Complement

Question 1

functions of complement

Answer 1

lysis
opsonization
activation of inflammatory response
clearance of immune complexes

Question 2

describe the classical pathway

Answer 2

• Ab (IgM or 2 IgG) binds C1q
• C1r C1s (2 of each) bind C1q - Ca2+
• C4, C2 - C4bC2a (C3 convertase) - Mg 2+
• C3 activated & C3b binds = amplification
• C4bC2aC3b = C5 convertase
• C5b678-C9 = MAC
• split off products = C3a, C4a, C5a

Question 3

describe the alternative pathway of complement

Answer 3

• no Ab involved
• spontaneous hydrolysis of C3
• fluid phase (plasma) and cell bound
• sialic acid on host cell inactivates C3b
• proteins involved = factor B, D (serine protease), Properdin

Question 4

pathogen activators of alt pathway

Answer 4

gram neg = LIPOPOLYSACCH
gram pos = teichoic acid
fungi & yeast cell wall = zymosan
some viruses

Question 5

non-pathogen activators of alt pathway

Answer 5

IgG, IgA, IgE
cobra venom
pur carbs (agarose, inulin)
anionic polymers = dextran sulphate

Question 6

describe the lectin pathway

Answer 6

• lectins acute phase reactants produced in liver = collectins
• mannose-binding lectin (MBL)
  > mannose, N-acetyl glucosamine, D-glucose, L-fucose
• proteins involved = MBL, MBL-associated serine proteases = MASP1, MASP2, MASP3

Question 7

what happens in the lectin pathway?

Answer 7

MBL binds CHO residues on microbes
MASP binds and is activated
C4 C2 cleaved to C4BC2a
C3 activated

Question 8

pathogens with D-mannose, L-fucose

Answer 8

gram neg = Salmonella
gram pos = Streptococci
yeast = C. albicans
viruses = influenza A, HIV
parasites = Leishmania

Question 9

complement receptors

Answer 9

bind complement coated organisms to aid in clearance
- used in conjunction with regulator proteins (PROTECT HOST CELLS)
- amplify B cell signal
- used by some pathogens to enter cell

Question 10

examples of complement receptors

Answer 10

CR1
CR2
CR3/4

Question 11

CR1

Answer 11

• aid phagocytosis by monocytes, macs, and neuts
• binds C3b, C4b
• help with immune complex clearance via rbc delivery to spleen
• required for factor I to function
• receptor for P. falciparum

Question 12

CR2

Answer 12

• co-receptor on B cell surface
• amplification signalling with associated CD19 and CD81 (TAPA-1)
• EBV uses CR2 as receptor

Question 13

CR3 and CR4

Answer 13

CD11b/c/CD18 integrins
- aid phagocytosis by monos, macs, neuts
- help neuts and monos with extravasation
- present on NK cells

Question 14

describe the three components of complement regulation

Answer 14

• inhibitors regulate complement cascade = localize activation, protect host
• soluble (plasma proteins)
• membrane bound (host clls and some pathogens)

Question 15

list the soluble complement inhibitors

Answer 15

C1-inhibitor (C1-Inh)
factor H
factor I

Question 16

describe C1-Inh

Answer 16

binds C1r2s2 and dissociates from C1q

Question 17

describe factor H

Answer 17

• prevent binding of B to hydrolyzed C3 (C3H2O) and C3b
• acts as a cofactor for factor I

Question 18

describe factor I

Answer 18

• cleaves C3b into C3d + C3c
• cleaves C4b into C4d + C4c
• requires help = cofactor (CR1, factor H, CD46)
• also called C3 inactivator

Question 19

membrane-bound complement inhibitors

Answer 19

DAF
MIRL

Question 20

describe DAF

Answer 20

decay-accelerating factor
- CD55
- inactivates C3 convertases

complement needs to bind in close proximity to CD55?

Question 21

describe MIRL

Answer 21

membrane inhibitor of reactive lysis
- CD59
- binds C5b678 preventing C9 insertion
- AKA protectin

Question 22

early complement deficiencies

Answer 22

C1q, C1r, C1s, C4, C2

Question 23

middle complement deficiencies

Answer 23

C3

Question 24

late complement deficiencies

Answer 24

C5, C6, C7, C8, C9

Question 25

SLE

Answer 25

systemic lupus erythematosus - C1, C2, C4-def ppl at risk - immune complexes not cleared - build up in tissues (BM, vascular surfaces) = lead to tissue damage (neuts)

Question 26

C1-Inh deficiency

Answer 26

- hereditary angioedema - localized edema = subcutaneous tissue, bowel, resp tract - autosomal dom - treat with C1-Inh or frozen plasma

Question 27

C1 esterase inhibitor

Answer 27

Berinert

Question 27

C1-Inh deficiency leads to _________ formation due to excess kallikrein

Answer 27

bradykinin

Question 28

factor I and H deficiencies

Answer 28

pts get recurrent infections

Question 29

CD55/CD59 deficiency

Answer 29

- paroxysmal nocturnal hemoglobinuria - no PIG-A (phosphatidylinositol glycan A) - diagnosis = historical Hamm's test; flow cytometry - anemia (susceptible to hemolysis), cytopenia, thrombosis - 10-15 yr survival without treatment => DVT - treatment = correct anemia, prevent thrombosis, BMT, Eculizumab (anti-C5)

Question 30

microbial evasion of complement (GPOS)

Answer 30

thick peptidoglycan prevents insertion of MAC capsule provides physical barrier between C3b and CR2 = S. pneumoniae

Question 31

microbial evasion of complement (GNEG)

Answer 31

long polysaccharide chains prevent MAC insertion (E. coli and salmonella) some N. gonorrhoeae have outer membrane protein that MAC will bind to = preventing insertion P. aeruginosa has elastase which inhibits C3a and C5a

Question 32

protein mimicry by microbes

Answer 32

microbial membrane bound proteins similar to inhibitor proteins such as CR1, DAF, C1-Inh - Vaccinia virus, Herpes, EBV, T. cruzi, C. albicans

Question 33

HIV evasion of complement

Answer 33

- lipid envelope lysed by MAC - MBL can bind gp41 and 120 (no Abs) - helps neutralize Ab-coated viral particles = lyse HIV infected cells BUT - gp-41 and 120 on lipid envelope binds factor H - virus incorporates host DAF and MIRL into membrane during budding - complement coated virus gets picked up by CR1,3,4 = RBC transport virus, bind Mo, dendritic cells which interact with T lymphs, NK rich in CR4