1
Q
- What type of cells can be lysed by complement?
- What happens to the other cells?
A
- relatively fragile cell types
Gram negative bacteria and RBCs - they are opsonized
2
Q
Complement
- how many different proteins are there?
- what organs/cells produce it?
A
- About 35 different proteins
- Synthesized by the liver, monocytes, macrophages and epithelial cells
3
Q
Complement
- when can synthesis increase
- when can the levels decrease?
A
- increases in acute inflammation so the levels of complement components can rise
- In chronic inflammation or in liver disease the levels can decrease
4
Q
How does complement help the host fight infection chemically?
A
- Lysis, opsonization, chemotaxis, leukocyte activation
5
Q
- What type of cells does complement clear from the body?
- What pathway does it interact with?
A
- Clearance of immune complexes
- Clearance of apoptotic cells
- Interacts with the coagulation pathway
6
Q
Functions of Complement
- what role does it play in innate and acquired immunity?
A
Helps join the forces of the innate immune system with the acquired immune system
7
Q
Functions of Complement
- what role does C3b and C4b have on the innate/acquired immune system?
A
- C3b, C4b, and other fragments have roles in the activation of B cells and antigen presenting cells
- Enhances memory through interactions with B cells and follicular dendritic cells
8
Q
Complement activation pathways
- what are the three pathways?
- what do the pathways all lead to?
- what complement fragment do all of these pathways activate?
A
Pathways
- Classical pathway
- Alternative pathway
- Lectin pathway
- All lead to cell lysis
- Three different ways to activate C3
9
Q
Complement activation pathways
- what happens after C3 is activated?
A
- After the activation of C3 all pathways converge and activate components C5–9 in succession
10
Q
Complement components
- how are they identified?
- how are they activated?
- how are they written once activated?
A
- Numbered
- Activated by one or more of the activated components before it
- Activated complex is denoted by a bar over the top
11
Q
Functions of Complement: cleavage
- what happens to the cleaved product pieces?
- how is each piece named?
A
- Larger cleavage product lands on the cell that initiated the activation, smaller piece floats away
- When the component is broken into two pieces the pieces are called a and b (i.e., C3a and C3b)
- Further breakdown forms other pieces like C3d
12
Q
Complement conventions
- which piece of the cleaved complement tends to “float away”?
- where does it go?
- what is the exception to this convention?
A
- The piece that floats away and has its biological activities in solution is the “a” component
- Exception is C2; C2a lands on the surface of the cell and C2b floats away
13
Q
What is a convertase and how is it labeled?
A
- A component that has enzyme activity and effects the next piece is called a convertase, as in C4bC2a is called C3 convertase
14
Q
Classical pathway
- how is it initiated?
A
- Initiated by antibody bound to antigen
- - Activated by IgM and the IgG subclasses, IgG3, IgG1 and IgG2 (in order of their efficiency)
15
Q
Classical pathway
- what happens after the antibody binds to the antigen?
A
- After antibody binds to antigen, a conformational change occurs
- Reveals a site on the antibody molecule that binds the C1q molecule
16
Q
Classical pathway
- aside from Ab-Ag bonding, how can C1q be activated?
A
- C-reactive protein
- some gram negative bacteria including E. coli
- several viruses
- some protozoa
- some mycoplasmas
- factor XXIIa of the coagulation pathway
17
Q
Formation of C3 Convertase: Classical pathway
- how does it happen?
A
- Combination of the acquired (antibodies) and the innate (complement proteins) immune systems to destroy bacteria
18
Q
Formation of C3 Convertase: Alternative pathway
- how does it happen?
- what are some examples?
A
- Microorganisms and certain structures called activator surfaces can directly interact and initiate the complement cascade
- LPS in bacterial cell walls, fungi, viruses
- Some parasites including trypanosomes, endotoxins
- Aggregated IgG2, IgA, IgE are all activator surfaces
19
Q
Formation of C3 Convertase: Lectin pathway
- how does it happen?
A
- Either MBL or serum ficolin bind to surface terminal carbohydrates that have either mannose or N-acetylgalactosamine as a nonreducing terminus on the pathogen
- MASP-2 binds to the MBL and cleaves C2 and C4, creating C2a and C2b and C4a and C4b
- C2b and C4a diffuse away and C2aC4b forms C3 convertase
20
Q
Complement system
- what type of pathogens does it clear?
- increase or decrease inflammation?
A
- Clears
- Bacteria
- Viruses
- Immune complexes
- Increases inflammation
21
Q
Complement system
- what happens if left unchecked?
- where are the controls located?
A
- Left unchecked can cause severe cell and tissue damage
- Controls in the fluid phase and on the cell surfaces
22
Q
- What is DAF?
- Where is it found?
- What does it do?
A
- Decay-accelerating factor/CD55
- On most cells
- Keeps cells from being hurt by bystander lysis
23
Q
Measurement of Components
- what are the two types of assays and what do they measure?
A
- Antigenic assays
- Measure the amount of each protein using traditional serologic assays
- Functional assays
- Lytic function of the components is measured
24
Q
Functional Assays
- what are the two types and what do they measure?
A
CH50 assay
- Measures the function of complement initiated through the classical pathway
- Srbc lysis and hemoglobin measurement
- Newer test measures neoantigen formation with formation of Membrane Attack Complex
AH50 assay
- Measures the function of complement initiated through the alternative pathway
25
AH50 assay
- how is it performed?
- how is it measured?
- Rabbit red blood cells are mixed with the serum
| - Amount of hemoglobin released by the cells is proportional to amount of alternative pathway activity
26
What components are required by the CH50 assay?
- C3
- C5 through C9
- C1
- C2
- C4
- C1 INH
27
What components are required by the AH50 assay?
- C3
- C5 through C9
- Factor B
- Factor D
- Properdin
- Factor H
- Factor I
28
Antigen Assays: Serologic tests
| - how can individual components be measured?
- by radial immunodiffusion
29
Antigen Assays: Serologic tests
- what does an increased C4a mean?
- what does an increased Bb mean?
- how is terminal pathway activation measured?
- Increases in C4a indicates complement activation (classical or lectin pathway)
- Increases in Bb indicates complement activation (alternative pathway)
- Terminal pathway activation can be measured by measuring C3a, C5a and SC5b-9
30
Antigen Assays
- what can cause high complement levels?
- what can cause low complement levels?
High Complement levels
- Acute inflammation can raise C levels
Low Complement levels
- Genetic deficiencies
- Chronic infection
- Incorrectly processed serum samples
- - obtain in a red top
- - separate, freeze, and store at -70°C
31
Complement Deficiencies
| - what do deficiencies in C1, C4, and C2 recognition increases risk of ?
- Autoimmune connective tissue diseases such as SLE
| - Recurrent infections with Staphylococcus and Streptococcus
32
Complement Deficiencies
| - what are deficiencies in the lectin pathway associated with?
- Associated with bacterial infections in infants
33
Complement Deficiencies
| - what are deficiencies in the C1 INH pathway associated with?
- Involved in inhibiting both the classical and lectin pathways
- Can cause hereditary angioedema, rapid swelling of the effected site
34
Complement Deficiencies
| - what do deficiencies in C3 effect?
- Profound affect all pathways
- Decrease Phagocytosis
- Decrease Immune complex clearance
- Decrease class switching from IgM to IgG
35
Complement Deficiencies
| - what do deficiencies in the alternative pathway effect?
- Related to pus forming infections
36
Complement Deficiencies
| - what happens when there are deficiencies in terminal components (MAC)?
- Severe Neisseria meningitides infections
| - SLE
37
Complement Deficiencies
| - what do deficiencies in DAF and CD59 effect?
- Paroxysmal nocturnal hemoglobinuria
| - Anemia
Immunohematology and Serology
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