Chapter 8 : Complement Regulation and the Host Response to Infection

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The complement (C) system comprises some 15 soluble plasma proteins that interact with one another in three distinct enzymatic activation cascades (the classical, alternative, and lectin pathways) and in the nonenzymatic membrane attack pathway. C is an important component of the host innate immune system. This chapter reviews briefly the main situations in vivo where C may cause disease, discusses recent strategies for regulating C activation in order to reduce C-mediated pathology, and addresses the potential problems related to therapies that inhibit the physiological effects of C activation. Harm will result when C activation occurs in an uncontrolled manner and/or at an inappropriate site; the end result of this will be inflammation and tissue destruction. "Iatrogenic" (treatment-precipitated) C activation is a common consequence of the many modern therapies that involve contact of blood with a foreign surface. The naturally occurring C regulators are excellent inhibitors of C and have potential as therapeutic agents. Inhibitors acting in the terminal pathway are less likely to predispose to bacterial infections and immune complex disease, particularly when used for long-term therapy. With the realization that hyperacute rejection was mediated by C attack came the suggestion that the human C regulators might be utilized to overcome this hurdle. The simplest approach to protecting the xenograft would be to utilize the fluid-phase C regulators. A xenograft hyperexpressing human membrane cofactor protein (MCP) might be rendered highly susceptible to infection with measles virus with consequences for the graft that are not predictable from current knowledge.

Citation: Morgan B. 2001. Complement Regulation and the Host Response to Infection, p 159-174. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch8

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Figure 1

Complement and its control. The C system comprises three activation pathways— classical pathway (CP), alternative pathway (AP), and lectin pathway (LP)—and a common final terminal pathway (TP). The activation pathways and terminal pathway are tightly controlled by a number of fluid-phase and membrane-associated proteins acting either to inhibit the enzymes of the activation pathways (activated CI, C3 convertases, C5 convertases) or to restrict assembly of the MAC. Arrows indicate where in the system each of the regulators exerts its effect. Membrane-bound regulators are boxed, and fluid-phase inhibitors are in bold. Abbreviations as in footnotes to Table 1 .

Citation: Morgan B. 2001. Complement Regulation and the Host Response to Infection, p 159-174. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch8
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Figure 2

Recombinant soluble C regulators. Recombinant soluble forms of each of the major membrane C regulatory proteins have been generated. Recombinant soluble CR1 (sCR1) consists of the 30 short consensus repeats (SCRs, represented as overlapping ovals) of CR1, which represent almost all of the extracellular portion of this molecule (1 is N-terminal). Recombinant soluble MCP (sMCP) and DAF (sDAF) consist of the four SCRs that contain the C regulatory activities together with a portion of the rigid C-terminal STP region. CAB-2 is a chimeric molecule in which sMCP is attached through the C-terminus to the N-terminus of sDAF. CD59 is a globular molecule with no SCR structures. DAF/CD59 chimeras have been expressed on cells but not, to date, as the soluble molecules depicted here. (Modified from reference .)

Citation: Morgan B. 2001. Complement Regulation and the Host Response to Infection, p 159-174. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch8
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Table 1

Summary of human complement regulatory proteins

Citation: Morgan B. 2001. Complement Regulation and the Host Response to Infection, p 159-174. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch8
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Table 2

sCR1 in animal models of disease

Citation: Morgan B. 2001. Complement Regulation and the Host Response to Infection, p 159-174. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch8

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