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