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C4d: Good or Bad? C4 C4b C4b C4d C1qrs Factor I C4b C4b C2 C4d 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 What Could Be Good About C4d? Complement, particularly C4, inhibits humoral immunity Complement removes immune complexes C4d blocks reactive sites Complement repairs endothelium Complement and/or Ab induces Accommodation Regulation of Humoral Immunity by C4 and its Receptors CR2 (C4b receptor) suppresses auto-immunity C4 Facilitates clearance of immune complexes SLE associated with C4 deficiency C4 deficiency Impairs clearance of apoptotic cells Complement Removes Immune Complexes Healthy EC Sick EC Normal Lung Transplanted Lung Spleen Liver vWF C3 Complement Repairs Endothelium Saadi and Platt J Exp Med 181: 21, 1995 Complement Bocks Reactive Sites C4 C4b C4d C4d C4d C4d C4d C4d C4d Accommodation Anti-A titer 1:64 C4d in Accommodation No Complement Complement Pre-treated Ca2+ Ca2+ Ca2+ C5a ? MAC MAC Ca2 Raf Ras Gi STAT Raf Gi STAT + JAK G ADENYL PLCb2 q CYCLASE STAT PI-3K STAT PLCb2 Atk PI- MEK-1 cAMP DAG IP 3K 3 DAG ERK-1 ERK- PKC S6k 1 Ca2 + PKC Nucleus 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 C1rs MASP MBP C1q H C3b Bb Organ Acute Vascular Transplantation Rejection Cellular Chronic Rejection Rejection Hyperacute Rejection Accommodation C4d deposition in peritubular capillaries Collins BA, et. al. JASN 10:2208, 2000 C4d: Good or Bad? How C4d helps How complement harms How complement benefits Cardiac Xenograft After Kidney Perfusion The Need for C4d Kidneys absorb Ig very well Bound Ig disappears by endocytosis and shedding Some Ig binds “non-specifically” IgM Binding Lung Heart
"good or bad"