complement

What are the 3 major functions of complement?

Opsonization, chemotaxis, and lysis.

What are the 3 complement activation pathways?

Classical, alternative, and MBL/lectin.

Which complement component is involved in all 3 pathways?

C3.

Where are most complement proteins produced?

Liver.

What triggers the classical complement pathway?

Antigen-antibody complexes.

Which antibodies activate the classical pathway?

IgM and IgG.

Which antibody is better at initiating complement?

IgM.

Where does C1 bind on IgG?

CH2 region of the Fc portion.

Where does C1 bind on IgM?

CH3 region of the Fc portion.

What 3 components make up C1?

C1q, C1r, and C1s.

What does C1q do?

Binds the Fc portion of antibody.

What does C1r do?

Activates C1s.

What does C1s do?

Splits C4 and C2.

What stabilizes the C1 complex?

Ca²⁺.

What happens when C4 is split?

C4a enters blood; C4b binds the target.

What happens when C2 is split?

C2b enters plasma; C2a joins C4b.

What is the classical C3 convertase?

C4b2a.

What does C3 convertase do?

Splits C3 into C3a and C3b.

Where does C3a go?

Into the blood.

What happens to C3b?

It binds the target and is a major opsonin.

What is the classical C5 convertase?

C4b2a3b.

What does C5 convertase do?

Splits C5 into C5a and C5b.

Where does C5a go?

Into the blood.

What does C5b do?

Stays on the target and begins MAC formation.

What components form the MAC?

C5b, C6, C7, C8, and C9.

What does C8 do during MAC formation?

Makes the initial small hole; lysis begins.

What does C9 do during MAC formation?

Forms the transmembrane channel and completes the hole.

According to the lecture, C8 alone can lyse what cell?

RBC.

According to the lecture, C9 is needed to lyse what type of cell?

Nucleated cells.

What is the final result of successful complement activation?

Cell lysis.

Does the alternative pathway require antibody?

No.

What can trigger the alternative pathway?

Bacteria/LPS, fungi, yeast, viruses, infected cells, tumors, and some parasites.

Which components does the alternative pathway bypass?

C1, C2, and C4.

What complement component begins the alternative pathway?

C3.

What binds to C3b in the alternative pathway?

Factor B.

What does Factor D do?

Splits Factor B.

Which Factor B fragment remains with C3b?

Bb.

What is the alternative C3 convertase?

C3bBb.

What is the role of properdin?

Stabilizes the alternative pathway convertase.

Does the MBL/lectin pathway require antibody?

No.

What does MBL bind?

Mannose and related sugars on microorganisms.

What does MBL stand for?

Mannose-binding lectin.

Which proteins associate with MBL?

MASP-1, MASP-2, and MASP-3.

What does MASP-2 split?

C4 and C2.

After C4 and C2 are split in the MBL pathway, what happens?

The pathway proceeds like the classical pathway.

What are the 3 anaphylatoxins?

C3a, C4a, and C5a.

What do anaphylatoxins increase?

Vascular permeability.

What 3 effects are caused by anaphylatoxins?

Increased vascular permeability, smooth muscle contraction, and histamine release.

Which complement fragment is a major chemotaxin?

C5a.

Which complement fragments act as opsonins?

C4b, C3b, and iC3b.

Which complement fragment is described as a great opsonin?

C3b.

What is opsonization?

Coating a target to enhance phagocytosis.

What does C1 inhibitor do?

Inactivates C1.

C1 inhibitor deficiency causes what disease?

Hereditary angioedema.

Why does C1-INH deficiency cause swelling?

Excess C4/C2 splitting increases vascular permeability.

What does DAF do?

Breaks/inhibits C3 convertases and protects self cells.

DAF deficiency is associated with what disease?

Paroxysmal nocturnal hemoglobinuria (PNH).

Why are RBCs destroyed in PNH?

Loss of complement regulation allows complement-mediated lysis.

What does CR1 do?

Transports C3b-coated immune complexes to liver/spleen macrophages.

Which cells transport C3b-coated complexes using CR1?

RBCs and platelets.

What happens to the RBC after delivering an immune complex?

It returns intact.

What do Factor H and Factor I do?

Help inactivate C3b.

What does S protein do?

Prevents C5b67 from attaching to the cell membrane.

What is the purpose of complement regulation?

Prevent complement from damaging host tissues.

C3 deficiency causes susceptibility to what type of infection?

Severe recurrent encapsulated bacterial infections.

Which organism is especially associated with C3 deficiency?

Streptococcus pneumoniae.

C5-C8 deficiencies are associated with what organism?

Neisseria.

C1-INH deficiency is associated with what disorder?

Hereditary angioedema.

DAF/CD59 deficiency is associated with what disorder?

PNH.

MBL deficiency is especially important in what population?

Infants.

MBL deficiency can cause what infections?

Pneumonia, sepsis, and meningococcal disease.

What happens with complement in cold autoimmune hemolytic anemia?

Complement fixes at cold temperatures; warming can lead to lysis.

What does CH50 evaluate?

Functional activity of the classical complement pathway.

What does CH50 measure?

Serum needed to lyse 50% of antibody-sensitized sheep RBCs.

What happens to CH50 if an essential complement component is deficient?

CH50 is low; complete deficiency may be near zero.

What methods can measure complement antigens?

RID and nephelometry.

What can cause decreased complement levels?

Decreased production, consumption, or in-vitro problems.

How is patient serum prepared for complement fixation?

Heat at 56°C for 30 minutes.

Why is serum heated before complement fixation testing?

To inactivate the patient's native complement.

What complement source is added in complement fixation?

Guinea pig complement.

What indicator cells are used in complement fixation?

Sheep RBCs coated with hemolysin.

What does NO hemolysis mean in complement fixation?

POSITIVE test.

What does hemolysis mean in complement fixation?

NEGATIVE test.

Why does a positive complement fixation test show no hemolysis?

Patient antibody fixes/uses complement, leaving none to lyse indicator RBCs.

Why does a negative complement fixation test show hemolysis?

No patient antibody fixes complement, so free complement lyses indicator RBCs.

Which ions are required for complement activation?

Ca²⁺ and Mg²⁺.

Which ion is NOT required for complement activation?

K⁺.

Which complement component is present in the highest concentration?

C3.

What does complement attach to on an antibody?

Fc portion.

What is the classical pathway sequence?

Ag-Ab → C1 → C4/C2 → C3 → C5 → C5b-9 → MAC → lysis.

What is the alternative pathway sequence?

Microbe → C3b → B → D splits B → C3bBb → C5 → MAC → lysis.

What is the MBL pathway sequence?

MBL binds mannose → MASPs → C4/C2 → C3 → C5 → MAC → lysis.