CHAPTER III – COMPLEMENT Flashcards
COMPLEMENT Meaning -
to Help or to make Complete
COMPLEMENT year
1890s
Coined the term:
Paul Ehrlich
Elucidate the control of the complement; Novel price
Jules Bordet
A primary part of the
Innate immune response
Substance under the
humoral-mediated immunity
Group of
30 different proteins
Designation
• Numerals (C1-C9)
• Letter symbols (factor D)
Cleavage Products – enzyme activation
a and b
named with a capital C followed by a
number
- results from the cleavage of a larger precursor by a protease
small letter
Ex. C3a/ C3b
• Larger fragment- designated as
• Smaller fragment- designated as
b
a
Exception:
C2 fragments
Larger-
smaller fragment-
C2a
C2b
Functions of Complement
- Lysis of cells, bacteria and viruses
- Opsonization
- Triggers specific cell functions, inflammation and secretion of immunoregulatory molecules
- Immune clearance: removal of immune complexes and deposition in the spleen and liver
Proteins and glycoproteins synthesized mainly by
liver hepatocytes
Most circulate in the serum functionally inactive forms as
proenzymes or zymogens
PRODUCES A
CASCADE PHENOMENON
WHERE THE PRODUCT OF ONE REACTION IS THE (?) OF THE NEXT
ENZYMATIC CATALYST
Heat Labile: destroyed when heated at
56°C for 30 mins
Anaphylatoxin
C3a, C4a, C5a
Increase Capillary Permeability
Role of C2b fragment
Chemotaxis
C5a
Virus neutralization
C4
Opsonization
C3b
They bind to receptors on mast cells and basophils
Anaphylatoxin
Induce degranulation and release of influx mediators including histamine
Anaphylatoxin
Can lead to edema if complement is not controlled
Increase Capillary Permeability
Attract cells and play important role in recruitment of wbc cells to an influx site
Chemotaxis
Enhances neutralization of viruses by homologous antibodies
Virus neutralization
C3b on particles such as bacteria or an Ab-Ab complex promotes the attachment and ultimate ingestion of the particles.
Opsonization
Initiated by: Antigen-antibody complex
CLASSICAL
First to be studied
CLASSICAL
Initiated by:
1. Aggregates of IgA
2. Yeast cell or zymogen
3. CVF
4. LPS
ALTERNATE/ ALTERNATIVE/ PROPERDIN LECTIN
Initiated by: With mannose and other similar sugars in the cell wall
LECTIN
Ab-dependent
CLASSICAL
ALTERNATE/ ALTERNATIVE/ PROPERDIN LECTIN
LECTIN
Ab-independent
Biological Functions
Initiation of Pathways
Phases of Complement Activation
Recognition event which will initiate complement cascade
INITIATION PHASE
Classical and alternate pathway differ at this phase
INITIATION PHASE
Activation of early components culminate in activation of C3 which is the critical component
AMPLIFICATION / ACTIVATION PHASE
Classical and alternate pathway differ at this phase
AMPLIFICATION / ACTIVATION PHASE
Culminates in target cell lysis
MEMBRANE ATTACK PHASE
Classical and alternate pathway is the same at this phase
MEMBRANE ATTACK PHASE
Begins with the formation of soluble antigen-antibody complexes or with binding of antibody to antigen on a suitable target such as a bacterial cell
CLASSICAL PATHWAY
IgM or IgG
CLASSICAL PATHWAY
Ag-Ab-IgM: conformational change in Fc : exposing a binding site for C1
CLASSICAL PATHWAY
Antibody is not required
ALTERNATIVE PATHWAY
Innate immunity
ALTERNATIVE PATHWAY
4 serum proteins: C3, factor B, factor D and properdin + C5 + C6789
ALTERNATIVE PATHWAY
Initiated by cell-surface constituents that are foreign to the host (gram + and gram - bacterial cell walls)
ALTERNATIVE PATHWAY
: proteins that recognize and bind to specific carbohydrate targets
Lectins
After initiation proceeds thru action of CA and C2 to produce C5 convertase
LECTIN PATHWAY
Activated by binding of mannose-binding lectin to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms such as
Salmonella, Listeria, Neisseria, Cryptococcus and Candida
3 pathways : active C5 convertase to cleave C5 — C5a and C5b (initiates the final steps to form MAC)
Membrane Attack Complex
Forms a large channel through the membrane of the target cell enabling ions and small molecules to diffuse freely across the membrane
Membrane Attack Complex
105
C1 inhibitor (C1INH)
240
C1 inhibitor (C1INH)
Dissociates C1r and C1s from C1q
C1 inhibitor (C1INH)
88
Factor I
35
Factor I
Cleaves C3b and C4b
Factor I
150
Factor H
300-450
Factor H
Cofactor with I to inactivate C3b
Factor H
prevents binding of B to C3b
Factor H
520
C4-binding protein
250
C4-binding protein
Acts as a cofactor with I to inactivate C4b
C4-binding protein
84
S protein (vitronectin)
500
S protein (vitronectin)
Prevents attachment of the C5b67 complex to cell membranes
S protein (vitronectin)
165,000 to 280,000
CR1 or Complement Regulator 1
It is found mainly on peripheral blood cells, including neutrophils, monocytes, macrophages, erythrocytes, eosinophils, B lymphocytes, some T lymphocytes, and follicular dendritic cells.
CR1 or Complement Regulator 1
It binds C3b and C4b but has the greatest affinity for C3b
CR1 or Complement Regulator 1
CD45
CR1 or Complement Regulator 1
50,000 to 70,000
Membrane Cofactor Protein
found on virtually all epithelial and endothelial cells except erythrocytes.
Membrane Cofactor Protein
is the most efficient cofactor for factor Imediated cleavage of C3b
Membrane Cofactor Protein
CD46
Membrane Cofactor Protein
70,000
DAF or Decayaccelerating factor
It is found on peripheral blood cells, on endothelial cells and fibroblasts, and on numerous types of epithelial cells.
DAF or Decayaccelerating factor
capable of dissociating both classical and alternative pathway C3 convertases
DAF or Decayaccelerating factor
CD55
DAF or Decayaccelerating factor
widely distributed on the cell membranes of all circulating blood cells, including red blood cells, and on endothelial, epithelial, and many other types of cell
MIRL or Membrane inhibitor of reactive lysis
bind to C8 and prevent insertion of C9 into host cell membranes
MIRL or Membrane inhibitor of reactive lysis
CD59
MIRL or Membrane inhibitor of reactive lysis
C3b, iC3b, C4b
CR1
RBCs, neutrophils, monocytes, macrophages, eosinophils, B and T cells, follicular dendritic cells
CR1
Cofactor for factor I
CR1
mediates transport of immune complexes
CR1
(CD35)
CR1
C3dg, C3d, iC3b
CR2
B cells, follicular dendritic cells, epithelial cells
CR2
B-cell coreceptor for antigen with CD19
CR2
(CD21)
CR2
iC3b, C3d, C3b
CR3
Monocytes, macrophages, neutrophils, NK cells
CR3
Adhesion and increased activity of phagocytic cells
CR3
CR4
(CD11b/CD18)
CR3
(CD11c/CD18)
CR4
C3b, C4b
DAF
RBCs, neutrophils, platelets, monocytes, endothelial cells, fibroblasts, T cells, B cells, epithelial cells
DAF
Dissociates C2b or Bb from binding sites, thus preventing formation of C3 convertase
DAF
(CD55)
DAF
C8
MIRL
RBCs, neutrophils, platelets, monocytes, endothelial cells, epithelial cells
MIRL
Prevents insertion of C9 into cell membrane
MIRL
(CD59)
MIRL
C3b, C4b
MCP
Neutrophils, monocytes, macrophages, platelets, T cells, B cells, endothelial cells
MCP
Cofactor for factor I cleavage of C3b and C4b
MCP
(CD46)
MCP
• associated with inflammatory conditions, trauma, or acute illness
INCREASED COMPLEMENT LEVELS
• Limited clinical significance
INCREASED COMPLEMENT LEVELS
• Low levels of complement suggest one of the following biological effects:
- Complement has been excessively activated recently.
- Complement is currently being consumed.
• A single complement component is absent because of a genetic defect
DECREASED COMPLEMENT LEVELS
HYPOCOMPLEMENTEMIA
DECREASED COMPLEMENT LEVELS
• result from the complexing of IgG or IgM antibodies capable of activating complement
HYPOCOMPLEMENTEMIA
• associated with diseases that give rise to circulating immune complexes.
HYPOCOMPLEMENTEMIA
Lupus-like syndrome; recurrent infections
C1 (q, r, or s)
Lupus-like syndrome; recurrent infections; atherosclerosis
C2
Severe recurrent infections; glomerulonephritis
C3
Lupus-like syndrome
C4
Neisseria infections
C5-C8
Properdin
No known disease association
C9
Hereditary angioedema
C1INH
Paroxysmal nocturnal hemoglobinuria
DAF
MIRL
Recurrent pyogenic
Factor H or Factor I
Pneumococcal diseases, sepsis, Neisseria infections
MBL
Pneumococcal diseases
MASP-2
Marks the start of Recognition unit CLASSICAL
C1qrs
Marks the start of Recognition unit ALTERNATIVE
C3
Marks the start of Recognition unit LECTIN
C1-like complex (MASP-1, MASP-2, and MASP)
Marks the start of Activation unit CLASSICAL
C4b2a (C3 convertase)
Marks the start of Activation unit ALTERNATIVE
C3bBb (C3 convertase)
Marks the start of Activation unit LECTIN
C3 convertase
Marks the start of Membrane attack complex CLASSICAL
C5b
Marks the start of Membrane attack complex ALTERNATIVE
C5b
Marks the start of Membrane attack complex LECTIN
C5b
C3 convertase CLASSICAL
C4b2a
C3 convertase ALTERNATIVE
C3bBb
C5 convertase CLASSICAL
C4b2a3b
C5 convertase ALTERNATIVE
C3bBb3b
Binds to Fc region of IgM and IgG
C1q
Activates C1s
C1r
Cleaves C4 and C2
C1s
Part of C3 convertase (C4b)
C4
Binds to C4b—forms C3 convertase
C2
Key intermediate in all pathways Initiates membrane attack complex
C3
Initiates membrane attack complex
C5
Binds to C5bC6 in MAC
C7
Starts pore formation on membrane
C8
Polymerizes to cause cell lysis
C9
Binds to C3b to form C3 convertase
Factor B
Cleaves factor B
Factor D
Stabilizes C3bBb–C3 convertase
Properdin
Binds to mannose
MBL
Unknown
MASP-1
Cleaves C4 and C2
MASP-2
Binds to C5b in MAC
C6
