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Review
. 2015 May 26:6:257.
doi: 10.3389/fimmu.2015.00257. eCollection 2015.

Complement System Part II: Role in Immunity

Nicolas S Merle  1 , Remi Noe  2 , Lise Halbwachs-Mecarelli  1 , Veronique Fremeaux-Bacchi  3 , Lubka T Roumenina  1
Affiliations
Review

Complement System Part II: Role in Immunity

Nicolas S Merle et al. Front Immunol. .

Abstract

The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b-9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target.

Keywords: adaptive immunity; anaphylatoxins; complement and innate immunity; complement in cancer; complement system; complement-related diseases; crosstalk TLR-complement; pathogen strategies for immune evasion.

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Figures

Figure 1
Figure 1
Complement activation. Complement system is composed of three different pathways. CP is activated by immune complex formation on pathogen surface and by calreticulin expressed on apoptotic cells, leading to C1 complex association. LP recognizes mannose-terminating glycan on pathogens leading to MBL MASP complex activation. Both induce formation of the classical C3 convertase C4b2a. AP is permanently activated at low level by spontaneous hydrolysis of C3 into C3(H2O). Lack of complement inhibitor on pathogens induces alternative C3 convertase activation C3bBb. Complement activation leads to opsonization and phagocytosis by C3b deposition, bacterial lysis by C5b–9 complex formation and inflammation by recruitment of immune cells, endothelial and epithelial cells activation, and platelets activation.
Figure 2
Figure 2
Role of complement in physiology. (A) Protection of host cells against complement. Complement AP is permanently activated and deposits C3b molecules to any surface. On host cells, these C3b molecules are rapidly inactivated by different membrane expressed or plasma complement regulators. (B) Immunologically silent clearance of apoptotic cells. Limited complement activation occurs on apoptotic cells. C1q recognizes “eat-me” signals on the surface of dying cells. It serves as a bridging molecule, facilitating the phagocytosis by dendritic cells or macrophages. Uptake of C1q-opsinized cargo induces an anti-inflammatory program, increased expression of immunological checkpoint molecules, and prevents up-regulation of maturation markers. iC3b on apoptotic cells interacts with CR3 on phagocytes and induces anti-inflammatory response. (C) Complement in human T cell homeostasis. Cathepsin L cleaves C3 intracellularly, generating C3a and C3b. C3a binds on C3aR, expressed in the lysosomes, and stimulates mTOR signaling pathway. This signaling is important for the cell survival in resting state.
Figure 3
Figure 3
Complement in the defense against pathogens. (A) Complement-mediated bacterial killing. C3b is deposited on any pathogen surfaces due to the constant activity of the AP. Since most pathogens do not have complement regulatory molecules, C3b is not inactivated and interacts with FB and FD to form a C3 convertase C3bBb. This enzymatic complex cleaves more C3 molecules, resulting in pathogen opsonization with C3b. Further, the cascade proceeds to a C5 convertase and MAC formation, contributing to bacterial killing. (B) Complement receptors-mediated phagocytosis of C3b and iC3b-opsonized pathogens. Extracellular stimulatory signals, which are necessary for the CR3-mediated phagocytosis, include chemoattractants (not only chemokines but also bacterial formylpeptides and C5a for neutrophils), cytokines (e.g., TNF-α), and bacterial products (e.g., lipopolysaccharide). External stimuli activate the integrin CR3, (i.e., change to a conformation with high affinity for iC3b) by a Rap-1-mediated signaling. Stabilization of CR3 high-affinity conformation by its engagement with iC3b triggers a RhoA-mediated signaling, which drives the actin polymerization to engulf iC3b-coated target. Complex actin movements are then involved in the intracellular movement of the phagosome during its maturation to the phagolysosome.
Figure 4
Figure 4
Role of anaphylatoxins C3a and C5a. Anaphylatoxins C3a and C5a participate in inflammation by interacting and activating immune cells via C3aR and C5aR, respectively. C3a is implicated in the adaptive immunity by inducing monoclonal response from B cells and up-regulation of pro- inflammatory cytokines. Moreover, C3a facilitates the contraction phase of T cells by increasing IL-10 synthesis. C5a is implicated in Th1 expansion to improve adaptive immunity response, and allows C5aR internalization in presence of C5L2 to induce ERK signalization and pro-inflammatory effect of macrophages. Both are chemoattractant molecule, and allow mast cells migration for C3a, basophils, macrophages, neutrophils, and lymphocytes recruitment for C5a at the inflammatory site. Nevertheless, C3a has an anti-inflammatory effect on neutrophils by inhibiting their degranulation and recruitment.
Figure 5
Figure 5
Crosstalk between complement and TLR pathways. C5a/C5aR signaling pathway can cooperate with TLR-4 activation by LPS on macrophages. Intermediate signaling pathways JNK and MAPK are activated and thus lead to pro-inflammatory effect by TNF-α, IL6, and IL1-β synthesis. On dendritic cells (DCs), TLR-4 and C5aR cooperate in different manner between mice and human. In vivo experiments have demonstrated an implication in Th1 cells expansion, whereas in human, an anti-inflammatory role of TLR-4/C5aR collaboration has been described by an antagonized effect on IL-12 and IL-23 synthesis by DC.
Figure 6
Figure 6
Complement receptors implication in adaptive immunity. CR2 activation by interaction with C3d-opsonized antigen on follicular dendritic cells increases CMH expression and allows antigen presentation to TCR. Then, costimulatory molecules are expressed and T lymphocytes help in memory B cells maturation in germinal centers. Moreover, C3d/CR2 interaction lowers the activation threshold of B cells and increases BCR signaling activity. Cumulated, C3d/CR2 interaction induces specific IgG generation by B cells, and C3d works as a natural adjuvant. CR3 and CR4, expressed on immune cells.
Figure 7
Figure 7
Local synthesis of C3 by antigen presenting cells (APC) is implicated in antigen-specific T cell response. C3 synthesis by APC in case of pathogen internalization induces late apoptotic cargo and allows high expression of MHC on APC surface. Thus, it participates in antigen-specific T cell proliferation and Th1 generation. Local C3 and C5 generate C3a and C5a, which induce up-regulation of Bcl-2 and down-regulation of FAS expression via C3aR and C5aR to facilitate T cell proliferation. Moreover, C3a/C3aR and C5a/C5aR signaling pathways activation promotes Th1 generation and avoid Treg differentiation.
Figure 8
Figure 8
T cell response is modulated by complement components. MHC/TCR interaction between APC and T cell decrease CD46 expression on T cell and allows cis interaction between jagged1 and Notch-1 on T cell surface to promote T cell proliferation, IL-2, and IFN-γ production. Thereafter, trans interaction between jagged1 and Notch-1, and CD46 work as negative feedback to control T cell homeostasis. Soluble C5b–9 and CR1 regulate T cell activation. Interaction between soluble form of C5b–9 and its specific inhibitor CD59 on T cells decrease TCR re-expression after its internalization to limit T cell activation by transmitting a signal via Lck. CR1 activation by iC3b decreases IL-2 synthesis and proliferation of T cell to promote a negative feedback of T cell activation. CD55 engagement on T cells negatively regulates Th1 induction cells by inhibiting IFN-γ production. Intracellular C3 in T cell is cleaved by CTSL and promotes C3b and C3a intracellular generation. Interaction between C3a and C3aR induces mTOR signaling and survival signal of the immune cell.
Figure 9
Figure 9
Pathogens are able to protect themselves from complement activation. Pathogens have developed different strategies to inhibit complement activation. They can be classified in four different groups. Several pathogens are able to bind regulators of complement activation (RCA), such as FH and C4BP, to decrease C3 deposition. RCA-like expression allows pathogens to block complement activation without the need to recruit complement regulator. Synthesis of proteases specifically against complement proteins degrades complement components. The last group is pathogens able to express C3 convertase inhibitors.
Figure 10
Figure 10
Implication of complement deficiencies in pathologies. Deficiencies of the components of the CP C1q, C1r, C1s, C2, and C4 are associated with autoimmunity. Lack of regulators of the AP FH, CD46, and FI (as well as overactivation of the components of the C3 convertase C3 and FB) is linked to aHUS and C3G. Deficiencies of the terminal complement components C5, C6, C7, C8, and C9 as well as of the only positive regulator of complement – properdin is susceptibility factors to development of meningococcal meningitis. Lack of expression of the regulators of the C3/C5 convertase CD55 and the terminal pathway CD59 on erythrocytes are a cause of red cell lysis in paroxysmal nocturnal hemoglobinuria (PNH).
Figure 11
Figure 11
Role of factor H Y402H polymorphism in age-related macular degeneration. FH binds to GAG, oxidized lipids, including malondialdehyde via CCP7 on the membrane of injured retinal epithelial (RPE) cells and protects them from complement attack. H402 variant has a weaker affinity to these products of the oxidative stress and protects less well the cells surface. Deposited C3b is not inactivated to iC3b and promotes complement activation. Less iC3b is generated, which contributes to the silent clearance of the injured cells. RPE cells are activated, secrete pro-inflammatory cytokines, and activate macrophages in their microenvironment. This chronic inflammation predisposes to AMD development with aging.
Figure 12
Figure 12
Role of complement in cancer. Complement plays an important role in the chronic inflammation and tumor development. Tumor cells produce complement components and generate C3a, C5a, and C5b–9 in their microenvironment. This result in autocrine tumor cells stimulation, leading to proliferation, migration, and invasiveness. C5a stimulates MDSC, which dampen the immune response, suppressing cytotoxic T cells, and stimulate Treg. C3a, C5a, and C5b–9 promote angiogenesis, helping in tumor nutrient support and dissemination.
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