Chapter 7- Complement • Where we’re going, and make sure you spell it right! • Overview of what complement does • Concept of a cascade • Details of the classical, alternate, and lectin systems- some stories to learn here. • Control • Genetic defects
Concept of a cascade • allows a very rapid, controlled, and localized response to a stimulus; in the case of complement, as little as a single Ab molecule bound to a bacterium. Clotting is a similar cascade. • Characterized by a small stimulus activating an enzyme, which activates other enzymes; because they are enzymes, the response is enormously magnified. • All these responses must be carefully controlled to keep them localized; systemic clotting or complement fixation would be rapidly fatal.
Components & Terms • There are 19 components (we won’t learn them all!)- concentrations range from 20 µg/ml for Properdin to 1300 µg/ml for C3- which makes it the most important player in the reactions. • 5% by weight of serum globulin. • Most are proenzymes (AKA zymogen)- inactive forms, waiting to be activated by proteolytic cleavage, and many, when activated are proteases • The active parts can be multifunctional
Terms • We use letters or names- C1, etc. • When activated, the fragments are given letters- C3a, C3b, usually C3a is smaller than C3b, etc. • Complexes: bar over the top: C4bC2a
Most do other things- opsonization, etc. Note that the production of C3b changes the specificity of the C3 covnertase to a C5 convertase! C3a, C5a are inflammatory, chemotactic Normally inactivated- activated by bacterial surface, stabilized by B Major effect!
Alternate pathway • Innate • Turns a problem (spontaneous slow hydrolysis of C3) into a method of killing bacteria • Based on “us vs them” differences in cell surface- PAMPS!
Table 7-1 Mimic capsule
The Lectin Pathway • Lectins are carbohydrate-binding proteins- this one binds mannose- a hexose. • one of the liver products stimulated by IL-6 • binds to mannose on bacteria. • looks like the C1q, and is then able to bind MBL Associated Serine Proteases 1&2, a serine protease that is similar to C1s. This can then activate C4 & C2, producing the C4bC2a C3 convertase.
Regulation! • Overview- have some components highly labile unless stabilized- C3b; hydrolyzed w/in 40 nm if not bound to a surface! • Regulatory proteins: big point of action- C3 convertase!
Reviewing Complement functions • Lysis • Opsonization • Inflammation/chemotaxis • Clearing immune complexes
Complement deficiencies • The worst- no C3- almost like being immunodeficient- lots of bacterial infections, immune complex disease. • Early components- C1,2,4- more immune complex disease- lupus, glomerulonephritis, clearing immune complexes is important! • MAC deficiencies- Neisseria infections! Meningitis, gonnorrhea. Neisseria may have evasive means anyway!
Quiz on Wed: • How would you– test for HIV +, Find Lymphocyte • Complement- • The three paths, • What does C3 do? • What does the C3 convertase do? The convertase in each path? • How does it become a C5 convertase?
Things to know • Cascade • How does complement manage to be rapid, yet localized? • The three activation stories- • Control: three places to work: before and after C3 convertase Knowing an inhibitor and what it does will only be EC. (C4bBP, H,I), and preventing a MAC formation, (S,HRF) • Effects of complement deficiencies.