c4d: good or bad?
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C4d: Good or Bad?
C4 C4b C4b
C4bC4d
C1qrs
C4b
Factor I
C4d
C2
Saadi et al. J Exp Med 182: 1807, 1995
How to Detect Humoral Rejection Dysfunction of graftAnti-donor antibodies in the bloodIg depositsComplement depositsPlatelet countFibrinRBC morphology
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
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
Healthy EC Sick EC
Complement Removes Immune Complexes
Normal Lung Transplanted Lung
vWF C3L
iver
Spl
een
Saadi and Platt J Exp Med 181: 21, 1995
Complement Repairs Endothelium
C4dC4dC4d
C4dC4d C4d
C4 C4b C4d
Complement Bocks Reactive Sites
Anti-A titer 1:64Anti-A titer 1:64
AccommodationAccommodation
C4d in Accommodation
ComplementPre-treated
NoComplement
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
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
C1q
C1rs MB
P
MASP
C3b Bb
H
OrganTransplantation
HyperacuteRejection
Acute VascularRejection
Accommodation
CellularRejection
ChronicRejection
Collins BA, et. al. JASN 10:2208, 2000
C4d deposition in peritubular capillaries
C4d: Good or Bad?
How C4d helps How complement harmsHow complement benefits
Cardiac Xenograft After Kidney Perfusion
The Need for C4d
Kidneys absorb Ig very wellBound Ig disappears by endocytosis
and sheddingSome Ig binds “non-specifically”
Lung Heart
IgM Binding
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