Lecture 5

Question 1

What is complement? (C’)

Answer 1

Complement is one of the first weapons of the immune system to be mobilized against a pathogen.

Consists of a system of circulating and cell membrane proteins

Made constitutively by the liver

Present in the blood, lymph, and extracellular fluid

Question 2

what functions does complement have? (slide 5 IMAGE)

Answer 2

1. Innate immunity
2. Disposal System
3. Adaptive Immunity

Question 3

Complement activation

Answer 3

occurs by a series of enzymatic reactions, in which each enzyme cleaves and activates the next component of the pathway, eventually forming effector molecules that participate in eliminating microbes.

Question 4

zymogens.

(IN TERMS OF COMPLEMENT)

Answer 4

Many complement components are proteolytic enzymes that circulate in inactive forms, called zymogens.

Question 5

C-activation:

Answer 5

cleavage of C proteins such that they gain effector function and interact with the next component of the pathway.

Question 6

C-fixation

Answer 6

The binding of active serum complement to an antigen-antibody pair, or the microbial cell surface.

Question 7

Convertase/esterase

Answer 7

altered C-protein which acts as a proteolytic enzyme for another C-component

Question 8

Hemolytic units (CH50

Answer 8

used to quantify complement activity, the dilution of serum which lyses 50% of a standardized suspension of Ab-coated red blood cells.

Question 9

Amplification

Answer 9

Amplification of the C’ pathway allows an initially small number of activated C’ proteins to generate a large number of effector molecules.

Question 10

Fx of complement once it has been activated

Answer 10

Once activated, one of the main functions of complement proteins is to coat the surface of bacteria and extracellular virus particles, making them more easily phagocytosed. Thus, many activated complement components serve as opsonins.

Question 11

Complement mediated cytolysis

Answer 11

Help in the formation of the membrane attack complex (MAC)

this leads to the Osmotic lysis of bacteria (poked a lot of holes into the cell

Question 12

3 pathways for complment

Answer 12

alternative
lectin
classical

Question 13

alternative

Answer 13

The pathway that is activated during the early innate response to infection is the alternative pathway.

Question 14

lectin pathway

Answer 14

The lectin pathway also acts during the innate response, however, it requires time to gain strength.

Question 15

classical (anitbodies needed)

Answer 15

The classical pathway is initiated by antibodies attached to microbial antigen, and thus is considered a component of the humoral arm of adaptive immunity.

Question 16

what is central to all 3 pathways?

Answer 16

Central to all C’ pathways is the cleavage of the complement component, C3

Cleavage of C3 results in the formation a small C3a fragment and a large C3b fragment.

The C3b fragments become covalently bound to the pathogen’s surface, serve as an opsonin

The soluble C3a fragment acts as a chemo-attractant for effector cells and activates mast cells to release vasoactive chemicals.

Question 17

Unique proteins in the ALTERNATIVE PATHWAY

Answer 17

1. Factor B
2. Factor D
3. Properdin (helps to stabilize)

if you see elevated levels of these in blood or in tissues, can assume that the alternative pathway of complement is underway

Question 18

Mannose binding lectin (MBL

Answer 18

Mannose binding lectin (MBL) is an acute phase reactant produced by the liver during periods of inflammation.

human cells dont have the mannose residue—but microbial cells do!!

required in the Lectin Pathway

Question 19

Lectin Pathway

Answer 19

Initiated in the absence of antibody
requires the binding of circulating lectins [such as mannose-binding lectin (MBL)] to microbial polysaccarides.
Shares proteins of the classical complement pathway, but because it is initiated by a microbial product, it is a component of innate immunity.

Question 20

C4bC2a complex

Answer 20

aka the C3 convertase nin the Lectin pathway—this will breakdown a lott of C3 into the a and b parts

Question 21

c5 Convertase

Answer 21

initiates the late steps in C’ activation

Question 22

what are the only antibodies that can activate complement?

Answer 22

IgG and IgM

Question 23

What is the overall result or purpose of the complement pathways

Answer 23

Whether by the alternative, lectin or classical pathway, the net result of these early steps of C’ activation is that microbes acquire a coat of covalently attached C3b, which acts as an opsonin.

Question 24

C3b attracts….

slide 26

Answer 24

Phagocytes, neutrohils, macrophages have a receptor for C3b and make it a marker/easoer for the junk to be phagocytosed

Question 25

What and who is an anaphlotoxin

Answer 25

C5a
c3a
C4a

these activate the inlam response and recruit Mast cells to bring histamine and degranulate and release it

C5a and C3a are most powerful

Question 26

Explain how MAC (Membrane attack complex) is formed

Answer 26

The C5 convertase formed during the early stages cleaves C5 into C5a and
C5b.
The remaining components (C6-C9) bind sequentially to C5b.
The final protein in the pathway, C9, polymerizes to form a pore in the cell
membrane (called the membrane attack complex, MAC), through which water
and ions can enter, causing the cell to rupture

Question 27

what is uniqur about the late steps of complment?

Answer 27

The late steps of complement activation are the same for all three pathways.

Question 28

Clinical Correlation: Complement Deficiencies

Answer 28

Hereditary deficiencies have been described for virtually all components of the complement system.
Defects in complement can result in immune complex disease in affected individuals. Why?
C3 deficiencies are usually fatal, resulting in recurrent severe bacterial infections. Why?

Question 29

Why are C3 def usually fatal?

Answer 29

C3 deficiencies are usually fatal, resulting in recurrent severe bacterial infections. Why?

because the C3 is common to all 3 complment pathways. without it you wouldnt be able to mount a response with complment via the innate immune system

Question 30

recurrent Neisserial infections….

Answer 30

Terminal Component Defects
C5-C9 are required for the assembly of the membrane attack complex.
A deficiency of these late-acting components causes an increased susceptibility to recurrent Neisserial infections.

Question 31

Why Neisseria?

Answer 31

These bacteria have thin cell walls and are especially susceptible to the lytic actions of complement.

MAC isn’t working!!!

Question 32

C1-inhibitor def

Answer 32

Hereditary angioedema
Hereditary angioedema is caused by excessive C1 activation and subsequent activation of the kinin system.

An inherited deficiency in the production of C1 INH (a.k.a. C1 esterase inhibitor)

Presents as: unpredictable and recurrent episodes of periodic swelling in subcutaneous or submucosal tissue at various anatomical locations.

Question 33

C1 inhibitor

Answer 33

C1 Inhibitor (C1 INH) stops activation of the classical pathway by interfering with the C1q component.

Question 34

Factor H

Answer 34

Fx:
causes dissociation of alternative pathway C3 convertase subunits

co-factor for Factor 1-mediated cleavage of C3b

Question 35

C1 (C1qr2s2)

Answer 35

only found in the classical pathway.

is the intiator of the classical pathway

binds to the antibody

binding leads to the activation of C4 and C2

C4 and C2 will go on to make the C3 convertase complex for the classical pathway

Question 36

C4

Answer 36

only found in the classical and the lecitin pathways