c4d: good or bad?
DESCRIPTION
C4d: Good or Bad?. C4b. C4b. C4. C4b. C4d. C4d. C4b. C1qrs. Factor I. C2. Saadi et al. J Exp Med 182: 1807, 1995. How to Detect Humoral Rejection. Dysfunction of graft Anti-donor antibodies in the blood Ig deposits Complement deposits Platelet count Fibrin RBC morphology. - PowerPoint PPT PresentationTRANSCRIPT
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C4d: Good or Bad?
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C4 C4b C4b
C4bC4d
C1qrs
C4b
Factor I
C4d
C2
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Saadi et al. J Exp Med 182: 1807, 1995
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How to Detect Humoral Rejection Dysfunction of graftAnti-donor antibodies in the bloodIg depositsComplement depositsPlatelet countFibrinRBC morphology
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What Could Be Good About C4d?
Complement, particularly C4, inhibitshumoral immunity
Complement removes immunecomplexes
C4d blocks reactive sitesComplement repairs endotheliumComplement and/or Ab induces
Accommodation
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CR2 (C4b receptor) suppresses auto-immunity
C4 Facilitates clearance of immune complexes
SLE associated with C4 deficiency
C4 deficiency Impairs clearance of apoptotic cells
Regulation of Humoral Immunity by C4 and its Receptors
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Healthy EC Sick EC
Complement Removes Immune Complexes
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Normal Lung Transplanted Lung
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vWF C3L
iver
Spl
een
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Saadi and Platt J Exp Med 181: 21, 1995
Complement Repairs Endothelium
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C4dC4dC4d
C4dC4d C4d
C4 C4b C4d
Complement Bocks Reactive Sites
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Anti-A titer 1:64Anti-A titer 1:64
AccommodationAccommodation
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C4d in Accommodation
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ComplementPre-treated
NoComplement
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Nucleus
Ca2+Ca2+
Gi STAT
MACRaf Ras
MEK-1
PI-3K
ERK-1
Atk
S6k
STATSTAT
Raf JAKSTAT
MAC
cAMP
ADENYLCYCLAS
E
Gi
PLCb2
PKCCa2+
Ca2
+
G
Ca2+
?
C5a
DAGIP3
PI-3K
ERK-1
PLCb2
PKC
DAG
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Caveats of Accommodation
May allow organ to survive long enough to acquire chronic rejection
May fail to avert whatever causes chronic rejection
May cause chronic rejection
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C1q
C1rs MB
P
MASP
C3b Bb
H
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OrganTransplantation
HyperacuteRejection
Acute VascularRejection
Accommodation
CellularRejection
ChronicRejection
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Collins BA, et. al. JASN 10:2208, 2000
C4d deposition in peritubular capillaries
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C4d: Good or Bad?
How C4d helps How complement harmsHow complement benefits
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Cardiac Xenograft After Kidney Perfusion
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The Need for C4d
Kidneys absorb Ig very wellBound Ig disappears by endocytosis
and sheddingSome Ig binds “non-specifically”
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Lung Heart
IgM Binding