Transcript 投影片 1 - 國防醫學院數位學習系統

Complement associated immune disorder
Dr. Chen Hung Chen ( 陳 政 宏 )
Division of Rheumatology, Immunology and Allergy
Department of Internal medicine
Tri-Service General Hospital
Introduction of Complement system:
Definition:
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A group of sequentially reacting proteins,
which upon activation, mediate a number of
biological reactions important to host
defense
Nomenclature:
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“C”-designation for 11 of complement
proteins( C1, C2, etc)
“Factor”-designation for many alternative
pathway components( factor B)
Overbar-indicates an enzymatically active
protein or complex
Lower case letters-indicates a proteolytic
cleavage fragments(C3a, C5a)
“R”-designation for receptors in the
complement system(CR1, CR2)
Complement Biosynthetic Sites
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Hepatocytes
Monocyte/Macrophage
Hematopoietic
Fibroblasts
Endothelial
Reproductive
Adipocytes
Astrocytes
Neurons
Modular Structure of Complement Proteins
• Enzymes-(Serine Protease Domain)
C1s, C1r, C2, MASP 1/2,factor B, D, I
• Collectins-(Collagen Stalk, Gobular Domain)
C1q, MBL, Ficolin
• Cytolytic-(C9/Perforin Domain)
C6, C7, C8, C9
• Regulatory and Receptor (SCR Domain)
DAF, MCP,C4BP,CR1 & factor H
• “True” Complement Proteins
C3,C4,C5
Protein of the Complement System
Activation
Serum
Soluble
Membrane
Bound
C1q, C1r, C1s,
C2-C9, Factor
B & D,MASP1/2
sMAP, ficolin
Regulation
Receptors
C1-INH, C4BP
Factor H & I
Properdin,S
protein(vitrone
ctin), Sp40(clusterin)
CR1,CD59,
DAF(CD55),
MCP(CD46)
CR1-CR4
C3aR, C5aR
C1qR
Complement Activation
• Classical PathwayAg-Ab complexes
• Mannan-Binding Lectin PathwayMannose, N-acetylglucosamine
• Alternative PathwayLPS, lipopolysaccharides
Complement-fixing potential of Ab:
IgM>IgG3>IgG1>IgG2>IgG4
Transmission EM of the C1q (left) and C1r-C1s complex (right)
Properdin
(C3aBbP)
(C3bBbC3bP)
(Potent chemotactant)
Initiates the assembly of MAC
“Classic doughnut
hole formation”
(C4b2a)
(C4b2a3b
)
(Initiates
by C3b5b)
C3 convertases
C5 convertases
(C3bBbC3bP)
(C3bBbC3bP)
Complement regulatory proteins & primary location
Fluid phase
-C1-INH
-Factor I, H, C4-bp, S protein (vitronectin), SP-40 (clusterin)
-Carboxypeptidase
Cell membrane
-DAF (CD55)
-MCP (CD46)
-Protectin (CD59), membrane C3-proteinase
Matrix
-Decorin
Complement Activation Regulation
CLASSIC
MBP
ALTERNATIVE
C4-bp:Cofactor
for factor I
C1-INH:inactivate
C1r,C1s, MASPs
Factor I: inactivate C3b, C4b
Factor H: cofactor for Factor I
DAF(CD55):Bind
C3&C5convertase
MCP(CD46): cofactor for factor I,
bind C3& C5 convertase
CR1(CD35): combine activities of
factor H, C4bp,MCP & DAF
C3a
C3
C3b
Vitronectin: Bind C5b67 & C9
to prevent membrane
insertion
Protectin(CD59): Bind C5b-8,
C5b-9 to prevent pore
formation
Carboxypeptidas
e:inactivate C3a
& C5a
C5a
C5
C5b+C6-9(MAC)
Clinical relevant biologic activities of complement
Foreign organism, antigen
RBC
Tumor cells
Blood vessels
Heart
Reproduction
Lymphocyte
Opsoniztion for phagocytosis by PMN,
Monocyte, macrophage, lysis; in vivo
trafficking
Lysis( intavascular or extravascular)
Immune complex trafficking
Promotion of ADCC activity
Promotion of NK activity
Lysis
Atherosclerosis
Ischemia-reperfusion injury
Antibody-mediated infertility, recurrent
fetal loss
Coactivation, antigen present
Autoimmune and/or inflammatory disease
Renal
CNS
Joints
Platelets
Blood vessels
Skin
Pulmonary
Xenotransplantation
Allotransplantation
Mediates GN, proteinuria, stimulation of
collagen & cytokine synthesis & cellular influx
Demyelination in MS, Ab-mediated
neuropathies
Alzheimer’s disease
Recruitment & activation of PMNs
Activation of clotting pathway;
Immune thrombocytopenia
Immune complex vasculitis; neutrophil
chemotaxis, binding and activation
Ab-mediated inflammation
ARDS by anaphylatoxin-mediated neutrophil
activation
Hyperacute rejection
Chronic rejection
Inflammatory Disorder associated with Complement
Activation
• Severe trauma, burn, sepsis •
• Systemic inflammatory
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reaction syndrome (SIRS)
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• Adult respiratory distress
syndrome (ARDS)
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• Multiple organ dysfunction
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syndrome (MODS)
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• Ischemia reperfusion injury •
• Angioedema, capillary leakage
syndrome
Hyperacute graft rejection
Vasculitis, nephritis
Autoimmune disorder, systemic
lupus erythematosus
Rheumatoid arthritis
Multiple sclerosis
Alzheimer’s disease
Reaction to dialysis, apheresis,
cardiopulmonary bypass
Vasculitis & Immune complex disease
• Local deposition of C3, C5b-9 and/or alternative pathway
components.
• Evidence of systemic depletion ( low C3, C4 or THC )
• Associated Disease:
Immuneocomplexes disease, PAN, hypersensitivity vasculitis,
vasculitis and GN in SLE
HSP( alternative pathway activation:C3, properdin with IgA)
except:
Wegener’s or lymphomatoid granulomatosis:
no local complement deposition or systemic depletion
Rheumatoid arthritis
Synovial fluid: ↓THC, ↑C3d, C3a, C5a, C5b-9
Pulmonary disease
C3a and C5a induce neutrophils activationpulmonary injury
MAC stimulating endothelial cell relieve thromboxanes
increase adhesion molecule expression & pulmonary hypertensive
change
SLE with interstitial lung disease C1q, C3 with IgG, IgM
deposition
Renal disease
Protective role: trafficking of ICs from kidney by binding to
CR1 on RBC
Detrimental role: complement activation without cell reflux
(membranous), with cell reflux
(membranoproliferative)
e.g.: In MPGN, ↑C3 nephritic factor
C5b-9 on cells increase collagen synthesis & thromboxanes
and other proliferative molecules
Platelet disease:
ITP
C5b-9 has potentially profound effects on its functionincrease thromboxane synthesis, activation of protein
kinase C and myosin light-chain kinase
Hemolytic anemia:
Intravascular hemolytic anemia: alloimmunization during
prior transfusions
Extravascular hemolysis :in liver & spleen of opsonized cells
by Fc & complement receptor
HUS: 1/3 pts have hypocomplementemia & poor prognostic
indicator
Myocardial disease:
↑serum complement activation products in unstable angina
↑C3, C4, C5, C5b-9 & ↓CD59 & DAF in infracted zone
reperfusion injury cause complement activation
Atherosclerosis:
C5b-9 & activated C3 found in lesion, ↑complement
regulatory protein expression on Mac in lesion
C5a promote peripheral vasoconstriction
Cutaneous disease:
SLE: C3 with Ig deposition(even in non-involved area)
Evidence of complement activation: Autoimmune bullous
disease(Pemphigus, bullous pemphigoid, epidermolysis bullosa)
Acne: C3 in basement zones
Psoriasis: C3a, C5a in lesion & complement activated products
in serum
Reproduction & pregnancy:
Complement-fixing antibodies with specificity for paternal
determinants on sperm mediate infertility
High levels of complement regulatory protein on
reproductive system  prevent uncontrolled complement
activation (e.g.: DAF, MCP,CD59)
Myositis:
DM : C5b-9 with IgG, IgM, C3 deposition in venules &
arterioles
PM: C5b-9 in muscle fiber
Neurologic disease:
Asceptic meningitis :↑in C3, C4: CSF/plasma index
MS’s CSF: ↑C3a, C4a & ↓C9
SLE’s CSF :↑C5b-9
Alzheimer’s disease:↑C4d, C1q & C5b-9 in brain
Xenotransplantation:
Immediate hyperacute rejection: mediated by performed
Abs and/or complement
Chronic rejection: unclear
Tumor resistance to complement:
Increase complement regulatory protein level in some
malignancies, e.g. MCP, DAF, CD59 provide tumor cells to
escape the evasion of Ab or enhanced ADCC & NK activity
mediated by C3b and/or C3bi bound to the tumor cell
Disease in which complement inhibitors will probably be effective
•Some forms of vasculitis
•RA
•ARDS
•SLE
•Many types of renal diseases
•ITP
•Hemolytic anemia
•Myocardial infacion
•Neurologic disease( possibly Alzheimer’s disease)
•Ischemia-reperfusion injury
•Antiphospholipid syndrome & recurrent fetal loss
•Ab-mediated cutaneous disease
•Xenotransplant rejection
•Allotransplant rejection(? Accelerated atherosclerosis)
Selected Complement Activation Inhibitors Under Development
Product
TPO10, TPO20
Description
Actions
Company
sCR1 without(TPO10) or with sLe*
Degrade C3b/C4b, decay
Avant Immunotherapeutics
TPO20
C3 & C5 convertase, TPO20
(Needham, MA)
block selectin binding
h5G1.1
Humanized, high-affinity anti-C5mAb Blcok cleavage of C5 to C5a &
as single-chain Fv or intact mAb
APT070
CAB-2
C1q RNA aptamers
Amino-terminal 3 SCR of CR1
C5b by C5 convertase
Alexion Pharmaceuticals
(New Haven, CT)
Inserts in cell membranes and
AdProTech
myristoylated at the carboxyl
provides intrinsic protection
(Royston, Herts, UK)
terminus
via CR1-like mechanisms
Soluble recombinant chimera of
Degrades C3b/C4b and
Millenium Pharmaceuticals
MCP & DAF
decays C3 & C5 convertases
(Cambridge, MA)
Small molecule inhibitors of C1q
Block C1q
NeXstar Pharmaceuticals
(Boulder, CO)
C1q analogs
Low-molecular-weight inhibitor of
Block C1q
Gliatech(Cleveland, OH)
Inhibit AP activation
BioCryst Pharmaceuticals
beta-amyloid-induced activation of C1q
Serine protease
Low-molecular-weight inhibitors of
factor D
(Hoover, AL)
Thanks for your attention!