Biochemistry 5-6: Complement System Regulation And Deficiency Disorders

Question 1

List the 3 pathways of activation of complements?

Answer 1

1- the classical pathway.
2- the alternative pathway.
3- the MB lectin pathway.

Question 2

List the 4 types of complement deficiencies?

Answer 2

1- components of activation pathway.
2- control proteins: soluble control proteins, membrane regulatory proteins.
3- complement receptors deficiencies.
4- acquired deficiencies.

Question 3

List the components that my get defected in a deficiency of components of activation pathways?

Answer 3

C1q, C1r, C1s, C4, C2, C3, MBL, D, B, C5, C6, C7, C8, C9.

Question 4

List the components that my get defected in a deficiency of soluble control proteins?

Answer 4

C1 inhibitor, Factor I, Factor H, C4b binding protein, S protein.

Question 5

List the components that my get defected in a deficiency of membrane regulatory proteins?

Answer 5

CD55 (DAF), MCP CD46, CD59, HRF/C8bp.

Question 6

List the components that my get defected in a deficiency of complement receptors?

Answer 6

C1q receptor, CR1 (CD35), CR2 (CD21), CR3 (CD11b/CD18), CR4 (CD11c - CD18).

Question 7

List clinical manifestations in complement deficiencies?

Answer 7

1- increased susceptibility to infections: with systemic course - bacteremia + meningitis.
- S.pneumoniae, S.pyogenes, H.influenzae (early components, defect in opsonization).
- Neisseria meningitidis (defect in terminal components).
2- autoimmune disorders: defective immune complex clearance.
3- angioedema.

Question 8

List ways to test for complement deficiencies (laboratory testing)?

Answer 8

1- CH50.
2- AH50.
3- plasma C3 and C4 levels.
4- other tests:
- C5a, C3a, Bb..
- tissue deposition of complement (immunofluorescence).

Question 9

What is CH50 testing used for?

Answer 9

Detecting a deficiency of the classical pathway.
Assesses the ability of the test serum to lyse sheep erythrocytes optimally sensitized with rabbit antibody.

Question 10

What is AH50 testing used for?

Answer 10

Measure the total alternative pathway (lysis of unsensitized rabbit RBCs).

Question 11

What is plasma C3 and C4 levels testing used for?

Answer 11

Measured in nephelometric immunoassays.
Helpful in following patients.

Question 12

What is CH50 testing sensitive to?

Answer 12

Sensitive to reduction, absence and/or inactivity of any component of the pathway.

Question 13

What does the CH50 test?

Answer 13

Tests the functional capability of serum complement components of the classical pathway to lyse sheep RBCS, pre-coated with rabbit anti-sheep RBC antibody (hemolysin).

Question 14

List the results for CH50 and what do they mean?

Answer 14

When antibody-coated SRBC are incubated with test serum, the classical pathway of complement is activated and hemolysis results.
- if a complement is absent, the CH50 level will be zero; if one or more components of the classical pathway are decreased, the CH50 will be decreased.

Question 15

List the clinical manifestations of complement component deficiencies?

Answer 15

• rare.
• individuals have a variety of clinical presentations.
• individuals are susceptible to infection.
• other are susceptible to immune complex-mediated syndromes ( SLE, glomerulonephritis, dermatomyositis, anaphylactoid purpura, and vasculitis).
• others have angioedema.
• in rare instances, patients may even be asymptomatic.

Question 16

List the 7 classifications of complement component deficiencies?

Answer 16

1- inherited classical pathway deficiencies.
2- inherited mannose-binding lectin pathway deficiencies.
3- inherited alternative pathway deficiencies.
4- C3 and late-acting components deficiencies.
5- inherited deficiencies of complement inhibitor proteins: autosomal recessive, autosomal dominant (C1 inhibitor deficiency), X-linked (properdin deficiency).
6- complement receptor 1, 2 or 3 deficiency.
7- acquired deficiencies of complement components.

Question 17

Defects in the early components of the classical pathway do not lead to overwhelming infection, why?

Answer 17

Because the MBL and alternative pathways can bypass these defects.

Question 18

A deficiency of the early components of complements results in what?

Answer 18

Results in poor clearance of immune complexes resulting in increased immune complex disease.

Question 19

List the complement proteins, defects, and diseases associated with inherited classical pathway deficiencies?

Answer 19

Complement proteins: C1q, C1r, C1s, C4, C2.
Defect: impaired solubilization of immune complexes; poor immunoregulation.
Diseases associated: autoimmune disease (SLE), may be severe; infections with encapsulated organisms.

Question 20

What is systemic lupus erythematous (SLE)?

Answer 20

• autoimmune disorder characterized by multi system inflammation with the generation of autoantibodies.
• autoimmune reactions directed against constituents of cell nucleus, DNA.
• antibody response related to B and T cell hyperactivity.

Question 21

List the dermatological manifestations that may arise with SLE?

Answer 21

1- Malar rash: butterfly-shaped red rash over the checks below the eyes and across the bridge of the nose, may be flat or a raised rash, made worse by sun exposure.
2- Discoid lupus: red, raised patches with scaling of the overlying skin.
3- Vasculitis skin lesion.
4- swan neck deformity.

Question 22

What happens in a C1q deficiency?

Answer 22

SLE, SLE like syndrome, chronic rash-vasculitis, septicemia and meningitis.

Question 23

What happens in a C2 deficiency?

Answer 23

• 10-30% of individuals present with an SLE-like illness.
• usually no infection, but they are prone to recurrent pyogenic infections (particularly due to encapsulated bacteria).
• associated with IgG subclass deficiency.
• other diseases associated include polymyositis, glomerulonephritis, Hodgkin lymphoma, vasculitis and Henoch-schonlein purpura.

Question 24

List the complement proteins, defects, and diseases associated with inherited mannose-binding lectin pathway deficiencies?

Answer 24

Complement protein: MBL, MASP.
Defect: impaired first line defense against microbes.
Diseases associated: repeated infections; accelerated course of SLE and RA reported.

Question 25

List the complement proteins, defects, and diseases associated with inherited alternative pathway deficiencies?

Answer 25

Complement proteins: B, P, D.
Defect: impaired solubilization of immune complexes; impaired first line of defense against microbial pathogen.
Diseases associated: infections often with encapsulated organisms; neisserial infections.

Question 26

List the complement proteins, defects, and diseases associated with C3 component deficiencies?

Answer 26

Complement proteins: C3.
Defect: critical to function of all pathways; important opsonin.
Diseases associated: severe infection; severe autoimmune disease.

Question 27

List the complement proteins, defects, and diseases associated with late-acting component deficiencies?

Answer 27

Complement proteins: C5-9.
Defect: critical for lysis of cells and bacterial; C5 important for chemotaxis.
Diseases associated: neisserial infections; autoimmune manifestations of disease.

Question 28

What is the clinical manifestation associated with C3 deficiency?

Answer 28

Severe, recurrent infections with encapsulated bacteria.

Question 29

List the complement proteins, defects, and diseases associated with control proteins/complement inhibitor proteins deficiencies?

Answer 29

Complement proteins: C1 inhibitor.
Defect: improper regulation of C1 with secondary consumption of C4 and C2.
Diseases associated: hereditary angioedema.

Complement proteins: factors H or I.
Defect: uncontrolled activation of the alternative pathway
Diseases associated: pyogenic infections; glomerulonephritis, secondary C3 deficiency.

Complement proteins: DAF and CD59.
Defect: inability to inhibit C3 and C5 convertases and MAC on host cells.
Diseases associated: paroxysmal nocturnal hemoglobinuria.

Question 30

List the complement proteins, defects, and diseases associated with complement receptor deficiencies?

Answer 30

Complement proteins: CR3.
Defect: important in phagocytosis.
Diseases associated: leucocyte adhesion defect; infection.

Question 31

List the acquired deficiencies of complement components?

Answer 31

1- accelerated consumption by immune complexes.
2- reduced hepatic synthesis.
3- abnormal loss of complement in renal disease.

Question 32

List the properties of C4 deficiency?

Answer 32

• encoded by 2 highly polymorphic genes, C4A and C4B; MHC class 3 on chromosome 6.
• Total C4 deficiency is rare.
• Partial C4 deficiency predisposes to SLE.

Question 33

What is the mutation in C1 inhibitor deficiency?

Answer 33

Mutations in chromosome 11

Question 34

What is the defect in C1 inhibitor deficiency?

Answer 34

C1 INH deficiency - failure to regulate C1

Question 35

List the 2 types or C1 inhibitor deficiency?

Answer 35

1- type 1 C1ID.
2- type 2 C1ID.

Question 36

List the properties of type 1 C1 inhibitor deficiency?

Answer 36

• 85% patients.
• no detectable protein.

Question 37

List the properties of type 2 C1 inhibitor deficiency?

Answer 37

• 15% patients.
• dysfunctional protein.
• recurrent angioedema; first 2 decades of life.
• not prurit or painful; disappears in 2-4 days.
• without urticaria; abdominal pain.

Question 38

List the treatment for C1ID?

Answer 38

1- clonal C1-INH infusion; fresh frozen.
2- plasma; antifibrinolytic agents; Stanazolol.
3- no specific Tx except for hereditary anigoedema.
4- quick administration of antibiotics.
5- vaccines (high titer antibody might opsonize effectively without complement).

Question 39

What is the defect in paroxysmal nocturnal hemoglobinurea?

Answer 39

CD55 and CD59 failure to function - lack of complement regulation leads to RBC lysis.
Caused from a defect in the production of GPI protein anchors on the surface of RBCs produced by the BM stem cells.
This is caused by an acquired mutation of PIG-A gene.

Question 40

What happens in paroxysmal nocturnal hemoglobinurea due to PIG-A gene defect?

Answer 40

• Defect makes the RBCs susceptible to destruction by the complement system.
• The PIG-A mutation occurs in a BM stem cell.
• All blood cells by this defective stem cell are deficient in GPI-anchored proteins (glycosyl-phosphatidylinositol GPI).
• The GPI-anchored proteins are present on RBCS that protect RBCs from the activity of the complement system.
• When they are absent, no protection from complement and this leads to intravascular hemolysis.

Question 41

Clinical problem: a 23 yr man complains of fever (102F), headache, neck stiffness and fatigue of 2 days duration. Lumbar puncture shows increased pressure with cloudy CSF containing large numbers of neutrophils, increased protein, decreased glucose and gram negative diplococci. Laboratory studies show C5 (5th component of complement) levels at 18% and normal levels of C2, C3 and C7. The patient recovers after institution of IV antibiotic therapy.
What is your diagnosis?

Answer 41

Acute bacterial meningitis secondary to deficiency of C5.