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The Complement System: Pathways, Functions, and Regulation in Immune Response

This chapter provides an in-depth overview of the complement system, detailing its crucial roles in immune responses through pathways such as the classical, alternative, and lectin systems. It highlights the cascade concept, where a small stimulus can lead to a rapid amplification of response, resembling coagulation processes. Readers will explore essential components, regulatory mechanisms, and deficiencies that can lead to disease. The importance of localization and control to prevent systemic issues is emphasized, making the complement system a vital area of study in immunology.

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The Complement System: Pathways, Functions, and Regulation in Immune Response

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  1. 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

  2. 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.

  3. 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

  4. 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

  5. Spend some time on the next slide!!!

  6. 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!

  7. 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!

  8. Table 7-1

  9. Table 7-1 Mimic capsule

  10. 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.

  11. 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!

  12. Reviewing Complement functions • Lysis • Opsonization • Inflammation/chemotaxis • Clearing immune complexes

  13. Notice that CR1 gets around! It’s both a regulator and opsonizer!

  14. 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!

  15. 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?

  16. 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.

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