complement
DESCRIPTION
Complement. Objectives. Discuss the role of complement in the immune system. Discuss complement regarding its: Components Activation pathways Biological activities. Complement. System comprised of more than 25 glycoproteins Make up about 10% of total serum proteins - PowerPoint PPT PresentationTRANSCRIPT
Complement
Objectives
Discuss the role of complement in the immune system.
Discuss complement regarding its: Components Activation pathways Biological activities
Complement
System comprised of more than 25 glycoproteins Make up about 10% of total serum proteins
Components formed mainly in the liver C1 forms in intestinal epithelial cells Factor D forms in adipose tissues
Components form a cascade, with each step triggering (and often amplifying) the next step
Complement
In plasma – the components are in inactive form Once activated, each component splits
The smaller “a” fragment serves to stimulate the immune system
The larger “b” fragment further activates the cascade The exception to this is C2… C2a is the larger
molecule that promotes the cascade Activated components are written with a line over the
letter or number. For example: ____ C4b2a
3 Functions
1. Cell lysis – Cell swells and bursts
2. Opsonization - Neutrophils and macrophages have receptors for C4b or C3b, which promotes phagocytosis
3 Functions
3. Regulate immune and inflammatory response Immune adherence – enhanced response to an antigen.
Receptors for complement found on Red Blood Cells (RBCs), platelets, B lymphocytes, endothelial and epithelial cells
Anaphylatoxins - chemicals that increase vascular permeability, contract smooth muscle, and cause the release of histamine from basophils and mast cells
C3a, C4a, and C5a are anaphylatoxins Chemotaxins – signal leukocytes to migrate to an affected
area C5a is also a chemotaxin C5b67 promotes monocyte and neutrophil adherence
to blood vessel endothelium, and extravasation
3 Activation Pathways
Classical Alternative Lectin
Classical Pathway
Begins with antibody sensitization of antigen on cell
2 Fc pieces in close proximity IgM better than IgG (1 IgM vs.
800 IgG) IgG1 & IgG3 better at
activation than IgG2 or IgG4 C1 = Recognition unit
C1q C1r C1s
C1
YY
Recognition Unit
C1q combines with the Fc piece 6 globular heads attached to
collagen-like tails. C1r that acts as a protease on
C1s C1r and C1s intertwine with
the tails. 2 C1q heads must interact with
Fc pieces for complement to be activated.
YY
C4, C2, and C3 components participate Amplification of cascade
1 molecule of C1s activates approximately 30 C4 molecules.
C1
YY
C1s
C4
C2
C4a
C2b
C4b2a
Classical - Activation Unit
Activation Unit
C2 is active only if it binds to C4b before being cleaved by C1s This reaction is enhanced if C4b binds to the
antigen rather than being free in serum Once C4b2a is formed, antibody is no longer
necessary to ensure cell lysis
Activation Unit
C4b2a = C3 convertase One C4b2a complex converts about 200 C3
molecules Requires Mg+
C1
YY
C1s
C4
C2
C4a
C2b
C4b2a C3
C3a
C3b C4b2a3b
Activation Unit
C3 most abundant complement component C3 common to all pathways C3b on a cell enhances opsonization C3b combines with C4b2a to form C4b2a3b =
C5 convertase
Classical – MAC
Membrane Attack Complex = C5, C6, C7, C8, C9
C1
YY
C1s
C4
C2
C4a
C2b
C4b2a C3
C3a
C3b C4b2a3b C5
C5a
C5b
C9
C8
C7
C6
MAC
C5b binds to C6 and C7 in serum This complex will bind to any nearby cell membrane,
not just the cell that originally triggered the cascade. (The “innocent by-stander” effect)
May also form a micelle – free floating sphere- which has antiviral properties
C5b678 form a surface on the cell membrane for polymerization of C9
A pore forms in the cell, allowing an influx of water The cell swells and lyses
Hemolysin
An antibody that can activate complement, resulting in lysis of an RBC is termed a hemolysin. Y YC1
Alternative (Properdin) Pathway
Activated by bacteria, fungus, yeast, viruses, parasites, and tumor cells
Oldest pathway Relies on the natural splitting of C3 into C3a
and C3b (exact process unclear)
C3b
Factor B
C3bBb
Properdin
C3bBbP
C5a
C5
C5b
C9C8C7C6
Factor D
Alternative
C3b and Factor B need Mg+ to combine Factor D splits Factor B that has been bound
to C3b Properdin stabilizes the C3bBb complex C3bBbP is a C5 convertase Once C5b formed, cascade continues as in
the classical pathway
Lectin Pathway
Mannose is a sugar commonly found in bacterial cell walls
This pathway can be activated by bacteria, yeast, viruses and protozoa
MBL C4
C2
C4a
C2b
C4b2a C3
C3a
C3b C4b2a3b C5
C5a
C5b
C9C8C7C6
Lectin Pathway
MBL= Mannose Binding Lectin equivalent to C1q of classical pathway MBL also increases opsonization
MASP-1 and MASP-2 function similarly to C1r and C1s respectively MASP = Mannose Associated Serine
Proteases Once MBL activates the cascade, the
cascade continues as in the classical pathway
Inhibitors of Complement
Activated enzymes decay quickly. Half life of activated components ranges from
a fraction of a second to approximately 30 minutes.
If Ca+ and Mg+ are not present, the cascade can NOT be activated.
Carboxypeptidase N inactivates anaphylatoxins.
Heating serum at 56oC for 30 minutes destroys complement components.
Specific Inhibitors
C1-INH irreversibly binds to the active sites of C1r and C1s.
Factor I degrades C4b and C3b Membrane cofactor protein –cofactor for
Factor I C4-binding protein – prevents C4 and C2 from
joining (cofactor for Factor I)
Specific Inhibitors
Complement Receptor 1 (CR1) Found as a surface protein on most WBCs
and follicular dendritic cells Binds C3b allowing degradation by Factor I Increases clearance of C3b coated cells via
macrophages of liver and spleen Also increases the length of time antigen
remains near germinal centers of lymph nodes (May assist with B cell differentiation)
Specific Inhibitors
Sialic acid of cell membrane inactivates C3b bound to cells
Decay Accelerating Factor (DAF) – dissociates C2 from C3
S protein – prevents C5b67 complex from binding to cell
MIRL – Binds to C8 MIRL = Membrane Inhibitor of Reactive Lysis
Protectin – Prevents binding of C5b678 to cell, so no polymerization of C9 is allowed
Inhibitors - Alternative
DAF & Factor H – compete with Factor B for binding with C3b
C3b
Factor B
C3bBb
Properdin
C3bBbP
C5a
C5
C5b
C9C8C7C6
Complement Deficiencies
Complement deficiencies rare C2 deficiency most common (1 in 10,000) C3 deficiency most problematic as it
participates in all pathways Deficiencies in complement components can
lead to: Increased susceptibility to infection Accumulation of immune complexes Autoimmune disease
Pathologic Conditions
Complement is harmful if: Activated systemically Activated by tissue necrosis Allows build up of immune complexes
Immune complexes play a role in Goodpasture’s syndrome, SLE, MS, Guillain-Barre’ syndrome and other autoimmune diseases
Pathologic Conditions
Paroxysmal Nocturnal Hemoglobinuria (PNH) Abnormal DAF on RBCs Cells more susceptible to lysis
C1-INH deficiency – Hereditary angioedema C2b accumulates, but does not participate in
the complement cascade Increases vascular permeability
The End
Can you list the complement components in order of activation?