Complement in Transplant Rejection

Carmela D. Tan; E. Rene Rodriguez; William M. Baldwin III

doi:10.1128/9781555818722.ch117

Chapter 117 : Complement in Transplant Rejection

Authors: Carmela D. Tan¹, E. Rene Rodriguez², William M. Baldwin III³

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Affiliations: 1: Department of Pathology, 9500 Euclid Ave., Cleveland, OH 44022; 2: Department of Pathology, 9500 Euclid Ave., Cleveland, OH 44022; 3: Department of Immunology, 9500 Euclid Ave., Cleveland, OH 44022

Content Type: Reference

Publication Year: 2016

Category: Immunology

Book DOI: 10.1128/9781555818722

Chapter DOI: 10.1128/9781555818722.ch117

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Abstract:

Better reagents have led to an increased appreciation of the association between complement activation in transplants and poor outcome (1–4). As diagnostic markers, products of complement activation have two attractive attributes related to the fact that activation of complement proceeds through a series of enzymatic steps resulting in multiple cleavage products. First, each enzymatic step is capable of amplifying the number of molecules that are cleaved. Second, the cleavage process reveals cryptic epitopes that allow the activated products to be distinguished from the unactivated precursors. In addition, activation products from two complement components, namely, C4 and C3, have the unusual property of covalently binding to protein and carbohydrate substrates. All of these properties distinguish complement activation products from some of the molecules that activate complement, such as antibodies. Antibodies themselves are not readily detected in tissue sections because only transient binding of a small number of antibodies to tissue is required to activate exponentially larger amounts of complement.

Citation: Tan C, Rodriguez E, Baldwin W. 2016. Complement in Transplant Rejection, p 1123-1131. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch117

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Complement in Transplant Rejection

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FIGURE 1

Activation of the early complement components by antibodies. (a) A pair of IgG antibodies is bound by C1 through the C1q subcomponent, and the enzymatic C1r and C1s subcomponents are activated to cleave C4 into C4a and C4b. C4b can bind covalently to a membrane protein and provide an anchor for C2, which is then cleaved. (b) The complex of C4bC2a enzymatically cleaves C3 into C3a and C3b. C3b is structurally homologous to C4b and can bind covalently to a membrane protein. (c) The covalently bound split products of C4 and C3 remain attached to the cell membrane after the antibody, C1, and C2a have dissociated from the membrane. The sizes of the symbols for C4b and C3b are intended to reflect the potential for larger quantities of C3 than C4 activation products.

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FIGURE 1

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FIGURE 2

Regulation of C4b and C3b by circulating factor I and leukocytes expressing CR1. (a) CR1, which is expressed by leukocytes, associates with C4b or C3b, allowing factor I to cleave C4b and C3b. (b) The first enzymatic cleavage leaves iC4b or iC3b attached to the cell membrane. (c) Factor I then enzymatically cleaves iC4b or iC3b, and C4d and C3d remain covalently bound to the cell membrane. As described for Fig. 1 , the sizes of the symbols for C4b and C3b are intended to reflect the potential for larger quantities of C3 than C4 activation products.

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FIGURE 2

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FIGURE 3

C4d staining of a heart transplant biopsy by immunofluorescence (top) and immunohistochemistry (bottom) shows comparable discrete staining of capillaries between myocytes, indicative of antibody-mediated rejection.

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FIGURE 3

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