[DISCUSSION] MODULE 1 UNIT 4 Flashcards
•Includes more than 30 soluble and cell-bound proteins
COMPLEMENT
•Normally circulate in an inactive precursor form
COMPLEMENT
•Develop proteolytic activity upon activation
COMPLEMENT
•Can be induced to carry out a cascade of enzymatic
reactions
COMPLEMENT
•formation of certain opsonins & inflammatory
mediators
COMPLEMENT
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%
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
→ epithelial cells, monocytes/macrophages, and fibroblasts.
C1q
→ adipocyte
Factor D
→ synthesized mainly by monocytes and
macrophages, with some synthesis occurring in lymphocytes and granulocytes.
Properdin
Most (?) also appears to originate from monocytes and macrophages, although neutrophils were shown to store C7.
plasma C7
have the ability to synthesize all components of the classical and alternative pathways.
Monocytes, macrophages, cells of the synovial tissues, and astrocytes
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
• Promote phagocytosis of particulate antigens
Opsonization
Binding to specific complement receptors on cells of the immune system, triggering specific cell functions:
•inflammation
•secretion of immunoregulatory molecules
•removes immune complexes from the circulation and deposits them in the spleen and liver
Immune clearance
•Nine (9) proteins of the classical pathway
Designated by the upper-case letter C followed by a number
•Designated by the upper-case letter C followed by a number
Nine (9) proteins of the classical pathway
•Designated by the upper-case letter (?) followed by a number
C
Molecules comprising the C1 complex
C1q, C1r,
C1s
Alternative pathway proteins
→ factors and referred to by an upper-case letter ( Factor B , Factor D)
Fragments of complement proteins
Lower case letter ( C4a, C4b)
NOMENCLATURE
•Smaller fragment
a
NOMENCLATURE
Larger fragment
b
NOMENCLATURE
Exception is
C2
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
- CLASSICAL PATHWAY
- ALTERNATIVE PATHWAY
- 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:
- Mannose
- N-acetylglucosamine
- L-fucose
- N-acetylmannosamine
- 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
- C1 inhibitor (C1 INH)
- Factor J
- Human neutrophil peptide-1 (HNP-1)
- Factor I
- Factor H
- C4-binding protein (C4bp)
- S-protein/ vitronectin
- 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
- C1 inhibitor (C1 INH)
- Factor J
- Human neutrophil peptide-1 (HNP-1)
- Factor I
- Factor H
- C4-binding protein (C4bp)
- S-protein/ vitronectin
- 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
- Complement receptor type 1 (CR1)/ CD35
- Membrane cofactor protein (MCP) / CD46
- Decay-accelerating factor (DAF) / CD55
- Homologous restriction factor (HRF) / C8-
binding protein (C8bp) - 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