Chapter 11 : Complement and Its Receptors in Infection

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This chapter focuses on the general modus operandi of complement and its receptors in infection. It discusses the various pathways of complement activation and their microbial triggers and highlights some of the mechanisms and strategies pathogens have evolved to counteract or “hijack” the complement system. A portion examines how the source of complement affects adaptive immunity to infectious agents. Defined by the mode of activation and the subsequent proteolytic cascade in which activation occurs, three activation pathways are recognized: classical, mannan-binding lectin (MBL), and alternative. Complement receptors play an important role in the uptake and clearance of opsonized Ag, enhancing adaptive and innate cellular responses, and inducing inflammatory responses. The role of anaphylatoxin receptors becomes more complicated when relatively recent work describing an attenuating effect of C3aR on inflammation induced by lipopolysaccharides (LPSs) in an in vivo endotoxic shock model is considered. An additional factor that might have promoted cooperation between adaptive immunity and classical complement is the close linkage of some of their hallmark genes on the mammalian genome. To date, myeloid C3 is the only known source with a site-restricted complement function that does not overlap with alternative sources. Its fundamental importance in adaptive immunity in the periphery might make it a factor of consideration in vaccine development or possibly part of standard clinical analyses where serum complement is measured now.

Citation: Verschoor A, Carroll M. 2004. Complement and Its Receptors in Infection, p 219-240. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch11
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Image of FIGURE 1

Schematic overview of the complement cascade. Classical, MBL, and alternative pathways commence from the left side of the figure, leading to the converging point of C3 activation (top right). In every subsequent proteolytic step, the position of the new addition to the antigen complex is shown in black for clarity. From the central C3 activation step downwards, the C3 amplification loop through the alternative pathway is indicated by asterisks. The lytic pathway is initiated with the formation of C5 convertase and leads to the assembly of the C5,6,7,8,()9 MAC that interferes with the target's structural integrity by penetrating the cellular membrane (bottom right).

Citation: Verschoor A, Carroll M. 2004. Complement and Its Receptors in Infection, p 219-240. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch11
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Image of FIGURE 2

Molecular basis for complement enhancement of the humoral response. (1) Ag captured and presented on the FDC surface through CR1/2 or FcR is presented to Ag-specific B cell in the germinal center. (2) Recognition of Ag through the BCR and coligation of the CR2, CD19, CD81-signaling complex through complement leads to Bcell activation and (3) Ag-specific Ab production. (4) Specific Ab complexes with Ag result in (5 and 6) downregulation of the B-cell response by engagement of the cell surface BCR and FcR. Also, formation of Ag– Ab(-C′) complexes results in enhanced trapping of Ag onto the FDC surface through CR and FcR (7), creating a long-term Ag pool.

Citation: Verschoor A, Carroll M. 2004. Complement and Its Receptors in Infection, p 219-240. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch11
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Image of FIGURE 3

Impaired humoral responses in classical complement or complement receptor knockout mice. C3-, C4-, or CR1/2-deficient animals reveal impaired humoral responses upon peripheral HSV infection. Recombinant β-galactosidase-expressing HSV-1 (strain HD-2) was used for inoculation, giving essentially the same results as WT virus but also allowing assessment of the response to β-galactosidase (as reported by ).The results mirror, in a well-controlled way, early immunization experiments with animals that were transiently depleted or naturally deficient in one or more complement factors.

Citation: Verschoor A, Carroll M. 2004. Complement and Its Receptors in Infection, p 219-240. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch11
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Image of FIGURE 4

Local myeloid C3 synthesis is essential for humoral responses to peripheral HSV infection. (a) Peripheral HSV infection leads to robust humoral responses in WT but not C3 animals. (b) Local BM-derived myeloid C3 synthesis can rescue this defect in WT BM → C3 animals. Upon further investigation, local C3 synthesis appears essential, as evidenced by infection of C3 BM →WT animals. (c) C3 BM →WT animals show WT-like levels of circulating C3, but do not respond to HSV. In contrast, WT BM →C3 animals have essentially C3 serum levels, but respond with WT-like humoral responses. i.d., intradermally.

Citation: Verschoor A, Carroll M. 2004. Complement and Its Receptors in Infection, p 219-240. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch11
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Image of FIGURE 5

Model for myeloid C3 enhancement of the humoral response in the periphery. Upon HSV infection (1), viral Ag in the skin encounters complement from various sources, including those that are serum, keratinocyte, or myeloid derived (2). Although serum or keratinocyte C3 is clearly present, C3 BM →WT animals suggest that these sources of C3 do not result in enhancement of the humoral response. Carried by the afferent lymphatics (3),Ag reaches the peripheral lymph nodes in free, complement-complexed or antigen-presenting cell (APC)-processed form.There it is recognized by Ag-specific B- cells (4) that receive T-cell help generated though MHC-restricted APC interaction (5). Gamma interferon (IFNγ) is generated in this process and has been shown to stimulate macrophages to produce complement factors, which then can opsonize drained Ag (6). Opsonized Ag can enhance the B-cell response significantly (7), increasing the amount of specific Ab produced. Specific Ab aids the formation of Ag, Ab, Cʹ immune complexes, structures that are especially immunogenic. SS, subcapsular sinus; IC, immune complex;AFC, antibody-forming cell.

Citation: Verschoor A, Carroll M. 2004. Complement and Its Receptors in Infection, p 219-240. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch11
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