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26 ASHI Quarterly Third Quarter 2015 S C I E N T I F I C C O M M U N I C A T I O N S Significance of Complement Fixing Antibody Testing in Kidney Transplantation Gansuvd Balgansuren, MD, PhD, D(ABHI) Complement fixing (activating), donor specific (DSA) HLA antibodies (Ab) are the major cause of antibody mediated rejection (AMR) resulting in transplanted organ graft failure (GF) Poor and noncomplement activating HLA DSAs can also contribute to graft failure Tests that can distinguish between complement and non-complement activating DSAs are very important to the clinical transplant laboratory to help assess rejection risks Complement activity is initiated by three pathways; the classical pathway, the lectin pathway, and the alternative pathway The classical pathway is triggered by immunoglobulins IgG1, IgG3, and IgM, when they bind C1q, the first component of the complement system followed by the activation of C4 and C2 to form C3- convertase The lectin pathway is activated when molecules like mannose binding lectin bind to certain carbohydrates or glycoprotein components of microorganisms, which initiates the complement cascade resulting in C3 activation The alternative pathway of complement activation is based on the spontaneous low-grade hydrolysis of C3, which activates when its split product C3b binds to microbes All three activation pathways start from different initiation points utilizing different components The complement cascade merges at the level of C3, and then generates the common terminal component of C5b-C9, the membrane attack complex (MAC) on the cell surface (Figure 1) Figure 1. A Simplified Overview of the Complement System Adopted from: Cook HT, Botto M. Mechanisms of disease: the complement system and the pathogenesis of systemic lupus erythromatosus. Nature Clinical Practice Rheumatology. 2006;2:330-37. Classical pathway Antigen-antibody complex Lectin pathway Sugar residues (mannose) Alternative pathway Activating surfaces Terminal pathway C3 convertases C5 convertases C5b-9 (MAC) MBL MASPs C4 C2 C5b C6 C7 C8 C9 (n) C3b C3a C3b C5a C5b Anaphylatoxin Lysis Sublytic effects Anaphylatoxin Chemotaxin C3 C5 C3b B D Properdin C1q, C1r, C1s C4 C2