[DISCUSSION] MODULE 1 UNIT 4 Flashcards by Arriane Camacho

•Includes more than 30 soluble and cell-bound proteins

COMPLEMENT

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•Normally circulate in an inactive precursor form

COMPLEMENT

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•Develop proteolytic activity upon activation

COMPLEMENT

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•Can be induced to carry out a cascade of enzymatic
reactions

COMPLEMENT

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•formation of certain opsonins & inflammatory
mediators

COMPLEMENT

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About (?)% of plasma complement components are synthesized in the liver and are acute phase proteins with the exception of C1q, factor D, properdin, and C7.

90%

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About 90% of plasma complement components are synthesized in the (?) and are acute phase proteins with the exception of C1q, factor D, properdin, and C7.

liver

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→ epithelial cells, monocytes/macrophages, and fibroblasts.

C1q

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→ adipocyte

Factor D

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→ synthesized mainly by monocytes and
macrophages, with some synthesis occurring in lymphocytes and granulocytes.

Properdin

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Most (?) also appears to originate from monocytes and macrophages, although neutrophils were shown to store C7.

plasma C7

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have the ability to synthesize all components of the classical and alternative pathways.

Monocytes, macrophages, cells of the synovial tissues, and astrocytes

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4 FUNCTIONS OF COMPLEMENT

Lysis of cells, bacteria and viruses
Opsonization
Binding to specific complement receptors on cells of the immune system, triggering specific cell functions
Immune clearance

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• Promote phagocytosis of particulate antigens

Opsonization

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Binding to specific complement receptors on cells of the immune system, triggering specific cell functions:

•inflammation
•secretion of immunoregulatory molecules

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•removes immune complexes from the circulation and deposits them in the spleen and liver

Immune clearance

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•Nine (9) proteins of the classical pathway

Designated by the upper-case letter C followed by a number

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•Designated by the upper-case letter C followed by a number

Nine (9) proteins of the classical pathway

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•Designated by the upper-case letter (?) followed by a number

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Molecules comprising the C1 complex

C1q, C1r,
C1s

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Alternative pathway proteins

→ factors and referred to by an upper-case letter ( Factor B , Factor D)

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Fragments of complement proteins

Lower case letter ( C4a, C4b)

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NOMENCLATURE
•Smaller fragment

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NOMENCLATURE
Larger fragment

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NOMENCLATURE Exception is

Further degradation fragments of the large complement fragment of one component are designated by (?)

ted by lower case letters (e.g., C3c, C3d)

Components that have lost activity are designated with a (?)

lower case i (e.g., iC3b, iC4b)

Single components or multicomponent complexes that have enzymatic activity •Designated by a (?)

bar over the component/s

Proteins of the recently described Mannose-Binding lectin pathway •Designated by (?)

abbreviations of the proteins’ names (e.g., MBL, MASP)

3 PATHWAYS

1. CLASSICAL PATHWAY 2. ALTERNATIVE PATHWAY 3. MANNAN-BINDING LECTIN PATHWAY

Mechanism of humoral immunity

CLASSICAL PATHWAY

Initiation: antigen – antibody complex

CLASSICAL PATHWAY

• 1 IgM molecule on an antigenic surface 2 IgG adjacent molecules that have bound antigen

CLASSICAL PATHWAY

• 2 IgG adjacent molecules that have bound antigen

CLASSICAL PATHWAY (IgG3> IgG1>IgG2)

Effector mechanism of innate immunity

ALTERNATIVE PATHWAY

Also an effector mechanism of innate immunity

MANNAN-BINDING LECTIN PATHWAY

Give all Non immunologic classic pathway activators

• C-reactive protein • Serum amyloid P component • b-amyloid • Some gram-negative bacteria (Escherichia coli and Salmonella strains of low virulence) • Mycoplasma • Protozoa • Intracellular components (DNA,mitochondrial components, cytoskeletal filaments) • Other structures (surface of urate crystals, myelin basic protein, bacterial endotoxin, polyanions like heparin, lipid A, cardiolipin, dextran sulfate, chondroitin sulfate)

Give all Activators of alternative pathway

•Gram-negative endotoxins or bacterial products (dextrans, levans) •Complex microbial and plant polysaccharides (e.g., zymosan, inulin) •Human rbc stroma • Some virus-infected cells (e.g., EBV) •Aggregated human IgA • Trypanosomes, Leishmania, many fungi •Rabbit rbcs, aggregated F(ab’)2 fragments of guinea pig IgG1

Carbohydrates expressed on the surface of microorganisms

Activators of MBL pathway

Activators of MBL pathway •In order of importance:

1. Mannose 2. N-acetylglucosamine 3. L-fucose 4. N-acetylmannosamine 5. Glucose

activated by certain isotypes of antibodies bound to antigens

Classical Pathway

activated on microbial cell surfaces in the absence of antibody

Alternative Pathway

activated by mannose-binding protein that binds to surface carbohydrates on microbes

Mannose-Binding Lectin Pathway

Give all CONTROL AND REGULATION OF COMPLEMENT ACTIVATION

• Limit overly widespread inflammation • Avoid excessive activation • Protect host cells from inadvertent injury

Give all FLUID PHASE REGULATORS

1. C1 inhibitor (C1 INH) 2. Factor J 3. Human neutrophil peptide-1 (HNP-1) 4. Factor I 5. Factor H 6. C4-binding protein (C4bp) 7. S-protein/ vitronectin 8. Clusterin/ SP-40/ Apolipoprotein J

Serine protease inhibitor (serpin)

C1 inhibitor (C1 INH)

Dissociates the activated C1 complex

C1 inhibitor (C1 INH)

Binds C1r and C1s subunits

C1 inhibitor (C1 INH)

In vitro, it inactivates the mannan-binding lectin associated serine proteases (MASPs)

C1 inhibitor (C1 INH)

Hereditary Angioedema (Hereditary angioneurotic edema)

C1 inhibitor (C1 INH)

Inhibits C1 complex formation

Factor J

Inhibits cleavage of C3 by Factor B

Factor J

Defensin

Human Neutrophil peptide-1 (HNP-1)

May inhibit C1 at sites of inflammation by binding C1q in the fluid phase

Human Neutrophil peptide-1 (HNP-1)

Blocks classical pathway-mediated complement activation

Human Neutrophil peptide-1 (HNP-1)

Give all 8 FLUID PHASE REGULATORS

1. C1 inhibitor (C1 INH) 2. Factor J 3. Human neutrophil peptide-1 (HNP-1) 4. Factor I 5. Factor H 6. C4-binding protein (C4bp) 7. S-protein/ vitronectin 8. Clusterin/ SP-40/ Apolipoprotein J

C3b/C4b inactivator

Factor I

Acts enzymatically on C3b leading to iC3b

Factor I

Cleaves C3b and C4b

Factor I

Factor I Cofactors:

Factor H, MCP, C4BP, CR1

Acts as cofactor to Factor I

Factor H

Binds C3b

Factor H

Binds C4

C4-Binding protein (C4BP)

Mediates decay of classical pathway C3 convertase

C4-Binding protein (C4BP)

Binds C5b67 complex

S-protein/ vitronectin

Prevents insertion in the cell membrane

S-protein/ vitronectin

Primary MAC inhibitor /maidafatim

S-protein/ vitronectin

Same as vitronectin

Clusterin/ SP-40/ Apolipoprotein J

Regulates the MAC at the C5b67 and C9 levels

Clusterin/ SP-40/ Apolipoprotein J

Give all 5 CELL-ASSOCIATED REGULATORY PROTEINS

1. Complement receptor type 1 (CR1)/ CD35 2. Membrane cofactor protein (MCP) / CD46 3. Decay-accelerating factor (DAF) / CD55 4. Homologous restriction factor (HRF) / C8- binding protein (C8bp) 5. CD59 (Protectin, HRF-20, Membrane inhibitor of reactive lysis (MIRL), P-18

Cofactor for Factor I-mediated cleavage

Complement receptor type 1 (CR1)/ CD 35

Binds activated C4b and C3b

Complement receptor type 1 (CR1)/ CD 35

Promotes further cleavage of iC3b by Factor I into C3dg

Complement receptor type 1 (CR1)/ CD 35

Aids in transport of immune complexes that bear C3b to sites of degradation in Kupffer’s cells in the liver

Complement receptor type 1 (CR1)/ CD 35

Cofactor for Factor I-mediated cleavage of C4b and C3b into C4c and C4d and iC3b

Membrane cofactor protein (MCP) / CD46

Unable to promote further cleavage of iC3b

Membrane cofactor protein (MCP) / CD46

Expressed by almost every cell, except rbcs

Membrane cofactor protein (MCP) / CD46

Accelerates decay of classical and alternative pathway C3 and C5 convertases

Decay-accelerating factor (DAF) / CD55

Dissociates C2a and Bb of C3 convertases

Decay-accelerating factor (DAF) / CD55

binds C8

Homologous restriction factor (HRF)

binds both C8 and C9

CD59

AF, HRF & CD59 are absent from cells in (?)

PNH

4 BIOLOGIC ACTIVITIES OF COMPLEMENT

• Kinin production •Opsonins • Anaphylatoxins • Chemotactic Factors

• C2b

Kinin production

• C3b and C4b in the surface of microorganisms attach to C-receptor (CR1) on phagocytic cells and promote phagocytosis

Opsonins

• C4a, C3a and C5a (in increasing order of activity)

Anaphylatoxins

C5a and C5b67

Chemotactic Factors

(?) is also a potent activator of neutrophils, basophils and macrophages and causes induction of adhesion molecules on vascular endothelial cells

C5a

Degradation products of (?) also bind to different cells by distinct receptors and modulate their functions

C3 (iC3b, C3d and C3e)

Opsonization

C3b C3d

Cell lysis

C5b to C9

Clearance of immune complexes

C3b

B cell activation

C3d

Mast cell degranulation

C3a C5a

Chemotaxis

C5a