrin
  • Lactoperoxidase
  • B-Lysin
  • Chemotactic factors
  • Properdin
  • Lectins
  • Cationic peptides
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13
Q

Lactoferrin, transferrin function

A
  • Bind iron and compete with microorganisms for it
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14
Q

Lactoferrin, transferrin source

A
  • Specific granules of PMNs
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15
Q

Lactoperoxidase function

A
  • May be inhibitory to many microorganisms
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16
Q

Lactoperoxidase source

A
  • Milk and saliva
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17
Q

B-Lysin function

A
  • Effective mainly against gram-positive bacteria
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18
Q

B-Lysin source

A
  • Thrombocytes, normal serum
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19
Q

Chemotactic factors function

A
  • Induce directed migration of PMNs, monocytes, and other cells
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20
Q

Chemotactic factors source

A
  • Complement and chemokines
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21
Q

Properdin function

A
  • Activates complement in the absence of ab-aq complex
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22
Q

Properdin sources

A
  • Normal plasma
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23
Q

Lectins function

A
  • Bind to microbial carbohydrates to promote phagocytosis
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24
Q

Lectins source

A
  • Normal plasma
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25
Cationic peptides function
- Disrupt membranes, block cell transport activities
26
Cationic peptides source
- Polymorphonuclear granules (defensins)
27
Complement system definition
- Collection of circulating and cell membrane proteins | - Play important roles in host defense against microbes
28
Complement system is part of the innate immune system
- Not adaptable & does not change over time - Can be recruited & brought into action by the adaptive immune system - Alarm system, weapon against infection (especially bacterial)
29
Complement system name origin
- Complement = ability of these proteins to assist (complement) the antimicrobial activity of antibodies
30
Goal of complement system
- Elimination of microbes during innate and adaptive immune responses
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Functions of complement system
- Opsonization of microbes - Complement-mediation cytolysis - Stimulation of inflammatory reactions
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Opsonization
- Promotes phagocytosis of microbes for recognition by receptors on phagocytes
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Complement-mediation cytolysis occurs by
- Formation of membrane attack complex
34
3 pathways of complement activation
- Alternative Pathway (alternate, properdin) - Lectin Pathway (mannose binding) - Classical pathway
35
Alternate and lectin pathway initiation
- Initiated by microbes and microbe products in the presence of antibody
36
Classical pathway initiation
- Initiated by certain isotypes of antibodies attached to antigens (antigen-antibody complexes)
37
The three activation pathways of complement coalesce at a common junction point
- Activation of C3 component
38
Chemotactic factors are produced by
- Activation by either pathway | - Initiates a cascade of proteolytic events that produce them
39
Chemotactic factors functions
- Attract phagocytic & inflammatory cells to the site | - Increase vascular permeability to allow access to site of infection
40
Chemotactic factors bind to
- The agent to promote their phagocytosis (opsonization) and elimination
41
Most abundant complement protein in the plasma
- C3 | - Plays central role in all pathways
42
The sequence of events of activation
- Similar in all 3 pathways - Differ in their requirement for antibody - Differ in some of the proteins used in the process
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Common goal of classical, alternate, and lectin pathways
- Cleavage of C3 and C5
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C3a and C5a
- Provide chemoattractants and anaphylotoxins
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C3b
- Resposable for attachement to microbes | - An opsonin that adheres to membranes, and to initiate the membrane attack complex to kill cells
46
Alternate pathway activation
- Activated directly by bacterial cell surfaces and their components (endotoxin, microbial polysaccharides)
47
C3 hydrolyzation
- Spontaneously hydrolyzed in plasma at a low level to C3b | - Products are unstable unless deposited on the surface of a microbe
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The alternate pathway can be activated before
- Establishment of an immune response to infecting bacteria - Does not depend on antibody - Does not involve the early complement components (C1, C2, and C4)
49
Initial activation of the alternate pathway is mediated by
- Properdin factor B binding to C3b
50
Properdin factor D
- Splits factor B in the complex which yields the Bb active fragment - C3bBb - C3 convertase
51
C3bBb - C3 convertase
- C3b sticks to the cell surface and anchors the complex of proteins - Inactive Ba is split from this complex
52
Inactive Ba split from the C3bBb complex leads to
- Cleavage and activation of many C3 molecules (amplification of response)
53
Lectin pathway initiation
- Initiated in the absence of antibody by attachment of plasma mannose-binding lectin (MBL, mannose-binding protein MBP)
54
Mannose-binding protein (lectin)
- Large serum protein | - Binds to non-reduced mannose, fucose, & glucosamine on bacterial, fungal, & other cell surfaces
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MBL is structurally similar to
- Component of C1q of the classical complement pathway that activates C4
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MBL binds to bacterial surfaces & activates
- Cleavage of mannose-binding protein-associated serine protease (MASP)
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MASP cleaves the C4 and C2 components to
- C3 convertase - Junction point of the complement cascade - Subsequent steps same as other pathways
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MBP resembles and replaces
- C1q component and on binding to bacterial surfaces | - Activates the cleavage of MASP
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Classical pathway initiated by
- Binding to the Fc portion of antibody that is bound to cell surface antigens - An immune complex with soluble antigens
60
Aggregation of antibody isotypes IgG or IgM (not IgA or IgE) in the classical pathway
- Changes the structure of the heavy chain to allow binding to complement
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C1 complement protein in classical pathway binds to
- 2 adjacent Fc regions - 2 IgG molecules - 1 pentameric IgM molecule
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Classical pathway C1 complex
- Recognition unit composed of 3 proteins (C1q, C1r, C1s) - C1q bind to 2 Ig molecules - C1r & C1s are serine proteases
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Active C1s cleaves
- C4 & C2 - C4 to C4a & C4b - C2 to C2a & C2b
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C4b & C2b
- Active binding portion of protein | - C4b2b – C3 convertase
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C4b2b – C3 convertase in the classical pathway
- Binds to cell membrane - Cleaves C3 to C3a & C3b - Amplifies the response by splitting many C3 molecules - C3b binds to cell surface to remain active
66
C43b2b in the classical pathway forms on
- Cell membrane – C5 convertase | - C5 split into C5a & C5b
67
Early steps of complement activation are similar in all 3 pathways
- C3b binds to microbes in the alternate pathway to form C3 convertase complex - C4b2b binds to the microbe in the classical and lectin pathways to form C3 convertase complex - Cleavage of C3 central to all pathways to form C5 convertase
68
Cleavage of the C3 and C5 components produces important factors that
- Enhance clearance of the infectious agent - Promote access to the infection site - Attracting the cells that mediate protective inflammatory reactions
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C3b is an opsonin that promotes clearance of bacteria by
- Binding directly to the cell membrane | - Makes the cell more attractive to phagocytic cells (neutrophils and macrophages that have receptors for C3b)
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C3b can be cleaved further to generate
- C3d | - Activator of B lymphocytes
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In humoral immunity, complement activation is the
- Relevant innate immune response | - C3d is the second signal for B lymphocytes, analogous to the co-stimulators of APCs for T lymphocytes
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B lymphocytes express a receptor
- Type 2 complement receptor (CR2, or CD21) | - Binds C3d
73
B cells that are specific for a microbe's antigens recognize the antigen by
- Ig receptors - Simultaneously recognize the bound C3d by the CR2 receptor - This greatly enhances antigen-dependent activation responses of B cells
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C3a and C5a - powerful anaphylatoxins that stimulate mast cells to
- Release histamine | - Enhances vascular permeability & smooth muscle contraction
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C3a and C5a also act as attractants for
- Neutrophils | - Macrophages
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The terminal stage of the classical pathway involves creation of the
- Membrane attack complex (MAC) | - Also called the lytic unit
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Membrane attack complex
- 5 terminal complement proteins (C5 through C9) associate on target cell membranes to mediate injury
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The C9 component of MAC
- Similar to perforin, which is produced by cytolytic T cells and natural killer cells
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Cell lysis by complement
- Activation of C5 initiates the molecular construction of an oil-well-like membrane attack complex (MAC) - C9 resembles perforin (natural killer cells and cytotoxic T cells) to promote apoptosis in the target cell
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Last steps of complement activation (formation of MAC)
- Start after formation of the C5 convertase - Identical in all pathways - C5a induces inflammation - (C5b,6,7,8)1(C9)n complex forms
81
(C5b,6,7,8)1(C9)n complex
- Drills a hole in the membrane | - Leads to the hypotonic lysis of cells
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Humans have several mechanisms for preventing generation of the C3 convertase to
- Protect against inappropriate complement activation
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Mechanisms for preventing generation of C3 convertase to prevent inappropriate complement activation
- C1 inhibitor - C4 binding protein - Factor H - Factor I - Cell surface proteins (decay-accelerating factor (DAF) and membrane cofactor protein)
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CD59 (protectin) prevents
- Formation of the membrane attack complex (like a stop sign)
85
Most infectious agents lack
- Protective mechanisms and remain susceptible to complement
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The complement system is a collection of
- Circulating and cell surface proteins | - Important in host defense
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The complement system may be activated
- On microbial surfaces without antibodies (alternative and lectin, components of innate immunity) - After the binding of antibodies to antigens (classical pathway, component of adaptive humoral immunity)
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Complement proteins are sequentially cleaved, & active components, mainly C3b, become
- Covalently attached to the surfaces on which complement is activated
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The late steps of complement activation lead to the formation of the
- Cytolytic membrane attack complex
90
Different products of complement activation
- Promote phagocytosis of microbes - Induce cell lysis - Stimulate inflammation
91
Mammalian cells express surface and circulating regulatory proteins that
- Prevent inappropriate complement activation on host cells
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