Complement System Function in Immune System

Besides the well‐studied CR2 and C3d interaction, B cells also express CR1 and CR4 which recognize C3b and its degradation product iC3b 95, 96. Three key amino acids (R1182, R1203, R1206) are critical for this “common microbial binding site” for at least seven Gram-negative and Gram-positive pathogens (165). 4 ways to boost your dog's immune system, but they do have an immune system that's pretty similar to humans:. Complement activation promotes tumor growth. We hypothesize that the rapid degradation of C4b on the bacterial surface seriously compromises the ability of the classical pathway to form a C3 convertase and thus opsonize S.

Tables S1, Additional file 2: In the context of allergic diseases, a substantial amount of evidence is accruing to suggest that complement pathways are indeed activated in patients with asthma and that mediators of this pathway play an important role in both influencing the nature of the adaptive immune responses to inhaled allergens as well as amplifying the Th2 immune response once initiated. Formation of the initial C3 convertase of the alternative complement pathway. Pneumococcal vaccination history or immune status may need to be considered prior to initiating anti MASP-2 treatment in patients. We have characterized the nature of C1q-dependent innate immunity in more detail. C2a binds C4b forming the C4b2a complex whereas C2b goes away. The main pathway involved in activation of complement inside tumors is unclear, and evidence supports activation of each complement pathway in malignant tumors (40). Previous work on human neutrophil determined a role of C5L2 as a negative regulator of anaphylatoxin receptor activity after activation and interaction with β-arrestin, this was confirmed in mouse model (113, 114).

C4 is cleaved by activated C1s or MASP-2 to bioactive fragment C4b and a small fragment C4a (Figures 7A,B). The pathogenic process in C3G is presumed to be due to uncontrolled C3 and/or C5 convertases activation, leading to C3 deposits and intra-glomerular inflammation. However, it does cleave C5 at an alternate site, R947, generating intermediates C5T and C5bT. The central component of the complement system is C3. The complement system’s ability to distinguish self from non-self makes it an important part of the innate immune response to invading pathogens (46). This phenotype underlines our in vitro results and indicates that ficolin A (but not MBL-A or MBL-C) is a key recognition component of the lectin activation pathway in the innate host defense against pneumococcal infection. This therapeutic is approved for use in PNH and aHUS and gives excellent results (274, 275).

Both are chemoattractant molecule, and allow mast cells migration for C3a, basophils, macrophages, neutrophils, and lymphocytes recruitment for C5a at the inflammatory site. Interestingly, C5bT formed a C5bT-9 MAC with significantly more lytic activity than with C5b-9. These‐membrane bound regulators, CD46, CD55 and CD59, are expressed on all circulating cells, including all the cell types addressed in this review 21. Plasma therapy was the first line treatment for aHUS before the development of anti-C5 blocking antibody eculizumab (271, 272). Therefore, therapeutic strategies are needed to adjust the level of complement activation in pathological conditions. Some viruses, such as poxvirus, have found ways to produce soluble proteins that closely mimic the structure and function of host regulators, such as vaccinia virus, which produce VCP, a protein similar to CD55 and MCP. Food to boost your immune system and fight the flu. However, when a test was developed to measure MBL in the blood, it was determined that low or absent MBL is very common, affecting approximately 5-30% of all individuals. Lastly, anaphylatoxins may be generated by mechanisms independent of the classical and alternative pathways of complement activation.

2 mM Ca2+ and 1. This is externally hydrophobic allowing it to associate with the lipid bilayer, creating a hydrophilic internal channel that allows the passage of solutes and water into the cell disrupting the cellular integrity of the pathogen. This finding is consistent with the fact that Hammad and coworkers have shown that the production of CCL17 and CCL22 by human monocyte–derived DCs in response to Der p 1 exposure is preferentially in mDCs derived from HDM-allergic donors, whereas in non–HDM-allergic healthy control subjects, Der p 1 induced mainly CxCL10 (30). The type I interferons present in humans are IFN-α, IFN-β and IFN-ω. In a 2020 study, Tulamo et al. C3d; the first one, described in 2020 by Szakonyi et al. When this happens, the glomeruli can’t filter (clean) the blood, the kidney becomes damaged, waste builds up, and you feel sick. CR3 and CR4 are transmembrane heterodimers composed of an α-subunit (CD11b or CD11c, respectively) and a common β-chain (CD18) that belong to the integrin family and perform functions not only in the phagocytosis of opsonized surfaces but also in leukocyte trafficking, adhesion, migration, and costimulation, which all have important consequences in the defense of the host against pathogenic invasion 75, 82.

Histopathological Mechanisms Of Saccular Aneurysm Formation, Growth, And Rupture

The AP is activated spontaneously via a tick‐over activation mechanism, but a role for properdin (FP) has also been proposed 4. An abnormal result may be due to mishandling during transport of the specimen. J Immunol (2020) 1950(188): Three biochemical pathways activate the complement system: DCs in the respiratory tract form a network in the upper layers of the airway epithelium. Finally, we discuss complement as a therapeutic target. Apart from these traditional activities of the complement system in attacking invading pathogens, it has become clear that its effector functions extend to instruction of the adaptive immune system and to several physiological processes.

(A) Structure and domain organization of the central complement component C3 and its cleavage fragments C3b and C3a.

Complement System Product Portfolio

Functional analysis revealed that mutations located in the FH-binding sites resulted in decreased FH binding, thus showing the link with aHUS. First, the complement system is an important regulator of B cell activation, providing an important mechanism for pathogen (or “danger”) recognition by B lymphocytes. Mutations in the components of the C3 convertase (C3 and FB) induce the formation of overactive C3 convertase or a convertase that is resistant to regulation.

Understanding Complement-Related Diseases Using Structure–Function Relationships

Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. C4BP has an octopus structure and interacts with several C4b molecules. Clearly, different proteins have different functions that are partially independent from their role in the complement pathways. Several control proteins are also secreted by cultured monocytes, such as FH, FI, C4BP and C1INH 59, 62, 67. The C3 convertases are an excellent example of a general mechanism that governs different steps of the complement cascade. A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host.

There are only a handful of proteins in the complement system, and they are floating freely in your blood. The classical pathway, which has two components, globulin (C1) and albumin (C2) The alternate pathways Mannose-binding lectin. Histopathological mechanisms of saccular aneurysm formation, growth, and rupture The progression of saccular aneurysms from formation to rupture involves a complex interplay of hemodynamic forces and changes in aneurysm morphology (luminal factors), vessel wall integrity (extra-luminal factors), immunological pathways, and patient-specific factors. C3aR is also expressed on adaptive immune cells, such as T lymphocytes. Thus, the transcription and translation rates of complement components might be lower in lung cancer tissues than in normal tissues. Complements are manufactured in the liver. TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway. Currently, we know that complement is not only a simple lytic system, but rather a powerful innate immune surveillance tool, serving as a sentinel against pathogens, modulator of the adaptive immune response, and as a regulator of host homeostasis.


Expression of non-self antigens and lack of CRPs on microbes make them optimal targets for complement detection and, later on, complement-mediated elimination. Factor H binds to C3b and C3(H 2 O), but not to uncleaved C3. In conclusion, complement is a multifaceted and robust effector, which bridges the innate and adaptive immune systems.

C4d will likely remain to have a prominent research role in transplantation and autoimmunity. When a bacterium enters the host body, as a result of inflammation, complements reach towards the site, where C3 molecules directly touch antigen and become active. These data suggest that C5 may regulate resistance to allergen-driven AHR by enhancing the recruitment or activation of pDCs, which drive CD4+CD25+ Treg cell–induced tolerance.

In order to induce killing in these cells, multiple MACs must be inserted in the cell membrane together with coordination of calcium flux and not well-understood signal transduction (233). 1 M PBS (pH 7. )A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. Most of the proteins are normally inactive, but in response to the recognition of molecular components of microorganisms they become sequentially activated in an enzyme cascade – the activation of one protein enzymatically cleaves and activates the next protein in the cascade. There are two stages in this process: COMPLEMENT PATHWAY REGULA. CR2 activation by interaction with C3d-opsonized antigen on follicular dendritic cells increases CMH expression and allows antigen presentation to TCR. Compstatin has shown efficacy in complement blocking in vitro and in animal models including extracorporeal circulation (333), sepsis (334), and PNH (335).

Notify Me On Publication

This is a unique example of convergent evolution, resulting in enhanced immune evasion of important pathogens via utilization of a “superevasion site” (165). The recognition molecules also interact with MAp19 and MAp44 (alias MBL/ficolin-associated protein 1), which are non-enzymatic, truncated alternative splice products of the MASP2 and MASP1/3 genes, respectively. C4BP prevents the formation of the classical C3 and C5 convertases (148–151).

C3dg is rapidly transformed to C3d by tissue proteases. Only the cofactor CR1 allows FI to execute a second cleavage generating C3c (released in the fluid phase) and C3dg, which remains bound to the cell. C4b and C2b then bind together to form the classical C3-convertase, as in the classical pathway. Bbc two, so what can we do to avoid getting ill? An important example is the production, targeted secretion and local activation of complement in the T cell–DC synapse 89. The binding of both lectin pathway recognition molecules to the bacterial surface was confirmed using recombinant human CL-11 and recombinant murine ficolin A. The stabilized C3 convertase, C3bBbP, then acts enzymatically to cleave much more C3, some of which becomes covalently attached to the same surface as C3b.

The process now continues to form of C5 convertase and the MAC as in classical pathway.

A maximum of four C4b molecules can simultaneously interact with the α-chains of one C4BP molecule (154). Recognition leads to the activation of the system and elimination of the pathogens either by direct killing or by opsonophagocytosis and intracellular killing. Immunodeficiency, taking megadoses of a single vitamin does not. C5b recruits complement components C6, C7, C8, and C9 which polymerize to form the membrane-attack-complex (MAC) ring (Figure 12) (207). If you're behind a web filter, please make sure that the domains *.

The importance of the complement system in physiology is illustrated by severe and life threatening diseases, occurring in case of inefficient or exuberant complement activity (Figure 10).


C5a can bind to its anaphylatoxin receptors C5aR1 and C5aR2, whereas C5b marks the start of the formation of the membrane attack complex (MAC). This domain binds to heparin and other GAGs on the host cell surface, but the binding sites for GAG and for pathogens surface proteins are not identical (164, 165). These activation fragments will be generated at sites of activation of the coagulation cascade. The lectin pathway is initiated by either serum MBL or ficolins that recognize certain sugars on microbial surfaces. C1qa−/− (18); Bf−/− (19); C4−/− (20); C3−/− (16); and μ s −/− (21). They were named “natural killers” because of the initial notion that they do not require activation in order to kill cells that are missing “self” markers of major histocompatibility complex (MHC) class 1. Complement proteins that are already activated keep activating “sleeping” neighboring complement proteins down the line. Mice deficient in C4, a component of the classical and MBL pathways, were more susceptible to infection by group B Streptococcus and S.

Tumor Necrosis Factor

Some examples of complement protein deficiencies are: Recent research has suggested that the complement system is manipulated during HIV/AIDS, in a way that further damages the body. Antibody polyreactivity in health and disease:

The shapes of the cells used in this review are inspired by http: Also, the expression level of some complement regulators (such as MCP) can be reduced. Targeted inhibitors like TT30 (FH CCP1–5: )

Discover Content

An NK cell will first use perforin to create pores in a target cell, allowing it to inject granzymes through an aqueous channel. Here, for consistency, we shall call all large fragments of complement b, so the larger fragment of C2 will be designated C2b. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the adaptive immune response. P-selectin expression was partially triggered by the anaphylatoxin C3a contributing to a vicious circle of complement activation aggravating microvascular thrombosis HUS pathology (99). Additional strains used were the isogenic unencapsulated D39 strain (ΔD−; ref. )Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. The recognition event induces a structural change in the recognition molecule, which in turn induces the activation of enzymes able to cleave the subsequent molecules in the cascade and generate the central enzymatic complexes of complement, CP and AP C3 convertases.

Specifically, the complement system causes the lysis (bursting) of foreign and infected cells, the phagocytosis (ingestion) of foreign particles and cell debris, and the inflammation of surrounding tissue.


Survival times and mortality rates were similar to those reported for C1q and C4 deficient mice, using the same strains of bacteria and mice, and the same dose and route of infection [22]. The 13 best foods to boost your immune system. take that, coronavirus!! The availability of the first effective anti-complement therapeutic drug, eculizumab, has changed dramatically the outcome of this rare kidney disease. This time period varied widely among and within studies, including one of the studies in which samples varied from 4 h to 47 days. 4% (SD = 18%) of S. Upon cleavage, C5b undergoes a dramatic conformational change, similar to C3b, but with a TED domain ending up only halfway the distance to the MG ring (Figure 12) (224).


Although in vitro and in vivo studies show that rituximab activates the classical complement pathway (51, 52), the notion that its therapeutic benefits are mainly mediated by induction of complement attack on malignant B cells is questionable. However, its role remains unclear. C3a is an inflammation mediator and C3b is an opsonin, which can bind covalently and tag any surface in the immediate proximity to the site of its generation. Note that only IgM and IgG antibodies can bind to C1. Finally, CR3-mediated phagocytosis results in the apoptosis of phagocytic cells, an important step of the resolution of infection and inflammation (58).

The C5 convertase cleaves an inert molecule of C5 into a potent anaphylatoxin, C5a, and a bioactive fragment C5b. Since mouse CL-11 binds strongly to the surface of S. The loss of lectin pathway activity caused by MASP-2 deficiency or MASP-2 inhibition would remove a critical degree of C3 opsonization of S. While recent studies reported that the activation of complement system is an important component of tumour-promoting inflammation [19].

  • C3b and its degradation products binding to CR1, CR2, and CR3 provide ligands and receptors for cell-cell and stroma-cell interactions in many physiologic and pathologic conditions.
  • Interferons, like antibodies and complements, are proteins, and their job is to let cells signal to one another.
  • Authors identified a humoral component of innate immunity, the long pentraxin PTX3, as an important negative regulator of inflammation and complement activation.
  • To confirm this, 1 in 50 dilutions of sera from 23 mice (12 wild-type, 3 C1qa−/−, 3 μ s −/−, 2 Bf−/−, and 3 C1qa−/−.)
  • Moreover, C3a and C5a induce histamine production by basophils (64) and mast cells (65), resulting in vasodilatation.


The circulating proteins have been grouped into three activation pathways, based on the types of substances and proteins that initiate the activation. Markiewski et al. 7 trusted methods to boost your immune system flu season and flu. Furthermore, in vitro experiments on human EC have shown that heme-induced mobilization of specific EC granules that store von Willebrand Factor and P-selectin called Weibel Palade bodies, is at least in part induced by TLR4 (102, 103). Considering that complement is not efficient in immune surveillance against cancer cells and that the main antitumor effect of monoclonal antibodies might not arise from complement activation, the data supporting an antitumor role for complement activation are scant. Complement plays a central role in the homeostasis and the installation of the adaptive innate immune response. Lack of C4 coexpression in C1q-expressing tumors hints at a role for C1q in tumor progression independent of the classical pathway. C8 and C9 then bind to the complex and a similar event occurs. When C3d-opsonized antigen binds to CR2 on FDCs, they can present the antigen in the GC and induce effector and memory B cells (133).

Therefore, CP can be activated in either an immune complex-dependent and -independent manner.


When C3b binds to B-cell, it secretes more antibodies. Neutrophil migration and degranulation are prevented by the presence of C3a, whether others granulocytes are activated by this anaphylatoxin (63, 67, 68). GENETIC DETERMINANTS OF C. C5b interacts with C6, C7, C8, and multiple copies of C9 to form the membrane attack complex C5b-9 (MAC). It is important to stress that the finding of low or absent MBL does not indicate that the cause for an individual’s infections has been found and that the diagnostic process must continue until the correct diagnosis is determined. Looking at these areas in more detail and considering some of the wider roles of complement show that the complement system has crucial functions to play in: ’, Journal of immunology (Baltimore, Md. )It is composed of more than 40 proteins, the soluble ones being produced mainly by the liver.

This internalization is essential for the induction of the late stage of ERK signaling (291, 292). Next to receptors for the complement opsonins, a set of receptors can also be triggered by the anaphylatoxins, C3a and C5a. (Tables S7 and S8), we re-analysed the mRNA and protein levels of complement and complement-related components in plasma and lung tissues from patients with lung cancer and healthy subjects, and identified the differential expressions of 39 complement components (C1s, C1r, C1qa/b/c, C2, C4d/C4, MASP1, CFD, CFP, CFB, C3, C5, C6, C7, C8a/b/g, C9, C1NH, C1QBP, CFI, C4BPA/B, CFH, CD55, CD59, CD44, CD46, CD35/CR1, CD21/CR2, CD11b/CR3, CD11c/CR4, CD18/CR3, MRC1, C3ar1, C5ar1, C3bR and C1QR1) and 24 complement-related components (CLU, VTN, VWF, SerpinA1, SerpinA3, ApoA1, ApoA2, ApoA4, ApoB, ApoC1, ApoC2, ApoC3, ApoD, ApoE, ApoL3, A2M, SerpinB1, SerpinB2, SerpinB5, SerpinD1, SerpinF1, SerpinH1, SerpinI1 and Serbp1) (n = 63). Taken together, the results show that in the context of retinitis pigmentosa, complement activation is actually helpful for clearing away dead cells and maintaining a state of homeostasis, a physiological balance, in the retina. Host cells and plasma contain multiple regulatory proteins to assure that complement activation will be limited in physiological conditions. If complement does not attack cancer cells, how does local complement activation and deposition of complement proteins affect tumors? Complement activation relies on the versatility of the target patterns recognition molecules (C1q, MBL, ficolins) that can discriminate between self and non-self and bind to pathogen- or danger-associated molecules. In C3G, the complement system becomes over-active (too “revved up”).

Navigation Menu

On top of these important contributions to innate immunity, complement plays a vital role in shaping adaptive immune responses, functionally integrating it into the ability of the host to combat invasion from a wide range of pathogens. FH mutations are frequently located in the C-terminal domains and result in reduced capacity of FH to bind C3b and the GAG of the cell membrane (211–213). TLR signaling ultimately leads to the induction or suppression of genes that orchestrate the inflammatory response. Resting neutrophils express low levels of CR3 on their surface but these levels increase dramatically following cell activation, due to the externalization of large intra-granular pools of receptors. In contrast to CR3, CR4 binds to the C3c portion of iC3b (Figure 14).

Toll-Like Receptors

All these examples illustrate the importance of complement for the mounting of a successful immune response. Immune-boosting foods: berries, oysters, & more, a number of small studies have suggested garlic may enhance immune system function. Although the mechanism(s) by which C5a production in the airways protect(s) against allergic sensitization are not well understood, several lines of evidence suggest that C5a modulates the adaptive immune response through altering the phenotype and function of antigen-presenting dendritic cells (DCs) (20). A large part of these effects are translated into cellular effector functions via a set of complement receptors (CR) specific for proteolytically cleaved complement fragments. CR1 (CD35) is a multifunctional receptor that is expressed in the majority of peripheral blood cells and binds with high affinity to C4b and C3b, as well as to iC3b, C3dg, C1q, and mannose-binding protein 76, 77, 78, 79.

This residue is not conserved in C3b and the binding site seems to be located outside of the TED domain, in the α43 fragment (residues 1268–1641) (210), suggesting different topology of the two trimolecular complexes. This pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues on the pathogen surface. It can also be triggered by some components of innate immunity.

Appreciating this complexity is important for guiding the development of therapies that target the complement immune system to treat degenerative diseases of the retina," Dr. "Human colostrum (“first milk”) has the highest concentration, followed by human milk, and then cow milk (150 mg/L). The advantage of C4d is that it contains a thiol ester site ensuring it remains covalently bound closeto the site where the C4b was bound. Stover and Teizo Fujita are named inventors on patents held by the University of Leicester, protecting the I. Complement activation. In human, C3a-desArg is able to bind C5L2 and regulates triglyceride synthesis rate (110).

  • Complement receptors, such as CD35/CR1, CD21/CR2, CR3 (CD11b/ CD18), and CR4 (CD11c/CD18), are primarily located on peripheral blood cells, such as macrophages, B and T lymphocytes, and function by binding diffusible complement fragments released during the activation of the complement cascade or complement components deposited on cell surfaces [17].
  • Furthermore, it was demonstrated that T helper type 1 (Th1) induction, and not Th2, depended upon T cell‐produced C3 cleavage fragments, as was shown by using T cells from C3–/– donors and the earlier observation that not serum‐derived C3 but T cell‐derived C3 was needed for CD46 activation 106, 107.
  • However, the bacterial surface was abundantly decorated with C4dg, the final product of C4 decay.


However, in response to local signals, they also become a secretory, pro-inflammatory cell type characterized by upregulation of necrosis factor-κB signaling, increased production of MMP, IL-1β, tumor necrosis factor-α, and initiation of pathways leading to SMC apoptosis. C3 nephritic factor and FH or FI mutations, inducing an overactivation of the AP are found also in patients with another type of membranoproliferative glomerulonephritis, associated with immunoglobulin deposits in the kidney – MPGN type I (237). Exciting work lies ahead, where the relative importance of locally produced complement versus systemically delivered complement will be unravelled further. C1q recognizes pathogen-associated molecular patterns including lipopolysaccharide (LPS) (30) and bacterial porins (31). (17), the capsular serotype 3 strain (0100993, obtained from GlaxoSmithKline plc), and the capsular serotypes type 6B and 4 strains (M158 and M313, gifts from Brian Spratt, Imperial College London, London). In the case of TCR stimulation, CD46 is down-regulated, which allows Notch-1 and Jagged1 to bind in cis and in trans (from two different cells).

(2) and then fixed by re-suspension into 250 µl of 2. This induces conformational changes in the Fc portion of the antibody which exposes a binding site for C1 protein. Complement system can also be stimulated by abnormal stimuli, like persistent microbes, antibody against self antigens or immune complexes deposited in tissues.


Natural cytotoxicity receptors directly induce apoptosis after binding to ligands that directly indicate infection of a cell. IFNs belong to the large class of glycoproteins known as cytokines. However, over activation of the complement is associated with disease states such Lupus nephritis.

Depending on the type of the opsonin present (C3b, iC3b, or C3d), the phagocyte will generate a pro-inflammatory response or tolerogenic suppression. The complement system is described as a double-edged sword. Another function of interferons is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Chen N-J, Mirtsos C, Suh D, Lu Y-C, Lin W-J, McKerlie C, et al. Thus the RBCs are not protected by GPI anchored proteins such as DAF.

Second, complement activation regulates adaptive immune response (15) and might have a role in regulating T cell response to tumors. Acceptance of this classification is less universal than that of type I and type II, and unlike the other two, it is not currently included in Medical Subject Headings. These two regulators bind below the C5b-9 arc rendering it water soluble and preventing membrane binding (224, 236–238). Spontaneous hydrolysis, called tick-over, of C3 plays an important role in the immune surveillance and AP activation (2). The explanation for the relative rarity of pneumonia and septicemia is poorly understood but is likely to be influenced by the host's innate immune response to S. By competing with FB and FH, SCIN is able to block the formation of alternative C3 convertase on one side, and to block the generation of iC3b that could induce phagocytosis on the other side. The classical pathway can be set in motion by antigen-antibody complexes that react with activated C1q. Recent studies demonstrated that FH binds to pentraxin 3 (PTX3) in the tumor microenvironment, thus preventing local complement overactivation and generation of pro-tumorigenic C5a (266).

Role In Disease

C1q circulates in plasma-associated with the serine proteases C1r and C1s, forming inactive C1 complex. Other inhibitors, such as MCP and DAF, were only sparsely expressed by adventitial mural cells. Complement has now been shown to play a role in both B- and T-cell responses at the organismal level. CCP1–3 of CR1 carries a binding site for C4b allowing it to induce accelerated decay of the C3 convertase in the CP and AP (Figures 8A and 9B) (143, 159). 4 tips for boosting your immune system with vitamin d. First, C3 and C5 can be cleaved through the generation of the classical pathway convertases as a result of antibody formation; however, IgE antibodies do not fix complement, and thus activation of the classical pathway via antibody–antigen complexes is less likely in allergen-driven immune responses. In C3G, complement from the blood goes to the glomeruli and builds up. Fixation of the MBL protein on viral surfaces has also been shown to enhance neutralization of viral pathogens. Finally, C5 may mediate inhalational tolerance via recruitment and/or activation of pDCs as they have been shown to induce Tregs (CD4+CD25+ T cells).

C3b targets the pathogen for destruction by a phagocyte. FH binds to C3b in at least two regions, at the N-terminus and the C-terminus of the protein. In recent years, a number of other diseases and situations where the immune system is compromised have been suggested to be affected by complement activity. The auto-reactivity of B cell is also tightly regulated by complement. IFNs activate immune cells (natural killer cells and macrophages ), increase recognition of infection and tumor cells by up-regulating antigen presentation to T lymphocytes, and increase the ability of uninfected host cells to resist new infection by virus. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. In the mouse, C4 deficiency led to a significantly slower C3 turnover and in both species the absolute amount of C3 deposited on the bacteria was approximately half of that observed using WT serum.