Activators - U of M wiki

Report
The Complement System
Adapted from the Presentation of
Jean F. Regal, Ph.D.
Medical School - Duluth
Learning Objectives
 Explain the importance of the complement system in
host defense and inflammation and the clinical
consequences of complement deficiencies.
 Describe the biochemistry of activation of the three
different pathways including the initiators, sequence of
reactions, important enzymes, and fragments.
 List the proteins which control the complement system
and where they act.
 Describe the biological responses mediated by the
different complement receptors.
 Describe the biological effects of complement activation.
Complement:
Location of Complement Proteins
 Complement is not a single protein but a
complex of proteins that are found constitutively
in the plasma.
 Complement proteins are present in secretions,
such as bronchial fluids, where they protect
portals of entry.
 Complement proteins are present in interstitial
fluids where they protect against agents that
penetrate the protective barriers (skin, mucosal
membranes, etc.).
Production of Complement Proteins
 The molecular weights of complement proteins
range widely from 24-400 kDa.
 Complement proteins are synthesized
 Primarily by liver hepatocytes and by tissue
macrophages,
 Secondarily by epithelial cells, fibroblasts and
monocytes.
 Concentration ranges in plasma:
 1 or 2 ug/ml – Mannose-Binding Lectin and Factor D
 300 ug/ml – C4
 1200 ug/ml – C3
Roles of Complement
 Complement proteins are activated on demand.
 Complement proteins are activated in a cascade.
 In these ways, complement proteins are similar
to clotting proteins.
 Complement proteins are non-specific proteins
that play roles both in the innate immune
system and in the adaptive immune system.
 Destroy bacteria
 Destroy fungi
 Destroy viruses
Importance of Complement
 The complement system is so important to our
defense against microorganisms that there are
several pathways by which the complement
system can be activated.
 Classical pathway
 Alternative pathway
 Mannose-binding lectin pathway (aka, lectin pathway)
Nomenclature of Complement
Proteins
 Complement proteins in the common portions of the
Classical Pathway
 Denoted with the letter “C” followed by a number and are named
C1 through C9.
 Proteins in the Mannose-Binding Lectin Pathway are
 Mannan-binding lectin (MBL)
 MBL-associated serine protease-1 (MASP-1)
 MBL-associated serine protease-2 (MASP-2)
 Proteins in the Alternative Pathway that lead to the
common portions of the classical complement pathway
 Denoted as factors (Factor B and Factor D).
Function of the Complement
System
 The complement system acts as an
auxiliary system in immunity, both on its
own and in conjunction with humoral
immunity.
In its role in innate immunity, it is a primitive
surveillance and defense system for microbes,
independent of T cells and antibodies.
In its role in adaptive immunity, it is a major
effector system for humoral immunity.
Specific Functions of the Complement
System
Chemotactic Agent
Activator of
Inflammation
Complement also augments stimulation of B cells through complement receptor 2
(CR2/CD21) to increase the humoral immune response.
Biochemistry of the Complement
System
A. Activation of the complement system
1. The classical pathway
2. The mannose-binding lectin pathway
3. The alternative pathway
B. Control of complement activation
C. Activation/Inactivation of C4b and C3b
D. Complement receptors
Activation of the Classical Pathway
Activators
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign Surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Activators
Complement
Sensors
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Activation of C1
 C1 is present in plasma as an inactive C1qr2s2
complex
 Binding of two arms of the complex to
immunoglobulin (2 IgG or 1 pentameric IgM)
causes conformational change in C1q. This
initiates a cascade of events.
 C1q conformational change  C1r conformational
change
 C1r conformational change C1r active enzyme
 C1r active enzyme  C1s enzymatic cleavage
 C1s enzymatic cleavage  C1s active enzyme
 C1s active enzyme  C4 cleavage
 This result of this cascade is often referred to as
the C1 esterase cleavage of C4.
 Cleavage of C4 is controlled by the C1 inhibitor
(C1INH)
 The absence or mutation of C1 inhibitor leads to
hereditary angioedema (swelling of the face and
respiratory airways, as well as abdominal cramps).
2 IgG/1 IgM
C1q
C1q
C1r
C1r
C1s
C1s
C4
C4b
Italics = conformational change
Color = enzyme activity
Activation of C1
C1 esterase
Activation of C4
 C1 esterase cleaves C4.
 C4a can act a chemoattractant
 C4b has a thioester region which forms
covalent bonds with molecules on the
target surface.
 C4b can act as an opsonin and interacts
with complement receptors (CR1).
Activation of C2
 C2 interacts with C4b and is cleaved by
C1s, forming a C4b2a complex on the
surface.
 C4b2a is the classical pathway’s C3
convertase.
Thus, C4b2a is an enzyme that cleaves C3 to
C3a and C3b.
Note: There is some disagreement among scientists about the
nomenclature for the cleavage products for C2. For example, some
scientists identify the C3 convertase as the C4b2b complex.
C3 activation
 C4b2a cleaves C3, activating a labile thioester
bond on C3b.
 This thioester can bind COVALENTLY to free
hydroxyl or amino groups, resulting in C3b
covalently binding to target surfaces.
 C3b bound to a surface acts as an opsonin.
 Key points for the classical pathway
 Activation occurs in conjunction with specific antibody
 C3b and C4b covalently bind to target via thioester
bonds
 Because there is a series of enzymatic cleavage
events, there is tremendous amplification of the
signal as the signal progresses down the series.
Review of Activation of the
Classical Pathway
 The sequence of complement protein activation
in the classical pathway is
1>4>2>3>5>6>7>8>9
 Note that 4b gets “before (b 4)” its expected place.
 The classical pathway is triggered by antigen
binding to (crosslinking) two IgG molecules or
two subunit parts of one IgM molecule.
 The cascade of proteolytic steps in the classical
pathway are performed by serine esterases.
 C4b and C3b bind covalently to surfaces via
thioester bonds.
Sequential Enzymatic Cleavage Events
in Complement Activation
Activators
Complement
Sensors
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
Enzymatic
Cleavage
Events
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Activation through C5
 Involves proteolytic cleavage steps, liberating smaller
fragments from C2 through C5. The smaller fragments
are soluble and can have biologic effects. The larger
fragments remain bound in a complex required for the
next activation step.
 By convention,




Smaller fragments are denoted by the letter ‘a’ (e.g., C3a, C5a)
Larger fragments by ‘b’ (e.g., C3b, C5b)
Notable exception is C2 (C2a is the larger, active fragment).
Complexes with enzymatic activity are often denoted by a line
over the top of the numbers or letters, as in
• (C4b2a)
Activation of the Mannose-Binding
Pathway
MBL Pathway
 Activation of the MBL Pathway is primarily mediated by a
protein constituent in the plasma called mannan-binding
lectin (also called the mannose-binding lectin or MBL).
 Activation of the MBL Pathway does not require specific antibody
for activation.
 Activation of the MBL Pathway occurs by a C1-independent
mechanism.
 Activation of the MBL pathway occurs when MBL binds
to specific sugar residues like N-acetyl glucosamine or
mannose that are present in the cell wall polysaccharides
of microorganisms such as Salmonella, Listeria,
Neisseria, Candida, etc.
 MBL, which resembles C1q, interacts with MASP-1 and
MASP-2 by a mechanism similar to C1q interaction with
C1r and C1s, resulting in the formation of the classical
pathway C3 convertase (C4b2a).
Activators
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign Surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Activators
Complement
Sensors
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Activation of the Alternative
Pathway
Alternative Pathway
 Phylogenetically the oldest of the C3 activating
pathways.
 Does not require specific antibody/antigen
binding for activation.
 Can be triggered by a low level of spontaneous
lysis of C3 by water to C3i that functions in a
manner similar to C3b.
 Can be amplified by C3b binding to foreign
surface structures (LPS) or by additional
cleavage by bacterial proteases.
Some Initiators or Activators of the
Alternative Pathway of Complement
Activation
 Many Gram negative and Gram positive bacteria
 LPS from Gram negative bacteria
 Teichoic acid from Gram positive cell walls







Fungal and yeast cell walls (zymosan)
Some viruses and virus infected cells
Some tumor cells
Some parasites
Human IgA, IgG and IgE in complexes
Anionic polymers (dextran sulfate)
Pure carbohydrates (agarose, inulin)
Activators
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign Surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Activators
Complement
Sensors
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
C5a
(Anaphylatoxins)
Formation of the Alternative Pathway C3
Convertase (C3bBb)
 C3 tickover - spontaneous conformational change of a
few C3 molecules, leading to water hydrolyzing the
thiolester bond of C3 to form C3 H20 or C3i.
 C3i is then deposited in a random and non-specific
manner on the surfaces of host cells and pathogenic
organisms alike.
 On the normal host cell, bound C3i can inactivated by binding to Factor
I and Factor H.
 On the pathogenic organism, bound C3i can be further activated by
binding to Factor B to form C3iB which is then cleaved by Factor D to
form C3iBb (C3 convertase).
 Properdin acts to stabilize the alternative pathway C3 convertase
(C3bBb)
 Surfaces rich in carbohydrate and deficient in sialic acid
tend to be the best activators.
Activation and Inactivation of C3b
C3 = Complement C3
FB = Factor B
FD = Factor D
FI = Factor I (in conjuction with Factor H,
inactivates soluble C3b and C4b when
deposited on the surface of a normal cell)
FH = Factor H (cofactor of Factor I in mediating
cleavage of C3b to its inactive form C3bi
aka C3i
Stablized by
properdin
Target Cell Membrane
Normal Cell Membrane
Amplification of C3 Cleavage by Membrane-Bound C3bBb
Activation of C5 and the Terminal
Complement Pathway
 C5 is cleaved by either the Classical Pathway C5
convertase (C4b2aC3b) or by the Alternative
Pathway C5 convertase (C3bBbC3b) into 2
fragments: C5a and C5b.
 Cleavage of C5 is the last enzymatic step
 C5b binds to a target and then interacts with C6,
C7, C8 and C9 to form the Membrane Attack
Complex in the lipid membrane.
 The Membrane Attack Complex is a
transmembrane channel that allows passage of
ions, compromises of the semi-permeable
membrane, and causes lysis of the cell.
Activation of C5
 C5 is cleaved into 2
fragments (C5a and
C5b) by either
 The Alternative
Pathway C5
convertase
(C3bBbC3b) or
 The Classical
Pathway C5
convertase
(C4b2aC3b).
 Cleavage of C5 is the
last enzymatic step.
Activators
Complement
Sensors
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
(Anaphylatoxins)
C5a
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
Non-Cleavage
Events Involved in
MAC Assembly
Non-Cleavage Events in Assembly of
the Membrane Attack Complex
 C5b then interacts
with C6, C7, and C8.
 Lysis can occur in the
absence of binding of
C9 but it is slower.
Activators
Complement
Sensors
Classical Pathway
Lectin Pathway
Alternative Pathway
Antigen Antibody
Complexes (IgG/IgM)
Polysaccharides on
Microbes; Also IgA
Foreign surfaces (LPS);
Spontaneous (Nucleophiles)
C1q
MBL
MASP-1, MASP-2
C1r2 C1s2
C3 + H2O
Factor B
Factor D
C4
C2
C3
C3 convertase (C4b2a)
C3b (Opsonin)
C3a
C5 convertase (C4b2a3b)
(Anaphylatoxins)
C5a
C5
Terminal lytic
Pathway
C5b
C6
C7
C8
C9
Membrane
Attack
Complex
Punches Hole in Bacterial
or Viral Membrane
Assembly of C9 Channel
 If C9 molecules are
bound to the C5bC6C7C8
complex, they form the
Membrane Attack
Complex that can punch
a hole in the lipid
membrane.
 Since the Membrane
Attack Complex is a
transmembrane channel
that allows passage of
ions, it will compromise
the semi-permeability of
the membrane and
result in lysis of the cell.
Notes on C9 Assembly
 If the interaction with
C5b through C9
occurs in proximity to
a membrane, then the
MAC assembly occurs
in that membrane and
lysis is the end result.
 Alternatively, C5b-9
can bind to S protein
in the fluid phase. In
this case, lysis does
not occur.
Summary of Pathways of Activation
 Three Primary Pathways of Activation with
different start signals
Classical – antigen antibody
Mannose binding lectin - mannose
Alternative – LPS, carbohydrates, etc
 Proteolytic cleavages of complement
components operate through C5
 Non-proteolytic events for assembly of
C6789 membrane attack complex
Summary of Names You Need to Know
Classical Pathway:
C1q, C1r, C1s, C4, C2
Mannose Binding lectin pathway:
MBL (mannose binding lectin)
MASP-1 (MBL-associated serine protease)
MASP-2
Alternative Pathway:
Factor B
Factor D
Properdin
Common to all pathways:
C3
Terminal Lytic pathway:
C5, C6, C7, C8, C9
Control
What stops the activation?
Or
Why don’t we lyse all of our own cells?
Things That Limit Complement
Activation
 Short half life of the enzymes formed
 Properties of non-activator surfaces
 Inhibitors
Fluid phase inhibitors
• So active fragments don’t go too far
Membrane bound inhibitors
• On our own membranes
• So C3b and C4b don’t attach or don’t lead to lysis of
our own cells
Activation and Inactivation of C3b
C3 = Complement C3
FB = Factor B
FD = Factor D
FI = Factor I ( inconjuction with Factor H,
inactivates soluble C3b and C4b when
deposited on the surface of a normal cell)
FH = Factor H (cofactor of Factor I in mediating
cleavage of C3b to its inactive form C3bi
aka C3i
Stablized by
properdin
Target Cell Membrane
Normal Cell Membrane
Modes of Action of Complement Control Proteins
Control Protein
Main Site of Action
C4 Activation – Classical Pathway
C1-INH
Plasma
Formation of the membrane attack complex
S Protein
Plasma
CD59 or HRF
(homologous
restriction factor)
C3 and C5 Activation
Factor H
C4bp
CR1
c
Self membranes (wide tissue
distribution)
Plasma and nonactivator
membranes
Plasma
c
Self membranes (restricted
tissue distribution)
c
Self membranes (wide tissue
distribution)
c
Self membranes (wide tissue
distribution
Mode of Action
Binds covalently to active C1s and C1r so C4 is not
cleaved
Binds to soluble C5b-7 and blocks its integration into
membranes
Inhibits binding of C9 and its polymerization
Decay Acceleration of
a
Convertases
C3b,Bb
C4b,2a
+
-
Cofactor Activity
C3b
C4b
+
-
+
+
+
+
b
+
+
MCP (Membrane
+
+
cofactor protein)
DAF or CD55
+
+
(Decay accelerating
factor)
a
Decay acceleration is the ability to dissociate the C3 convertases C3b, Bb or C4b,2a.
b
Cofactor activity for the cleavage of C3b or C4b by factor I.
C
In this context, “self” stands for “within the same species.” Control proteins are mostly inactive for complement
of other species.
What If You Lack Control?
 Deficiencies of complement control proteins
can lead to uncontrolled activation of the
complement system
Consequences of activation – lysis, etc
Consumption (exhaustion) of the complement
components leading to the consequences of
secondary complement deficiency (immunecomplex disease and infections)
C1 Inhibitor Deficiency
 Roles of the C1 inhibitor
Inhibits C1 esterase
Also inhibits kallikrein, plasmin, Factor XIa and
Factor XIIa
 Deficiency in C1 inhibitor leads to recurrent
episodes of localized edema in skin, GI tract,
or larynx
 Results in HAE (hereditary angioedema)
Prevalence: 2-10 per 100,000
Hereditary angioedema
Deficiency in Decay Accelerating Factor
(CD55) & CD59
 DAF deficiency causes increased susceptibility of
erythrocytes to membrane attack complex-mediated
lysis
 See as complement-mediated intravascular hemolysis in
paroxysmal nocturnal hemoglobinuria (PNH)
 DAF deficiency is due to a defect in a posttranslational modification of the peptide anchors
that bind the proteins to the cell membrane
 Recent studies suggest that DAF deficiency can be
treated with an antibody to C5 reduces hemolysis
What If You Lack a
Complement Protein?
Review: What does complement do?
Lyses cells (MAC)
Inflammatory mediators (C3a, C5a)
Opsonization
Solubilization and clearance of immune
complexes
 Augmentation of humoral immunity




Review: What does complement do?
Lyses cells (MAC)
Inflammatory mediators (C3a, C5a)
Opsonization
Solubilization and clearance of immune
complexes
 Augmentation of humoral immunity




Anaphylatoxins
C3a  C3a receptor  Response
C5a  C5a receptor  Response
C3a and C5a can mimic the symptoms of
inflammation and anaphylaxis
Chemotaxis, smooth muscle contraction, increased
vascular permeability, degranulation of mast
cells, etc.
Distinct receptors on many cell types
Anaphylatoxin Receptors
CD88
Review: What does complement do?
Lyses cells (MAC)
Inflammatory mediators (C3a, C5a)
Opsonization
Solubilization and clearance of immune
complexes
 Augmentation of humoral immunity




Things C4b and C3b can do
Complement Activation
C4b and/or C3b
on surfaces
Participate in continued
pathway activation leading
to MAC
Interact with CR1
Degraded to fragments
Interact with
CR2 and CR3
Lysis
Opsonization
Clearance of IC
Opsonization
Clearance of IC
Augmentation of humoral
immunity
CR1 (CD35)
 Major ligands C3b, C4b
 Monocytes, macrophages, PMN,
Eosinophil, RBC, B and T cells
 Transport of immune complexes by RBC
 Promotes immune adherence (binding of
opsonized microbes to primate RBCs)
 Promotes phagocytosis in cooperation
with Fc receptors
 Blocks formation of C3 convertase
Complement Receptors
Receptor
Major Ligands
CR1 (CD35)
C3b, C4b
CR2 (CD21)
C3d, C3dg, iC3b
CR3
(CD11b/CD18)
CR4
(CD11c/CD18)
iC3b
Activity
Cellular distribution
Blocks formation of
C3 convertase;
Binds immune
complexes to cells
RBC, PMN,
monocyte,
macrophage, eos,
follicular DC, B cell,
some T cells
B cell co-receptor
Binds EBV
B cells, follicular DC,
some T cells
Cell adhesion
Binds immune
complexes
Monocytes,
macrophages,
neutrophils, NK,
some T cells
Review: What does complement do?
Lyses cells (MAC)
Inflammatory mediators (C3a, C5a)
Opsonization
Solubilization and clearance of immune
complexes
 Augmentation of humoral immunity




C3 fragment interaction with Complement Receptors
Bacteria or IC
Clearance of Immune Complex
Augments humoral
immunity
Immune Complex Disease
 High incidence of Immune Complex disease in
individuals who are deficient in C1, C4, C2 or C3
 Immune complexes are not solubilized and cleared
 Complement can also play a significant role in
tissue damage in Immune Complex diseases
such as SLE (systemic lupus erythematosus)
 Excess immune complexes cause pathological
complement activation  inflammation, tissue
damage
Immune Complex Solubilization
And Transport
 Complement prevents formation of insoluble
immune complexes (solubilization).
 Deposition of insoluble aggregates in the tissues can
cause damage and immune complex disease.
 Binding of C3b to the antigen antibody complex
interferes with lattice formation, limits its growth,
prevents precipitation of the antigen antibody
complexes and keeps them soluble.
Immune complex transport
 The complement system is a major mechanism
for removal of immune complexes (transport).
 Immune complexes coated with C3b bind to CR1.
More than 85% of the CR1 in the circulation is on the
RBC.
 CR1 receptors on the erythrocyte are responsible for
the transport of immune complexes to the
reticuloendothelial system for clearance
(macrophages in spleen, etc). The immune complex
coated with C3b is transferred from the RBC CR1
receptor to the macrophage CR1 receptor. The
immune complex is then internalized and degraded.
Review: What does complement do?
Lyses cells (MAC)
Inflammatory mediators (C3a, C5a)
Opsonization
Solubilization and clearance of immune
complexes
 Augmentation of humoral immunity




CR2 (CD21)
 Major ligands C3d, C3dg, iC3b
 B cells, activated T cells, epithelial cells
 CR2 forms an additional signal with
antibody to augment stimulation of the B
cell to increase the humoral immune
response (CR2/CD19/CD81).
 CR2 has high affinity for an envelope
protein of Epstein Barr virus, allowing the
virus to enter the B cell.
Complement Deficiencies
 Deficiencies of the various complement
components often present as infections
 Pyogenic infections and infections with encapsulated
bacteria (classical and alternative)
 Opsonization and phagocytosis are a primary host
defense.
 Neisseria infections (C3, alternative pathway and
terminal lytic pathway)
 Immune complex or autoimmune disease
 Classical pathway or C3 deficiencies
Complement Deficiencies and Associated Diseases
Component
Classical pathway
C1q
C1r or C1s
C4
C2
MBL pathway
MBL
MASP-2
C3 and alternative pathway
C3
B
D
Properdin
I
H
Number of cases
or Incidence
41
19
26
IC Diseasea
High incidence
1:10,000-1:20,000
2-7% UK
population
9 Caucasians
Undefined
27
1
<10
Glomerulonephritis>SLE
-
>100
-
31
22b
1
HUSc
Membrane attack complex
C5
30e
e
C6
80
e
C7
70
e
C8
70
C9
1:1000
a IC disease, SLE, SLE-like syndromes, glomerulonephritis, vasculitis.
c HUS, Hemolytic uremic syndrome.
e Higher incidence in Japanese (0.001-0.004%)
Infections
Encapsulated bacterial
infections or pyogenic
infections
Increased susceptibility to
bacterial infection
Undefined
Pyogenic and Neisseria
Meningococcal infection
Meningococcal and
encapsulated bacterial infection
Meningococcal infection
Encapsulated bacterial infection
Meningococcal infection
Meningococcal infection
Meningococcal infection
Meningococcal infection
Meningococcal infection
Factor H is One Fluid Phase Inhibitor of
C3 Convertase
• Factor H is a fluid phase inhibitor of C3 convertase. If
it sees C3bBb floating around, it binds and dissociates
the Bb, thus inactivating the C3bBb.
‘Decay acceleration of the convertase’
Factor H Can Inactivate C3bBb on the Surface of a Normal Cell
• If Factor H sees C3bBb on a membrane with sialic acid (like our
membranes), it will bind to the sialic acid residue and C3b, displacing
Bb from the convertase and inactivating C3bBb. Factor I than can
degrade the C3b, with Factor H as a cofactor.
• An activator surface (such as bacteria) does not have sialic acid and
therefore Factor H cannot bind and displace the Bb. In this case, the
Factor H does not inhibit the C3 convertase activity.

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