Complement

Question 1

Complement is a biochemical _______.

Answer 1

pathway/cascade

Question 2

Complement is a key part of the ______ immune system, but it also assists ______ immunity

Answer 2

Complement is a key part of the INNATE immune system, but it also assists ADAPTIVE immunity

Question 3

Complement plays an important part in defense against ______

Answer 3

Pyogenic organisms (bacteria capable of causing local purulent inflammation or generalized infection (pyemia, sepsis). Esp. staphylococci and streptococci

Question 4

Complement _____ the inflammatory response, _____ pathogens, and _____ the immune response

Answer 4

Complement PROMOTES the inflammatory response, ELIMINATES pathogens, and ENHANCES the immune response

Question 5

Complement is a component in both the ______ and ____ of immune complex diseases, such as systemic lupus erythematosus.

Answer 5

Complement is a component in both the PREVENTION and PATHOGENESIS of immune complex diseases, such as systemic lupus erythematosus.

Question 6

What does OIL stand for and why is it relevant to complement?

Answer 6

O: opsonization; I: Inflammation; L: Lysis.

These give the overall big picture function of complement.

Question 7

Opsonization:

Answer 7

Complement activation acts like a glue to attach substances or antibodies to invading organisms to help phagocytosis by PMN’s/macrophages.
[coat organism with C3b to make it easier for organism to be destroyed]

Question 8

Inflammation:

Answer 8

Complement activation induces acute inflammation to dilate blood vessels by activating mast cells/basophils and to recruit inflammatory phagocytic cells to eat the invading organism.

Question 9

Lysis:

Answer 9

Complement activation generates a group of proteins able to penetrate the invading organism’s cell wall to induce lysis.
[poke holes in the membrane]

Question 10

Complement is one of the earliest/latest responses in innate immunity

Answer 10

earliest - complement shows up in serum protein of edema, and activates the C3b protein.

Question 11

What is the most important step of the complement pathway?

Answer 11

The cleavage of C3 into C3a and C3b, because this allows C3b to covalently bind to the pathogen surface

Question 12

Alternative pathway

Answer 12

C3, which is always present in the bloodstream and produced in large amounts by the liver, is proteolyzed into C3b (and C3a). C3b migrates to site of infection in edema fluid, finds organism, and binds the pathogen. Once bound to the pathogen, C3b, in conjunction with fragments D, B, and Bb, forms C3b convertase. The C3 convertase is C3bBb. The convertase cleaves more C3 into C3b (positive feedback look, huge amplification). C3b is also used to form C5 convertase, which converts C5 to C5b (and C5a, a pro-inflammatory peptide). C5b joins C6-9 to form the membrane attack complex, which results in pathogen lysis.

Question 13

C3b acts as an _____ to facilitate phagocytosis by neutrophils and macrophages or further steps results in the generation of the ____ convertase which leads to the late steps of complement activation

Answer 13

opsonin; C5

Question 14

Lectin pathway

Answer 14

A normal serum protein called mannose binding protein (MBP) binds to bacterial surfaces (bacteria have mannose) and becomes activated, giving rise to an enzyme activity identical to activated C1qrs in the classical pathway, called a C1-like complex. This complex/protein, on the surface of a bacterial cell, cleaves C4 into C4a and C4b and cleaves C2 into C2a and C2b. The resulting complex (C4bC2b) is the C3 convertase that cleaves C3 and therefore is another mechanism to generate C3b and the subsequent C5 convertase (C4b2bC3b). This can then generate C5b, which will combine with C6-C9 to generate the MAC and cause lysis.

Question 15

Classic Pathway:

Answer 15

Activation of the classical pathway is the third pathway for complement activation when the host is exposed to the microbe for the first time because antibodies secreted by plasma cells take a few days to develop. Once generated, they can recognize and bind to the bacteria. This bound antibody to the surface of the microbe is the platform for complement activation. C1 is present in the plasma in an inactive form. The classical pathway of complement is initiated by the binding of C1 to the Fc portion of antibody. IgM and IgG subclasses 1, 2, and 3 can efficiently activate complement. Binding of C1 to Ig presumably produces a conformational change in C1 leading to the activation of C1r and C1s. C1r cleaves and activates C1s, which cleaves the next two components, C2 and C4 to produce C3 convertase. Then proceeds the same as alternative/lectin.

Question 16

Complement has __ starting points that merge into a common pathway (explain).

Answer 16

3 starting points:

1. Classical pathway (C1qrs, C2, and C4).
2. Alternative pathway (C3, factors B, D, and properdin).
3. Lectin pathway (plasma derived mannose-binding lectin or MBL).

Question 17

The classical pathway is triggered by interaction of the Fc portion of an antibody (___, ___, ___, ___) or C-reactive protein with ____.

Answer 17

The classical pathway is triggered by interaction of the Fc portion of an antibody (IgM, IgG1, IgG2, IgG3) or C-reactive protein with C1q.

Question 18

Anaphylatoxins:

Answer 18

Source of vasoactive mediators that increase vascular permeability.
(C3a, C4a, C5a)

Question 19

Chemoattractants:

Answer 19

Attract neutrophils and monocytes (C3a, C5a)

Question 20

What is the final phase of complement?

Answer 20

The assembly of the membrane attack complex (MAC). Components C5b-9 form a polymeric complex. MAC exerts powerful killing activity by creating perforations in cellular membranes.

Question 21

Microbes coated with C3b are phagocytosed by virtue of C3b being recognized by _______.

Answer 21

complement receptor type 1 (CR1)

Question 22

C3a, C4a, and C5a are chemotactic for ______, stimulate the release of ________ from various leukocytes, and act on endothelial cells to enhance movement of _______ and _______ into tissues.

Answer 22

C3a, C4a, and C5a are chemotactic for NEUTROPHILS, stimulate the release of INFLAMMATORY MEDIATORS from various leukocytes, and act on endothelial cells to enhance movement of LEUKOCYTES and ENDOTHELIAL CELLS into tissues.
[basically are super important in notifying the neutrophils where the site of infection is and getting them there to help destroy bacteria]

Question 23

MAC can induce ______ lysis of cells, including microbes. MAC-induced lysis is effective only against microbes that have _____ cell walls, such as the Neisseria species.

Answer 23

MAC can induce OSMOTIC lysis of cells, including microbes. MAC-induced lysis is effective only against microbes that have THIN cell walls, such as the Neisseria species.

Question 24

Key timing differences in alternative, lectin, and classic pathways:

Answer 24

Always have C3 in blood to activate alternative pathway, and always produce lectin binding proteins. These act quickly when an invasion occurs. Classic pathway takes time because need an antibody to bind to surface proteins on the bacteria to activate it.

Question 25

How is the complement system regulated?

Answer 25

1. Early pathway inhibitors,
2. Regulators of the C3 convertase,
3. Inhibitors of MAC

Question 26

Early pathway inhibitors (regulation of complement)

Answer 26

C1 inhibitor (C1INH) in human serum can inhibit the proteolytic functions of C1r and C1s, thus preventing the onset of the classical pathway and needless generation of potentially dangerous vasoactive compounds (C4a, C3a, C5a).

Question 27

Consequences of C1INH defects:

Answer 27

C1INH is responsible for regulating the classical pathway. Patients lacking C1INH develop a syndrome/disease called hereditary angioedema. C1INH also down-regulates the protease involved in bradykinin generation. Thus, C1 INH deficiency leads to uncontrolled complement activation and to excess bradykinin, producing angioedema.

Question 28

Regulation of C3 convertase (regulation of complement pathway):

Answer 28

This is a major point of complement downregulation.  
C3 convertase (C3bBb complex) is formed normally. In regulation, the decay accelerating factor (DAF) binds and displaces C3b from Bb. Then, MCP (or CR1) acts as a cofactor for Factor 1-mediated proteolytic cleavage of C3b.

Question 29

Patients with a DAF deficiency have:

Answer 29

Uncontrolled complement activation that leads to RBC lysis, which is paroxysmal nocturnal hemoglobinuria (PNH)

Question 30

C3 deficiency:

Answer 30

C3 is major opsonin. Deficiency results in profound risk of recurrent pyogenic infections, especially with encapsulated bacteria

Question 31

C5b, C6, C7, C8, C9 deficiency:

Answer 31

Increased susceptibility to Neisseria infections. Severe pyogenic infections and sepsis occur in children and neonates with a deficiency in MAC component.

Question 32

C1, C2, C4 deficiency:

Answer 32

Associated with increased risk of immune complex disease, SLE. (usually do not predispose patients to severe infections)

Question 33

C1-inhibitor deficiency:

Answer 33

Excess of vasoactive peptides (bradykinin) generated. Results in hereditary angioedema.

Question 34

CH50 Assay:

Answer 34

Ability of patient serum to lyse sensitized RBCs coated in antibody is evaluated. If the patient serum has a full constellation of fully functional complement components (classical pathway), the rabbit RBCs will rapidly be lysed. If the patient serum is missing (genetic lesion or particularly low concentration of one or more components because components are being used up in the patient), the sensitized RBCs will not lyse.

Question 35

AH50 Assay:

Answer 35

Similar to CH50, but tests Alternative pathway. Might order this if the classical test was negative but patient presentation strongly suggests complement pathway defect.

Question 36

Neisseria meningitidis:

Answer 36

Gram negative diplococci, only found in humans. Most commonly see meningococcemia, meningitis, also arthritis, conjunctivitis, and pericarditis. Treat with ceftriaxone (or penicillin). Antibiotic prophylaxis for close pt contacts are important.

Question 37

What is the major virulence factor of Neisseria meningitidis?

Answer 37

The polysaccharide capsule - the capsule and coating of IgA help evade complement activation in humans.

Question 38

Risk factors for meningitis:

Answer 38

• Asplenia;
• Deficiency in terminal complement or properdin (also other complement components; puts you at risk or encapsulated bacteria);
• Higher exposure risk (military, college freshman in dorm, microbiologist, foreign traveler)

Question 39

Invasive meningococcal (Neisseria meningitidis) disease and disseminated gonococcal (Neisseria gonorrheae) infections are the only conditions (i.e. no autoimmune diseases) known to be associated with complement deficiencies in:

Answer 39

C5-C9 (terminal complement deficiency).

In this case, C8.

Question 40

The three main anatomic locations involved in attacks of hereditary angioedema are:

Answer 40

Skin, upper airway, GI tract

Question 41

Pathogenesis of angioedema in hereditary angioedema is predominately mediated by excess:

Answer 41

bradykinin

Question 42

During an episode in a patient with hereditary C1 inhibitor deficiency, we would expect C1INH and C4 levels to be low, high, or normal?

Answer 42

Low C4, Low C1INH.

Question 43

Describe the genetic inheritance pattern of Hereditary Angioedema:

Answer 43

Autosomal dominant with variable penetrance