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IM M UNO LO G Y Bios 328 a textbook-based study ofim munology Spring 2003 http://w w w.lehigh.edu/~sk08/C ourses/Bios328/m ainpage.htm

The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

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Page 1: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

IMMUNOLOGY

Bios 328a textbook-based study of immunologySpring 2003

http://www.lehigh.edu/~sk08/Courses/Bios328/mainpage.htm

Page 2: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The overview….

• Complement has three functions:

– Opsonin

– Chemoattractant

– Membrane Attack Complex (MAC)

• Complement functions in two (three?) systems:

– Alternative

– Classical

– Lectin-based

Page 3: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathwayStimulated by antibodies:

specifically: IgM and IgG (subclasses 1, 2, 3)

Start with C1q a HUGE protein (410,000 daltons!)

Composed of 18 peptides. Peptides can associate to

form trimers; six sets of trimers make C1q.

C1q has helical “stalks” and globular “heads.”

(N. B. the heads are the carboxy end and the stalks are the amino ends)

Page 4: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathway

Also associated with C1 are C1r and C1s which associate to make dimeric pairs (C1r2s2); the dimeric pair joins C1q to form C1qr2s2.

Page 5: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathway

• C1qr2s2 binds to TWO immunoglobulins.

– The complement binding sites of circulating IgM are too far apart to bind complement;

– only when IgM is bound does it fold so that C1qr2s2 can “see” nearby complement binding domains.

– IgG concentrations must be high in the vicinity of antigens for threshold levels of complement binding domains to be present.

Page 6: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathway

• When C1qr2s2 is bound to requisite number of immunoglobulins, C1r “autocatalytically” converts to C1[r].

• C1[r], in turn, converts C1s to C1[s].

• C1[s] cleaves C2 and C4.

• C4 is cleaved to C4a and C4b; C4b associates with its “target” which is C2.

• C2 is cleaved by C1[s] making C[4b2a] which is a C3 convertase! (Note that 2a is bigger than 2b, this nomenclature being the one exception to the convention that “a” is smaller than “b.”)

• As with the other C3 convertase, C3b can join C[4b2a] to make

C[4b2a]3b which is also a C5 convertase.

Page 7: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathway

Page 8: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathway

Page 9: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The CLASSICAL pathway

Page 10: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The complement pathways…

Page 11: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The LECTIN pathway

• Lectins are proteins which bind to carbohydrates.

• Many bacteria have many mannose residues on their surface. The lectin-based complement system begins with a “mannose-binding protein” (MBP).

• MBP reacts, in turn, with a MBP-associated serine protease (MASP).

• MASP functions, in effect, like activated C1q[r2s2], that is a C3 convertase.

Page 12: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The mostamazingcircumstance:

• Erythrocytes (!) deliver the complex of antigen –antibody – complement to the liver and spleen for consumption by phagocytes.

Page 13: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

Monoclonal Ab’s

Page 14: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

Contrast with the normal circumstance…

• The normal response to an immunogen is polyclonal Ab’s

• The immunogen most commonly has multiple epitopes

• The multiple epitopes select multiple B-cell lineages

• Multiple clones mature to produce Ab’s for the multiple epitopes

Page 15: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

Monoclonals are just what they say they are:

• Remember: a single B-cell makes a single type of antibody– or, more precisely, a single idiotype

• The B-cell is made immortal– The clone, if stable, continues to secrete the

single type of Ab

Page 16: The overview…. Complement has three functions: –Opsonin –Chemoattractant –Membrane Attack Complex (MAC) Complement functions in two (three?) systems:

The scheme…• “HGPRT+” =‘s

hypoxanthine-guanine phosphoribosyl transferase

• The enzyme is used in the “salvage pathway” for DNA synthesis

• “HAT” =‘s hypoxanthine -- aminopterin -- thymidine medium

• aminopterin inhibits de novo DNA synthesis

• thymidine is needed for pyrimidine synthesis in the salvage pathway

• hypoxanthine for purines...