1. ABSTRACT

The complement (C) system is a vital arm of innate immunity with many roles, including control of inflammation. This article examines the (C) system with emphasis on recent developments on complement relevant to neurobiology, in particular regarding our understanding and treatment of immune-mediated diseases. We will briefly outline the C system, and provide an updated review of its many receptors and regulatory factors. This section concludes with a listing of important roles of the C system, from recruitment of neural stem/progenitor cells, to its' relation to coagulation and adaptive immunity, and its lesser-known but beneficial roles in physiology. We also review evidence for C-mediated diseases, which include multiple sclerosis and Alzheimer's disease. Therapeutic approaches for C-mediated diseases, considers emphasizing modulators of the C system including several less widely studied approaches such as heparinoids, vitamin D, and intravenous IgM. Finally, we summarize cutting-edge work on the role of C-mediated natural antibodies in autoimmunity and treatment strategies based on those findings, e.g., for remyelination and post-ischemic stroke repair. Improved understanding of the C system may hold great promise for the treatment of neurodegenerative diseases.

2. INTRODUCTION

The complement (C) system is a major arm of innate immunity, distinct from adaptive immunity (production of antibodies and effector T cells). It is an evolutionarily ancient and widely conserved system (1), yet significant differences in details are seen even between closely related species, such as human vs. mouse. It is analogous to the system of blood clotting insofar as it is comprised of a set of circulating proteins (zymogens, or pro-enzymes) which when triggered results in a cascade of reactions leading to several outcomes, all of which are aimed at killing pathogens and eliminating infected or damaged self-cells, and repair of collateral damage. However, complement also plays many other vital roles.

It is also "ancient" in terms of the history of immunology, having been discovered more than a century ago, and its main outlines were well delineated by the 1980's. For this reason, and because more recent discoveries such as the Toll-like receptors (TLR's), captured the limelight, the C system lapsed into relative obscurity. Fortunately, however, it has recently been "rediscovered" (2) and is again enjoying a renaissance of exciting new discoveries, many of which are reviewed here. Much of this new work has done by a comparatively small number of specialists, and is not yet widely appreciated. A recent special issue of Science on innate immunity (3), while highlighting important new discoveries, scarcely mentions the C system, (nor did a special issue of Nature on autoimmunity) (4). We shall see that some of the most exciting work on autoimmunity hinges on the C system. Likewise, reviews of the "inflammasomes" of innate immunity (5, 6) make no mention of the C system, although many pathogens and other signals can activate both, suggesting their connection. Lastly, because many reviews have thoroughly reviewed intracellular signaling pathways activated by C, it is not a focus of this examination.

3. OUTLINES OF THE COMPLEMENT SYSTEM

A major resource describing these pathways is Halkers' monograph 'Mechanisms in Blood Coagulation, Fibrinolysis and the Complement System' (7) and several other accounts (8, 9) and as noted below. Other general reviews are available (10, 11) but do not stress the detailed steps.

3.1. The classical pathway

The classical pathway is shown in Figure 1. Panel (A) shows the starting players in circulation: C1q, C1r and C1s. The C1r and C1s are widely understood to each circulate as dimers, but have also been shown to exist as

tetramers, C1r₂C1s₂, with some in complex with C1q (12), as more recently discussed (13). Panel (B) describes the classical triggering event, binding of C1q to IgG or IgM bound at plasma membranes. The C1q resembles a bouquet of 6 flowers. A single IgM is theoretically sufficient, or at least two IgG. Activation of this pathway by IgG is sensitive to subclass, usually IgG3 > IgG2 ≈ IgG1 > IgG4, but this may vary with specific conditions (14). This binding causes a conformation change in C1q giving increased affinity for C1r and C1s, binding a pair of each, as in (B). The bound C1r is then spontaneously activated, then immediately activates the bound C1s, resulting in the

activated C1 complex, symbol C1* in panel (C). The active C1s, called s' in the figure, then attacks circulating C4, breaking it into C4a + C4b, as in panel (D). The C4b then binds C2, and in this state, the C2 is split, also by active C1s in the complex, yielding C2a + C2b, in which the C2a remains bound to the C4b, as in panel (E). This complex, C4bC2a, is known as the C3 convertase because it converts C3 to C3a + C3b, as in panel (F). The C3b remains bound to C4bC2a, giving the trimolecular complex, C4bC2aC3b, called the C5 convertase because it converts C5 into C5a + C5b, shown in (F). The C3b readily binds covalently to pathogen (or other) surfaces via its thioester, and is a key opsonin, i.e., marks the cell for phagocytosis. The C3bC5b complex may then set in motion the sequential recruitment of C6, C7, C8, and C9, assembling the "membrane attack complex" (MAC), or "terminal complement complex" (TCC), also called "C5b-9", which punches a hole (pore) in the membrane of the invading cell, killing it. Like all of the steps, details of MAC formation are complex. Briefly, it is C5b-7 that inserts in the membrane, which then captures C8, which induces polymerization of a ring of C9 (as many as 18 C9 per pore) to form either a toroidal ("donut") or non-tubular pore (7). Some readers will notice that the sequence of interactions of the C1q complex is not first with C2, then C3, C4, but rather is with C4, C2, then C3. This is because the factors were discovered and numbered before these steps were established.

Thus, there are two main routes of pathogen killing, one being lysis by MAC ("lytic pathway"), the other being opsonization, meaning C fragments are deposited on the pathogen which designate it for phagocytosis. The relative importance of these routes depends on specifics (one example Neisseria meningitidis is discussed by Granoff) (15). Numerous regulatory mechanisms control all steps. For example, 'self'-cells are protected against the C3b opsonin in several ways, including heparin-like substances (like heparan sulfate) in the extracellular matrix (ECM) which potentiate the actions of specific C inhibitors (16), discussed presently.

3.2. The alternative pathway

A key distinction of this pathway is that it does not depend on immunoglobulin (Ig). This route involves two additional core components, complement factors B (CFB) and D (CFD), plus three main regulators (discussed later, CFH, CFI, CFP), and a hydrolyzed form of C3 in which water (H:OH) is added to its thioester bond; see Figure 2, top left (17). A small fraction of circulating C3 is always in this evanescent form, C3:HOH, which is able to bind CFB, keeping the system poised for explosive amplification. Bound B can then be cleaved by CFD, a serine protease present in trace amounts in plasma fully active but specific for B in the form, C3 (HOH)B, yielding C3 (HOH)Bb + Ba. This product has the ability to directly produce C3b from C3; see lower left of Figure 2. Now, factor B can bind to C3b, whose thioester can covalently bond to the pathogen surface, where B is attacked by D, yielding surface-bound C3bBb, known as the "alternative pathway C3 convertase". Since this produces more C3b, this sequence is called the "amplification loop". Mechanisms which normally restrict this amplification are considered in following articles. Mechanisms for distinguishing 'self'-cells from pathogens are discussed by Pangburn et al (18) and are described later.

3.3. The lectin pathway

This 'ancient' pathway (1, 19), which does not need a separate figure, adds a few more players: the mannose binding lectin (MBL) - a.k.a. mannan-binding protein (MBP) - and the MBL-associated serine proteases (MASP-1, -2, -3), plus a smaller one, sMAP (20-22). Here, MBL functions as the recognition element, similar to C1q, except in binding to unfamiliar carbohydrates or dying 'self'-cells rather than Ig. MBL circulates bound to a MASP, which is activated upon engagement, to split C4 and C2 into C4b and C2b, generating the C3 convertase. The rest is similar as previously described, with C3 the central effector. Recent work on this finds even closer parallels with the classical pathway (23), already evident by 1996 (20).

3.4. The extrinsic pathway

A fourth pathway, the "extrinsic" pathway operates through the proteolytic action of thrombin which directly cleaves C3 and C5 (24-26). Thrombin is normally active in appreciable amounts only briefly and locally during coagulation. This pathway may therefore be important in cerebral hemorrhage (27); other relations of the C system to coagulation are discussed below.

4. Regulatory factors of the complement system

It is often noted that the number of C regulatory factors is considerably greater than the number of core constituents, yet they are equally vital to the proper regulation of the system. The number of these "accessory factors" continues to grow.

4.1. Early or general regulators

The C1 inhibitor (or C1 esterase inhibitor) is a serine protease inhibitor ('serpin'), C1 inhibitor being the only known inhibitor of C1r (and, less potently, of C1s). It also inhibits MASP-1 in the lectin pathway (13), and is an important regulator of the contact pathway of coagulation, acting on factors XIa and XIIa, and on fibrinolysis by inhibiting plasmin, which interacts with the C system as discussed in part 5.4. C1 inhibitors' official name is SERPING1 (28) and is abbreviated C1-INH. Carboxypeptidase N (CPN) acts to detoxify the anaphylatoxins (C3a, C5a) by removal of the carboxy terminal arginine. An important recent discovery is that the plasma carboxypeptidase B (CPB) of the fibrinolytic system, (also known as the thrombin-activatable fibrinolysis inhibitor, TAFI), is at least equally effective (29), as may be other recently described CP's (e.g. CPM) (30). They are also important in thrombin-mediated inflammation (31). The C4b binding protein (C4b-BP, or C4BP) promote assembly of the convertases of C3 and C5, and when bound to membranes can function as a C receptor. Sjoberg et al. have suggested multiple regulatory roles for C4BP (32). The gene for C4BP is found in close proximity to those for several other C factors, on the long arm of chromosome 1, this cluster being known as the 'regulators of complement activation' (RCA).

4.2. Modulators of the alternative pathway

Complement factor H (CFH) binds to C3b or C3:HOH to inhibit binding to factor B, limiting formation of the C3bB proenzyme (33). Equally important, CFH is a cofactor for factor I, which degrades C3bH to inactive C3b, (designated iC3b). Factor I circulates in active form. Further degradation of iC3b releases the fragment, C3c (150 kDa), leaving the degraded portion, C3dg, to persist on circulating cells. The factor H-related proteins (FHR), of which there are 5, are similar in their short consensus repeats (SCR's) and amino acid sequence at the N terminus (34, 35). For example, unlike CFH, CFHR1 is not a cofactor of I, but it does bind C3b and so can be detected on pathogen surfaces. Most of these five FHR bind heparin, and associate with circulating lipids, but their specific functions remain unclear. (The "R" in acronym CFHR1 here indicates 'related', not 'receptor'.)

Properdin, or complement factor P (CFP), has been known for more than 50 years to stabilize C3bBb, sustaining C activation in the alternative pathway. This action is opposite to that of factor H. However, the details of this scheme have long remained obscure, and solid work was too rapidly dismissed, with the result that it came to be viewed as only a minor component, hardly even mentioned in many reviews. That has now changed due to work by Fourcade, Kemper, and others (recently reviewed in reference 36). Briefly, in addition to the above function, CFP is itself a pattern recognition molecule capable of binding to the surfaces of certain pathogens, as well as to apoptotic and necrotic 'self'-cells and fragments, leading to convertase formation and destruction of the target. Deficiencies of CFP predispose to several pathologies including certain infections, abdominal aortic aneurysms, and other inflammatory and autoimmune disorders (36).

4.3. The complement receptors

The chief function of complement receptor 1 (CR1, CD35) is to clear immune complexes (IC) (37). CR1 was formerly known as the C3b/C4b receptor because its main ligands are those components bearing immune complex (IC). It is widely distributed, but CR1 of erythrocytes (RBC) dominate because of their vast numbers. After capture, the IC is removed in the liver and the RBC return to the circulation unscathed (38). CR2 (CD21) is found on B lymphocytes, and can complex with CR1, CD18, CD81 and TAPA (39, 40). It binds the antigen-bearing C3 fragments, iC3b, C3dg, and C3d, by which it functions in linking innate immunity to adaptive immunity, as outlined in part 5.3 below. Some authors classify CR1 and CR2 among the 'RCAs' (41, 42).

CR3 is the CD11b/CD18 complex and CR4 is the CD11c/CD18 complex, also known as integrin Alpha₂Beta₁. These are often referred to collectively as "beta-2 integrins". A fourth member, CD11d/CD18 is described but is not yet understood in this system (43). Lambris mentions evidence for a "CR5" (his quotation marks) but it is not yet defined (44). CR3 on neutrophils recognizes β-glucans (45) and promotes T cell priming in viral infections (46). CR3 expression on splenic B cells is regulated in part by C3 (47). Of note, the T-regulatory (T_reg) subpopulation are CD11c⁺CD8⁺ (48), but those authors do not discuss their findings in terms of CR4, or the role of C in modulating T_reg population.

Ghebrehowet and Peerschke identified two C receptors, cC1qR, which is identical to calreticulin, and gC1qR/p33, where the prefix 'c' denotes binding to the collagen-like tail of C1q, and 'g' the globnular head (49). That review provides evidence of key roles of these receptors in infection (50), in the contact pathway leading to bradykinin generation, in the activation of platelets and endothelial cells, in inflammation, and in B-cells, T-cells, and other immune cell proliferation and responsiveness. For example, the hepatitis C virus appears to evade immunity via gC1aR (51, 52). The gC1qR/p33 (also 'hyaluronic acid binding protein' HABP-1) is located in various subcellular compartments, including mitochondria, as well as the plasma membrane (50), bringing up the important fact that the C system is now known to operates inside cells as well as in the plasma and at external cell surfaces. In the same journal issue, another C1q receptor was identified, integrin Alpha₂Beta₁, on T cells, natural killer (NK) cells, and some others (53). Its ligands include all the 'collectins'.

Phagocytosis of pathogens proceeds by several mechanisms involving C, illustrated by the fact that some fungi avoid phagocytic engulfment by blockade of CR2 and CR3 (54). Those authors suggest that CR3 is another link between the C system and adaptive immunity. With regard to the phagocytic clearance of apoptotic self-cells, which is highly relevant to autoimmune disease, both CR3 and CR4 have been implicated (55), as has the opsonin iC3b (56). It had been observed that C1q stimulated phagocytosis of apoptotic cells, and CD93 was implicated in this effect, whence it was termed C1qRp, where suffix 'p' stands for phagocytosis (57). However, knock-out of this gene in 2004 failed to eliminate the C1q-stimulation of phagocytosis (58), though it did hamper phagocytosis, as more recently discussed (59, 60). Thus, there must be redundancy, or yet-undiscovered receptors. Because of its many ligands and putative functions, some authors assert that the function of CD93 is unknown (61) while others support its role in phagocytosis (62). Another putative C-related receptor, or co-receptor, involved with phagocytosis is CD91 in complex with cC1qR / calreticulin (49, 63). However, CD91 (a.k.a. low-density lipoprotein-related receptor 1 (LRP1)) does not appear to be responsible for the C1q-triggered enhancement of phagocytosis (60).

The topic of C receptors is complicated by the different terminologies used by various authors, which may stem partly from the fact that multiple receptor complexes seem to be involved, partly from the promiscuity of these receptors leading to alternative names, and partly from the unsettled state of knowledge. For example, a recent review of calreticulin (cC1qR) does not discuss it as a C receptor at all (64), though it does discuss its role with CD91 in phagocytosis, as does Gardai et al (63), who find that it can either suppress or enhance inflammation.

4.4. Membrane-bound self-cell protecting proteins

Three proteins protect self-cells against autologous (self) C-mediated injury: the membrane cofactor protein (MCP, CD46), the decay accelerating factor (DAF, CD55), and the membrane inhibitor of reactive lysis (MIRL, CD59), a.k.a. protectin, a.k.a. homologous restriction factor (HRF). Both DAF and MIRL are anchored to the membrane by a glycosyl phosphatidyl inositol (GPI) tether, which can be cut by a specific phospholipase C (65). This topic was comprehensively reviewed by Morgan and Meri in 1994 (66) but new details and relations to disease have since come to light (67, 68). MCP, as its name implies, acts as a cofactor for the degradation of C3b and C4b by CFH and CFI. It is widely distributed but absent from RBC. Protectin protects self-cells by blocking completion of MAC via binding C8 and/or C9. DAF accelerates the decay of C3 convertase, and binds C3bBb (42) and is of interest in Alzheimer's disease (AlzD) (69).

4.5. Anaphylatoxins and their receptors

The cleavage fragments C3a and C5a are the main anaphylatoxins (AT's), so called for their inflammatory effects. Both are potent chemotactic agents which play essential roles in innate immunity (70, 71), and adaptive immunity, contributing to many pathologies such as sepsis (72), which will come up again in this review. When bound, the C5a receptor (C5aR, CD88) activates neutrophils increasing intracellular calcium, degranulation and respiratory burst. Less clear is the function of the pool of C5aR-like receptor-2 (C5L2), which is mainly stored in cytoplasm, and binds C5a or C5a_desArg. This may be involved with lipid metabolism in adipocytes, where it is known as acylation-stimulating protein (ASP) (73). ASP can sequester and internalize C5a to act as an anti-inflammatory, opposing C5aR. The duties of C5aR and C5L2 in chemotaxis overlap with the N-formyl peptide receptors (74). In the CNS, C5L2 is found on glia and neurons, and is reportedly anti-inflammatory (75).

Roles of AT's in neurodegenerative diseases have been discussed by Klos et al. (72) and chemotaxis towards AT gradients have been described (76). The gene for C5aR is near that of other peptide receptors e.g. bradykinin receptor. The AT's can also be generated directly by the mast cell enzyme, β-tryptase, acting on C3, C4 or C5 (77). Other AT's are known, such as C3f and C3f_des-Arg (78).

4.6. Additional pathogen recognition factors

In addition to C1q and MBL, several other proteins function in the C system to recognize pathogen-associated molecular patterns (PAMP's) (79). These are mainly lectins, proteins which bind to specific carbohydrates, usually those foreign to the host, or those which mark injured or dying self-cells. Lectins, also recognize some lipids, e.g. lyso-phosphatidyl choline. MBL belongs to the collectin family, which also includes the pulmonary surfactant proteins (SP) (21, 80), which participate in C regulation in the lung (81). Ficolins, also of the collectin family (where "coll-" denotes collagen-like), are active participants in the lectin pathway which recognize pathogens and activating MASP-2, similarly to MBL (82, 83). Runza et al. noted differences among species in ficolin specificities, which may underlie species differences in susceptibilities to particular pathogens or strains.

C-reactive protein (CRP) and serum amyloid protein (SAP) belong to the pentraxin family (84, 85), so called for their five subunits, and both are "acute phase reactants" (APR's). CRP was discovered and named for its ability to precipitate polysaccharides from pneumococci. CRP can bind pathogens and function like IgG or IgM, including by binding to FcγRI, II (86), by activation of C via C1q, as well as by binding to the inhibitory Fc receptor, FcγRIIb. CRP protects mice against infections which would otherwise be fatal (87), proving its role in immunity. Botazzi et al. (84) citing Szalai et al. (87) claim that CRP protects even when it does not bind pathogen but that citation does not support that. However, Agrawal et al. discuss theories about CRP functions, including bacterial killing without binding, concluding that it is an unsolved enigma (88). In addition to SAP and CRP, which are "short" pentraxins, there are "long" pentraxins such as PRX3, produced in macrophages and dendritic cells in response to proinflammatory stimuli (89).

This listing should also include at least some of the C-type lectins (90), as it has been demonstrated that SIGN-R1, a relative of DC-SIGN and the main receptor on macrophages for certain pathogens, initiates the classical C pathway, independent of IgG/M (91, 92). Also likely to be involved with the C system are the galectins, which are released or actively secreted by infected or dying cells, and which recognize many PAMP's and "danger-associated molecular patterns" (DAMP's) (93, 94). These authors do not discuss relationships of galectins to the C system.

4.7. Additional complement modulators

4.7.1. Clusterin

Clusterin (CLU) was known in earlier C literature as protein SP-40,40, owing to its two chains of 40 kDa each; or as complement lysis inhibitor (CLI). Clusterin was the name originally given for its ability to cluster several cell types (95). However, CLU has other functions, including lipid trafficking where it is known as apolipoprotein J (apoJ); CLU also acts as a chaperonin. CLU may be regarded as another acute phase reactant insofar as CLU serum levels often rise in stress. In the brain, CLU is secreted mainly by astrocytes. Its function in the C system is to sequester terminal C components C7, C8, C9, blocking assembly of the MAC (42). The relevance of CLU to the C system has been challenged (96), but this finding was not conclusive in view of decades of papers supporting CLU modulation of C, and for technical reasons. Current interest in CLU is increasing in cancer research. Its potential relevance to MS and Alzheimer's disease (AlzD) has also resurfaced (see part 5).

4.7.2. Osteopontin

Osteopontin (OPN) is a protein known to neurologists as one of a trio on the 'radar screen' of the MS community (97). OPN has been described as a proinflammatory mediator (98) but in the C-system, it can block or shut down the alternative pathway by potentiating inhibitory factor H, following binding to the vitronectin receptor, Alpha_VBeta₃ (S protein receptor) or CD44 (99). OPN can protect self-cells against C attack in a manner similar to the MCP, as does bone sialoprotein-1 (BSP1) (99, 100). Other authors find OPN to participate in tissue repair as a guidance molecule (101). Its Janus-like properties remind us of other C-related molecules in neurological disorders (such as CLU), a fact which gives pause when hearing them proposed as "targets of therapy" - should we inhibit, or increase them?

4.7.3. S protein, also vitronectin

Perhaps the best evidence that vitronectin (VTN) is important is the fact that at least two pathogens (Moraxella catarrhalis and H. influenzae) acquire this protein, using it as a defensive shield against C attack (102, 103). For example, if the serum source of C is first depleted of VTN, it kills the pathogen; if VTN is added back it survives (102). VTN contains the canonical RGD sequence (Arg-Gly-Asp) of fibrinogen and fibronectin which can bind to platelet GP IIb/IIIa and other integrins with this motif. VTN is also a heparin-binding protein with several important functions (104) including coagulation. In the C system, it binds incomplete MAC such as C5-b7, as well as to complete MAC (C5b-9), preventing MAC from harming cells, known as "non-lytic MAC", (referenced in 103). Of course, if plasma VTN always had this action the C system would be crippled, therefore this might happen mainly at the extracellular matrix (ECM), which is VTN-rich, for protection of self-cells, in much the way that the above-mentioned bacteria protect themselves by 'donning a cloak' of VTN.

4.7.4. Phospholipase A₂

Although phospholipase A2 (PLA2) is not usually listed among the C factors, it is an acute phase reactant (89), increasing up to 1000-fold in inflammation, closely paralleling CRP (105). PLA₂ participates in the C-mediated task of clearing apoptotic cells or debris, particularly those displaying anionic phospholipids such as phosphatidyl serine (PS), by inducing uptake of such particles, in partnership with CRP (106, 107). PLA₂ cooperates with C in killing Staphylococcus aureus and Listeria monocytogenes, and doubtless many other pathogens (108), establishing its role in innate immunity. Its role in the eicosanoid pathway (producing arachadonic acid) is one of several links between the C system and lipid mediators. Since it specifically degrades anionic phospholipids such as PS, it acts as an anticoagulant in vitro; however, this activity is inhibited in plasma (109). Interestingly, PLA₂ was inhibited by the multiple sclerosis therapy, FTY720 (fingolamide) (110). PLA₂ is a current drug target of neurodegenerative disease (111) including AlzD (112). In spinal cord injury, it leads to the production of the highly inflammatory platelet activating factor (PAF) (113). Plasma gelsolin, implicated in AlzD (114), is a regulator of PAF (115). In the brain, Herpes simplex, (a neurotropic virus), generates an miRNA that down-regulates factor H to evade C killing, and also up-regulates PLA₂, in experiments bearing on AlzD (116).

4.7.5. Note on acute phase reactants

As mentioned earlier, plasma levels of several C factors rise dramatically in the hours following infection. Therefore, experiments using serum as a source of C can yield very different results if serum from acute phase subjects is used compared to normal serum (108). A 1994 review of acute phase reactants (APR's) (117) listed about 30 APR's but did not include PLA₂ or several others more recently proposed, e.g., M-ficolin (83), pentraxin 3 (89). Several APR's are now used as clinical inflammatory biomarkers, most notably CRP.

4.7.6. Apha-2 Macroglobulin

Most authors do not include Alpha-2 Macroglobulin (A2M) among the C factors but it is one of many accessory proteins which modulate the C system (7). It is believed that A2M is the original ancestor of the core C factors (C3, C4, C5), the latter having arisen from gene duplications (11). A2M inhibits many proteases, including MASP-1 in the lectin pathway (118). Since many pathogens use proteases as virulence factors, A2M can be anti-microbial. For example, A2M is a key effector against trypanosomatids (119). A2M inhibit proteases by an unusual mechanism, offering its "bait" region to the likely protease, then trapping it by covalent attachment through trans-acylation to its thioester (11, 120). In humans, this large (700 kDa) plasma protein is abundant (2 mg/mL), is an acute-phase reactant (APR), and can also inhibit the coagulation enzymes, kallikrein, thrombin, and plasmin. Depletion of >35% of A2M in rats or dogs is lethal. It may also inhibit the zinc-dependent matrix metalloproteases (MMP's) which participate in neurodegenerative disease (121) and is of interest in AlzD.

4.7.7. The A2M receptor

CD91 is the A2M receptor (A2MR) and was originally termed the lipoprotein receptor-related protein (LPR). A2M engages CD91 with high affinity (Kd=0.5 nM) following capture of a protease (120). It is now considered to be also the receptor for heat-shock proteins such as HSP70 and HSP90, chaperonins (122) which govern proper protein folding. As mentioned earlier, CD91 complexes with calreticulin, which binds to the collagen-like tail of C1q (cC1q) and to lung surfactant proteins, SP-A and SP-D, to promote or suppress inflammation (63). Thus, CD91 is another C1qR. Other reports not here cited document its interactions with C1q and CD93, its role in antigen presentation and autoimmunity, in HIV infection, and its function as a "scavenger receptor". CD91 expression on monocytes was the only marker distinguishing HIV⁺ patients who did not progress to AIDS, and of melanoma patients with exceptionally long survival (122). In that study, however, the assay was by antibody against A2M, not CD91 per se, raising technical questions of interpretation. (For a review, see 123).

4.7.8. Others

Another plasma protein which deserves mention among the modulators of the C system is histidine-rich glycoprotein (HRG). HRG prevents aggregation of immune complexes, blocking inappropriate interaction of IgG with Fc receptors (FcR), aiding in safe disposal of apoptotic cells, and other effects involving the C system (124). The family of small leucine-rich regulatory proteins (SLRP's) of the extra-cellular matrix have also been shown to be important in governing C activation at the cell surface via factor H (125); those authors discuss implications of SLRPs' in inflammatory disorders. A more recent review of some members of this family in innate immunity focuses on the Toll-like receptors (TLR's), but does not discuss the C system (126).

4.8. Mouse models of C-mediated disorders

Since many studies are done in mice, it must be emphasized that significant differences between murine and human C systems are known to exist, which may confound or even invalidate the relevance to humans, depending on the study. These differences arise from variations in C gene duplications, alternative splicings, post-translational modifications, and tissue distribution (127). For example, the membrane cofactor protein (MCP) is ubiquitous in humans, but in mice is restricted to the testes. Mouse erythrocytes express a protein known as Crry (complement receptor-1 related protein, y), considered to be the functional counterpart of human MCP (68, 128). Common polymorphisms occur in human C4 and differ from those in the mouse (129). Such differences will affect sensitivity to a given activator, as might be expected from pronounced differences in species susceptibility to infectious diseases. This has been a serious impediment in some research fields. In transplant surgery, rodents do not mount C-mediated graft rejection as readily as humans (130). In murine models of Alzheimer's disease (AlzD), the mouse C system is less responsive to the Aβ protein than human, especially in formation of the terminal MAC (131, 132). In an effort to improve this situation for AlzD models, the murine C1q A chain was humanized, but this strategy failed to improve sensitivity to Aβ (133).

5. OTHER ROLES, OTHER SYSTEMS

A consensus is emerging that the C system has major roles beyond those traditionally recognized, and overlaps or interacts with other systems.

5.1. Neuroprotective roles of C

The C system has traditionally been viewed as a source of destructive inflammation but is now increasingly recognized as having beneficial actions as well (apart from immune defense). One of these is recruitment of neural stem cells. It was shown in 2006 that neural stem / progenitor cells are recruited via C factors, C3a, C5a and their receptors (134). Those studies suggest important therapeutic applications of this finding. Kimberly et al. cite three references which show a role for C factors in limb regeneration (135). The anaphylatoxins are believed to be critical also for recruiting hematopoietic stem cells (136, 137). On the other hand, blockade of inflammation by NSAIDs (e.g. indomethacin) was said to restore neurogenesis after endotoxin-induced inflammation or irradiation (138). That finding is not necessarily inconsistent, or may involve different pathways, since NSAIDs are not known to block the C system, (except possibly in platelets). With regard to stem cell recruitment, transformation of stem cells requires vitamin C (139) as a factor essential in cell culture (140).

Tegla et al. have discussed the neuroprotective effects of C in multiple sclerosis (MS) with a focus on oligodendrocytes (oligo's) (141). Oligo's are able to defensively shed off MAC with vesicles (142), as can other cell types (143, 144), but MAC readily lyses them if present in sufficient levels (145). Not mentioned by Tegla et al. is the fact that oligo's are exquisitely sensitive to C since they lack GPI-anchored proteins which are protective against autologous C (146). Tegla et al. cite data that sub-lytic MAC can protect oligo's from apoptosis, and that C5a protects axons, promotes remyelination, and inhibits gliosis. Support for this is found in several papers by them and others using the EAE mouse model of MS which shows that deficiency of C5 (and C6) worsens disease, and alters expression of some 2500 genes, about 900 of which were differentially regulated in acute vs. recovery of EAE (147).

Three independent reports found that deficiency of the early C components not only failed to protect in the AlzD mouse, but exacerbated progression (148-150), suggesting a protective action of C. However, as noted above, mouse models do not always faithfully reproduce human C activation in AlzD. Their meaning remains controversial and uncertain. Relatedly, it was reported that C5a was strongly neuroprotective against glutamate toxicity (151); but in a mouse model of AlzD, others found that blocking the C5a receptor (C5aR, CD88) was protective (152). Reiter et al. described "C-induced protection" by which sub-lytic amounts of C protected against subsequent lytic doses (153). Others have also reported neuroprotection by MAC in sub-lytic amounts (141, 154). This may be similar to the phenomenon of "accommodation" (155), the significance of which is not limited to transplant medicine. This refers to the observation that normally harmful antibodies can become benign, in a manner different from tolerance. Systemic lupus erythematosus (SLE) is a well-known example in which C appears to play a protective role, since deficiencies of early components (e.g., C1q, C4) predisposes to the disease (156). Turning again to AlzD, Veerhuis et al. report that Aβ in the presence of C1q and SAP, (but not in their absence), promoted secretion of proinflammatory cytokines from microglia in vitro (157). Hence, the putative protective role of C in AlzD mouse models remains an open question. Perhaps C is protective in the early stage of AlzD, since C can clear circulating Aβ (158), but is adverse in the later stages.

The broader question has been debated as to whether inflammation generally, and C in particular, is harmful or helpful in progressive neurodegeneration. This was recently discussed in light of new evidence implicating inflammation and C activation in AlzD (159). The term, inflammation, is exceedingly broad, obscuring important mechanistic differences among its pathways, including the compensatory anti-inflammatory response syndrome (CARS) (160). Our laboratory entered the debate about whether inflammation was helpful or harmful in surviving sepsis, and reported clear association of reduced mortality with increased inflammatory markers (161).

It was recently reported that the sushi domains characteristic of the C control proteins are vital to the proper clustering of acetylcholine receptors in the worm, C. elegans, leading those authors to expect a similarly vital role for C factors in human nerves (162). Findings from other lower organisms are also instructive. As noted later (part 7.4) the C system is involved in the release of antimicrobial peptides. It has been shown in the medicinal leech, (which depends on the C system for its immune function) (19, 163), that these peptides are synthesized in neurons and glia, and act to promote neuronal regeneration following axotomy (164).

5.2. Role in autoimmunity

As mentioned above, nearly all individuals who are deficient in early C factors, C1q, C2, or C4 develop SLE, as do mouse models with these defects (156). However, C activation is also responsible for progression of the disease in later stages, so this presents a paradox. According to Carroll (165), the tentative explanation has been based on evidence that these factors, which trap cellular debris such as apoptotic blebs, "present" these self-antigens to autoreactive B cells to induce anergic tolerance. Mice lacking C1q or C3 resist induction of tolerance (166). Similar observations have been made in ischemia-reperfusion (I/R) injury (167), and may apply also to MS and AlzD models. The role of C in clearance of apoptotic cells had been controversial but now appears to be established, such as by Fraser et al (62), who show C1q to play the central role, but C3b opsonization, the alternative pathway, and other serum factors contribute to this complex process. The scenario is modified somewhat in the CNS where the glia (astrocytes, microglia, ependymal cells) play prominent roles (168).

Defective clearance of apoptotic cells and debris by the C system is now thought to promote systemic autoimmune disease (62, 169). This mechanism has been discussed with specific regard to the brain (168). A mouse that spontaneously develops autoimmune diabetes and other autoimmunities was persuasively attributed to defective clearance of apoptotic cells (170). The role of C in autoimmune diseases is complex, as further considered later in this review.

5.3. Role in adaptive immunity

It had been known since the 1970's that depletion of C3 impaired the antibody response to antigens, and that lymphocytes possessed C receptors, yet two decades elapsed before the pivotal role of C in adaptive immunity came to be widely accepted (171). The key evidence clarifying this connection was supplied by Fearon, Dempsey and colleagues, who demonstrated that antigen bound to C3d greatly enhanced the humoral response, via CR2 (CD21) interacting with CD19 on B cells (39, 172). In effect, the C3d was acting as a natural adjuvant, greatly lowering the threshold of response (173). Another class of natural adjuvants was subsequently appreciated, namely, natural antibodies (174-176), discussed later. Additional C factors are now known to be involved with T- and B-cell signaling, such as MIRL (CD59) (135, 177). Interestingly, transcription of C genes increased when adaptive immunity was disabled by deletion of the recombination activation gene 1 (rag1), in zebra fish (178).

5.4. Links to coagulation

Some of the connections between C and the coagulation system have been recognized since the 1980s or before (179, 180). More recent developments include the thrombin-activated "extrinsic pathway" of C, and the role of TAFI in the C system, cited earlier. Plasmin can partner with MAC to induce the inflammatory lipid, PAF (181). Of growing importance in C research is the kinin-kallikrein system (KKS) of the contact pathway of coagulation, in part because of its possible involvement in MS (182), and because one of its most potent products, bradykinin, is controlled by C1-INH (183). Endothelial cells (EC) are a target of both the KKS and C systems (184). Already in 1993, the anaphylaxis caused by insect stings was attributed to enzymes of the contact pathway, which in turn induces activation of C (185). More recently, it was shown that coagulation factors Xa and XIa can directly cleave C5 and C3 to produce C5a and C3a (25, 26). In their most recent work, Amara et al. show how both coagulation and C are activated at a wound site and work together, including inflammatory response (26).

Other enzymes released in the micro-environment can likewise produce C3a and C5a directly, such as by neutrophils and mast cells (77, 186). Tissue factor (TF), the main initiator of coagulation and thrombosis, is now also linked to the C system (187, 188). Protein S, a cofactor in the protein-C anticoagulant system (not to be confused with the S protein, vitronectin) circulates bound to C4b BP (189). C4-BP genetic variant is a risk factor for venous thromboembolism (190). Another component of the protein C anticoagulant system, thrombomodulin (TM), was shown to be an important inhibitor of the C system (191), of special interest in neurology for several reasons: (i) the distribution of TM in brain endothelium is very uneven (192); (ii) coagulation products are found in lesions of several neurological diseases such as MS. Fibrinogen, a signal transducer in the CNS, interacts with CR3 and CR4 (CD11b/CD18, CD11c/CD18) and with platelets in brain (193). Last, (iii) recombinant soluble TM provided neuroprotection in spinal cord injury (194), as did C1-INH (195).

Platelets, which partner with coagulation in blood clotting, are themselves a rich source of C factors, receptors (C1qR, CR2, 3, 4), regulators (H, C1-INH, CD59, DAF), and factor D (196), and can deploy the C5b-9 attack complex (MAC) (197). For more recent perspective on how platelets and their microparticles (PMP) can "focus complement to sites of vascular injury", see Peerschke et al (198). Platelets can bind the S protein (VTN) of the C system at several of its receptors, especially Alpha_VBeta₃. The neurotoxic effects of thrombin following cerebral hemorrhage were ameliorated by inhibiting C (27). For the many roles of thrombin in the CNS, see Festoff et al (199).

Since osteopontin (OPN, also Eta-1) is of much current interest in MS (200), it is worth noting that thrombin can cleave OPN to yield OPN-Arg, which has greatly increased chemotactic potency for neutrophils and T cell subsets. At the same time it exposes a new integrin binding sequence (SVVYGLR) which increases its affinity for the more restricted ß₁ subset, a ₄ß₁ and a ₉ß₁. Finally, thrombin can further cleave this transiently active molecule into inactive OPN-Lys. OPN may also be cleaved by plasmin, cathepsin D, and even some matrix metalloproteases (201).

5.5. CNS influence, and roles in lipid traffic

It is reported that centrally administered C3a suppresses food intake, while C5a stimulates (202). In that report, the authors suggest that this is prostaglandin mediated. The C fragment, C3_desArg, also called 'acylation stimulating protein' (ASP), interacts with C5L2 to govern fat metabolism via adipokines (203). Several C factors are lipid-associated, notably CLU (ApoJ).

According to Baciu (204), a role for the CNS in regulating the immune system was proposed in 1945, and by 2005 the vagus nerve was established as an important conduit for this control (205). CNS regulation of innate immunity / inflammation has been well reviewed (206, 207) but the focus there is largely on cytokines, not the C system per se. It is now known that many leukocytes can themselves produce and secrete neurotransmitters which regulate and coordinate their functions in an autocrine / paracrine manner (C-mediated acute lung injury for example) (208). On the other hand, it has been shown that C1q family members present in the brain can function as "trans-neuronal cytokines" regulating synapse development and plasticity (209), though it is not clear how or if they participate in the C system per se.

The febrile response to endotoxin (lipopolysaccharide, LPS) was impaired by reducing C components (210) or by cutting the vagus nerve (211), implying that there is cross-talk between C and CNS. The febrile response to LPS had been attributed to cytokines, but Sehic et al. demonstrated that the cytokines emerge only after the febrile response, and hence, that C activation triggers the cytokine release (210). The same is likely true for many other phenomena attributed to cytokines or "cytokine storms".

5.6. Links to other arms of innate immunity

As mentioned in the introduction, the C system has been overshadowed by the more recently discovered Toll-like receptors (TLR's) (212), NOD-like receptors, inflammasomes, and other new elements of innate immunity (5, 6). We could not find articles devoted to connections among these arms but many lines of evidence suggest inter-connections. For example, dextran sulfate, a potent inhibitor of the C system, inhibited the TLR-mediated activation of human NK cells (213). The TLR's are involved in the vitamin D anti-microbial response (214), but so is the C system (215). A component of Neisseria meningitidis is a ligand for TLR2 (216) but this bacterium is also recognized by C, and likewise for numerous viruses and other pathogens beyond the scope of this article. Certain particles such as silica and alum which activate inflammasomes (5) are also classic activators of the contact pathway of coagulation which, as noted above, is intimately linked to the C system. The traditional distinction, that C acts in the plasma phase while TLR's are intracellular, is no longer valid since it is known that many C components are synthesized and active within many cell types, including neurons and glia of the CNS (168). There is no clear distinction in the kinds or classes of PAMP's and DAMP's that can activate the C system vs. TLR's vs. inflammasomes. Consequently, it is safe to assume that all components of immunity function cooperatively as an integrated whole; and that if hierarchy exists among them, the C system likely predominates; Zhang et al. provide evidence that TLR-mediated inflammation and adaptive immunity are controlled by the C system, chiefly via C3aR and C5aR (217).

6. COMPLEMENT MEDIATED DISEASES

The following paragraphs briefly review diseases known or suspected to involve C. Since the emphasis here is on neurological conditions, several major groups (cancers, heart disease, sepsis, etc.) are not included. On the other hand, some are included which are of limited interest in neurology, either for historical reasons or because they illustrate general or unusual mechanisms. There are various ways to group or classify these disorders, such as genetic, acquired, autoimmune, and secondary to other states; or by the C pathway involved; etc., but no such classification is attempted here. The section on therapeutic approaches, which follows this section, provides added dimension on some of the examples. For general review of manifestations of C deficiencies, see (218).

6.1. CNS infections & relation to autoimmune disease

Deficiency of late-acting components (C5 - C9) confers up to 10,000-fold increased risk of bacterial meningitis (219), while defective properdin (CFP) conferred a 250-fold higher risk (220). Most cases are caused by Streptococcus pneumoniae, Haemophilus influenza, or Neisseria meningititis, which gain entry to CNS via the laminin receptor at the BBB (221). Interestingly, meningitis related to C deficiency, although far more common than in the general population, is milder and has lower mortality. Welsch and Ram offer an hypothesis for why this is so, suggesting that the reduced level of terminal C components also reduces the C-induced release of lipid A from the bacteria, which in turn reduces the inflammatory response (219). They also mention that persons with these C deficiencies are more prone to less virulent strains (reasons are not given), offering this as another hypothesis for the lower mortality in these individuals.

Of special interest here is the close association between deficiencies of C and autoimmune diseases. Table 3, adapted from Tedesco (220), shows the frequency of some infections in relation to the factors deficient. Deficit of C5 - C9 are the "late-acting C component deficiencies" (LCCD). The reader may note that deficits of the early acting components (C1 - C4) correlate most strongly with autoimmunity.

6.2. Age-related macular degeneration

This leading cause of blindness is recently understood as a C-mediated disease. According to a perspective in Science (222), much credit goes to G. Hagerman and colleagues who over many years of study detected C components, including C5b-9, in eye deposits termed "drusen", from patients with age-related macular degeneration (AMD). In 2005, three groups independently found mutations in a gene for factor H in AMD patients, and in the following year the original group reported defects also in factor B and CR2, pushing the gene-based prediction rate (penetrance) to 74% of afflicted patients (223). (For an overview of the factor H genes in disease, see 34). Patel et al. discuss a single nucleotide polymorphism (SNP) in the C3 gene conferring an odds ratio of 2.6 for risk of AMD (if two copies) (224), and cites additional strong associations subsequently found for the genes of factors H and B, and for C2 in humans. As might be expected, this multiplicity of risk factors has resulted in some controversy, as discussed (225), but there is an emerging consensus that C defects are responsible for AMD. There is also evidence that prior infection with Chlamydia pneumoniae predisposes to AMD; not all studies agree on this (224). Exactly why the retina is targeted is not clear, or why it generally happens only after age 60. Several C-related disorders show high specificity for particular organs or tissues, and many transgenic rodent models of C-mediated diseases show characteristic age of onset of symptoms. It should be added that there are two main forms of AMD, "wet" and "dry"; the wet form is effectively treated by anti-VEGF to inhibit angiogenesis.

6.3. Myasthenia gravis

In 1993 myasthenia gravis (MG) was identified as an autoimmune disease against the bungarotoxin-binding receptor for acetylcholine (AChR) (226). Approximately 80% of patients have this AutoAb. However, it was subsequently found that C3 levels correlate with severity of MG (227), and that an SNP) of the DAF gene was closely associated with that subtype of MG involving extraocular muscle paresis (228). Further supporting C-mediation of MG is that an inhibitor of C ameliorated symptoms in animal model (229).

Sheng et al. made the interesting observation that AChR becomes over-expressed in the mouse model of MG, possibly compensating for the blockade by AutoAb, but these hastily-assembled receptors are defective in failing to bind bugarotoxin (230). The authors suggest that this helps drive the autoimmune response. Several C-mediated diseases exhibit age-dependent onset, including the model of MG used by Graus et al. (231).

6.4. Alzheimer's disease

The etiology and pathophysiology of Alzheimer's disease is complex and controversial, including with regard to the role of C in it. Accordingly, this article is limited to a few paragraphs suggesting a major role for the C system, supplementing earlier comments. Deposits of C components have been detected in AlzD brains since the 1980s in close proximity to the amyloid-beta (Aβ) plaques and neurofibrillary tangles. They occur along with other so called Aβ-associated proteins, many of which are acute phase reactants (232). Several of the Aβ-associated proteins, such as SAP, A2M and CLU, earlier discussed in part 3.6-7, are often listed apart from the C factors but are important modulators of the C system. In 1989, McGeer and colleagues documented the presence of terminal MAC in these deposits, but no evidence for participation of the alternative pathway was found (233, 234). A further advance was the discovery by Rodgers et al. (235), subsequently confirmed by others, that Aβ could itself activate the C cascade directly, independent of antibody, indicating activation by pattern recognition of altered self (236). More recently, it was shown by Rodgers et al that Aβ peptides occur also in the peripheral circulation but are normally eliminated via CR1 of erythrocytes in a C3b-dependent manner (158).

Work on the role of C in AlzD was for a time overshadowed by the clear association of APOE gene polymorphism with AlzD. However, a subsequent large study found strong new associations, notably including variants of the C factors, CR1 and clusterin (CLU) (237), now confirmed and extended (238). Similar results were found in another large study published in the same journal issue (239), the latter emphasizing also the PICALM gene, which participates in

lipid traffic. As mentioned earlier, the C system has links with lipid mediators, such as via CLU (ApoJ) and phospholipase A2 (PLA2), implicated in AlzD (112), as is gelsolin (114), a modulator of the inflammatory lipid, PAF (115). There is more limited evidence supporting involvement also of polymorphism of A2M (240). A2M, a zinc-binding protein which aids in control of matrix metalloproteases, is a mediator of TNF-alpha, and has also been discussed in relation to AlzD (121).

We have earlier mentioned the finding by three independent groups that deficiency of early C factors (such as C3) in mouse models of AlzD not only failed to protect, but actually exacerbated disease progression (148-150), consistent with protection mediated by C, at least in early stages. However, the transgenic mouse models of AlzD are considered unreliable (131), therefore the significance of these findings for human AlzD is uncertain. Nevertheless, Nuutinen et al. have outlined a good case for a central role of C in AlzD (95). Their article concludes by questioning if CLU, and C generally, are a "guardian or enemy" in AlzD. The high levels of CLU observed could be viewed as a protective response since CLU is a classical C inhibitor.

There is a great deal of evidence showing systemic inflammation in AlzD, such as the recent study showing that inflammatory markers, especially TNF-a, correlated with cognitive decline (241), and discussed in other reports (159). According to Emmerling et al. writing in 2000, "more than 20 studies" have documented the efficacy of NSAID in AlzD (242). Unfortunately, several later and larger studies failed to confirm their benefit. To our knowledge, NSAIDs have limited impact on C activation (except possibly in platelets), so those failures might be interpreted as evidence for the clinical significance of C in AlzD. Salminen et al., in reviewing the role of innate immunity in AlzD, listed a large number of components besides the C system that may be implicated in AlzD, e.g., TLRs, NOD-like receptors, N-formyl peptide receptors, cytokines, etc. (236). It is tempting to suggest that many or most of these effects might share a common cause, and might be networked with the C system.

6.5. Prion diseases

Like AlzD, the prion diseases are considered to be protein-misfolding diseases, and oligomers of prions, like oligomers of Aβ, appear to be cytotoxic. It is now emerging that the C system is involved in prion disease pathogenesis, recently by the demonstration that C1q binds oligomerice forms of cytotoxic prion (243).

6.6. Amyotropic lateral sclerosis

Amyotropic lateral sclerosis (ALS) is considered a motor neuron disease and several candidate causal factors are identified including defect in the superoxide dismusase (SOD) gene, immune involvement, and the C system (244). To further evaluate the role of C, Chiu et al. confirmed dense deposition of C in the affected areas of a mouse ALS model, but knockout of C4 failed to alter the age of onset or survival (245). However, this work may not have been completely conclusive. Others have shown that C activation can occur independent of C4, such as via the extrinsic pathway by which coagulation factors (thrombin, plasmin, FXa, FXIa) can activate C3 and C5 directly (26, 71). This possibility is supported by the fact that C4 deficiency does not predispose to infections as markedly as do deficits of C3 or C5 (220), suggesting that C4 is not essential to the efficacy of C3, C5 in fighting infection. The possibility therefore remains that ALS is significantly a C-driven disease.

6.7. Multiple sclerosis

Complement components were identified in multiple sclerosis (MS) lesions as early as the 1960's-70's, and the role of C in MS has been debated ever since. By the newer method of gene microarray analysis, several C components were identified in lesions at autopsy (246). It is of great interest that AutoAb's against C regulatory proteins, notably against CD46, were identified in CSF of MS patients, and correlated with exacerbations and EDSS (247). This is of special interest because herpesviruses like EBV and HHV6, which are increasingly implicated in MS etiology, express this protein in their genomes as a means of protection against C-mediated attack or entry (248). The presence of these antibodies could impair the normal function of CD46, rendering self-cells more sensitive to C-mediated injury. Although it is not possible in the space available here to review the 'infectious etiology' hypothesis of MS, a history of mononucleosis was shown to be more than additive with the MS risk haplotype, HLA-DRB*15 (249). The mechanistic significance of that haplotype is not yet clear (250). However, even in absence of genetic C dysfunction, it is possible for C activation to contribute significant inflammatory burden (or possibly to exert protective effects (141)), particularly if self-defense against C is impaired.

The role of C in MS was recently briefly reviewed (251), and pointed out that comparatively little research on C in MS has been accomplished. It was reported that the demyelinating influence of AutoAb towards MS target antigens was directly related to their ability to fix C (252). Space limitations prevent us from discussing some of the interesting but complicated relationships that could support a role of C in MS, such as amelioration of symptoms in a rodent model of MS by vasoactive intestinal peptide (VIP) (253), known to act on CR1 (CD35) and CR3 (CD11b) as well as on the VIP receptor (VPAC1) and the N-formyl peptide receptor-like-1 (FPRL1) (254), all of which seem to be related through certain C-relevant ligands. Relatedly, interferon-Alpha (IFN-alpha) has been identified as a fourth class of ligand for CR2 (40), which is of great interest in regulating autoimmunity (255). In a study of the classes and subclasses of AutoAb against two target antigens believed to be MS-specific (MOG, MBP), it was found that IgM predominated; however, only IgG3 correlated with exacerbations (256), which is noteworthy since IgG3 is most potent at activating C. On the other hand, we observed that anti-phospholipid antibodies in RRMS correlated with exacerbations, and were exclusively IgM (257). The specific protein target of those antibodies is not yet known.

6.8. Hereditary angioedema (HAE)

Although not strictly neurological, hereditary angioedema (HAE) well illustrates the complexity of C-mediated diseases, and in 1971, was historically the first non-infectious hereditary disease shown to be caused by a C deficiency, namely, lack of C1 inhibitor (C1-INH) (258, 259). Nearly 200 mutations or polymorphisms are now known, classified as types I and, II. (260). The disease has a highly variable course, and triggers of flareups are unclear, but seem to include psychological stress. Acquired forms can be induced by drugs such as ACE inhibitors or by AutoAb (261). It has been hypothesized that all of these effects involve altered B cell proliferation (262). A rare homozygous deficiency has been reported which is believed to be non-responsive to androgens for that reason (263).

The cause of the disease appears to be excessive bradykinin production, not C activation per se (183). Accordingly, HAE can also be caused by defects in coagulation factor XII gene responsible for bradykinin, termed type III HAE (264). Symptoms are often related to estrogen (oral contraceptives, onset at puberty) but according to Cugno et al., it is not clear why HAE responds to androgens such as danazol (183). Although C1-INH is the only known inhibitor of C1r and C1s, it also functions to control MASP-1, -2, and coagulation factors XI, XII, thrombin, plasmin, tissue plasminogen activator (tPA), and crucially, kallikrein, which yields bradykinin (28). It is beyond this review to convey the complicated interplay among systems resulting in the disease (183), but the reason for discussing it at all is to point out that complexity. Moreover, C1-INH, which is an effective therapy, has important functions which are independent of its action as an enzyme inhibitor; Davis et al list five roles: binding to components of the extracellular matrix; inhibiting the alternative pathway by binding C3b; binding to E- and P-selectins of endothelial cells; etc. (265). Thorgersen et al find other broad anti-inflammatory effects of C1-INH (266).

6.9. Ischemia reperfusion injury

Ischemia reperfusion injury (I/R) refers to the injury sustained by tissues when blood circulation is restored following ischemia and is of great importance in many areas of medicine, especially ischemic stroke. I/R injury has been recognized to be largely C-mediated since at least the 1980's (267), and was thoroughly confirmed through the 1990s (268, 269). One report questioned if the role of C was primary or secondary, based on experiments using cobra venom to deplete C (270). The consensus holds it to be primary, involving the role of C in clearing apoptotic and necrotic cells. Recent advances in understanding I/R injury are presented in part 7.

6.10. Paroxysmal nocturnal hemoglobinuria

Many important membrane proteins are anchored to the membrane by a glycosyl phosphatidyl inositide (GPI) linkage, including the C-protective DAF and MIRL (271). Paroxysmal nocturnal hemoglobinuria (PNH) was long of interest in hematology but is now known to have neurological consequences (272, 273), notably, persistent absence seizures in a familial pattern, although the affected children had no hematologic symptoms (272). The mystery of PNH was resolved with discovery of a PNH-associated gene, PIG-A, preventing formation of the GPI linkage and resulting in deficiency of cell-bound GPI-linked proteins (274). Most important for PNH is deficiency of MIRL (CD59), leading to sporadic episodes of self-cell destruction by C, the most obvious symptom being hemolysis, often at night. To our knowledge, it is not yet clear how this leads to the neurological complications, since absence of GPI-linked proteins unrelated to C could be responsible. It may be relevant to note that brain oligodendrocytes are reported to naturally lack these proteins (146).

6.11. Traumatic brain and spinal cord injuries

Activation of C is believed to contribute substantially to the sequelae of traumatic brain injury, including the systemic inflammatory responses syndrome (SIRS) (160). These events, both early and late, are very complex but the totality of data suggests that C activation could be the central and unifying player. The neuroactive steroid, progesterone, is known to alleviate symptoms by reduction of proinflammatory cytokines, and has been shown to upregulation the potent C inhibitor, DAF (CD55) which has been proposed to explain its observed benefits (275). Complement activation markers such as C5b9 in CSF correlated closely over time with the injury marker S100B in 20 patients post-TBI (276). Administration of C1-INH was protective against traumatic spinal cord injury (SCI) (195). Inhibition of the alternative pathway by a monoclonal antibody against factor B gave dramatic protection in a mouse model of TBI (277). On the other hand, it was reported that deficiency of mannan binding lectin (MBL) by gene knock-out worsened outcome of TBI in mice, suggesting a protective role for MBL (278). The review of Lu et al. cited above devotes a section to coagulopathy in TBI, stating that thrombin is a major player in brain edema, and that PAF, whose expression has links also to coagulation, is also implicated in TBI (160). That is to say, the coagulopathy seen post-TBI may be viewed as linked to C activation. For example, links between thrombomodulin (TM) and the C system were mentioned earlier (part 5.4 ) and TM was seen to be neuroprotective in SCI (194). The brain edema seen following intracranial hemorrhage in rats was also attenuated by systemic depletion of C (by cobra venom factor) (279). Work by Nguyen et al. demonstrates clearly a sharp upregulation of C factors, including MAC, specifically in PMN infiltrating the SCI site with time, and associated inflammatory markers (280), and other work by those authors demonstrates protection against SCI sequelae by C1q deficiency.

6.12. Atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) which frequently manifests with neurological symptoms (281, 282) and is a leading cause of renal failure. It was shown in 1983 that the majority of HUS cases (≈75%) are caused by certain strains of E. coli, chiefly 0157:H7, carried by cattle, which secretes a shiga-like verotoxin (283) as well as several secondary toxins (284). The remaining cases are termed "atypical" (aHUS) and have been shown to associate with hereditary C deficiencies. It must be added, however, that it was recently shown that the E. coli toxin itself strongly activates C (285), hence both HUS and aHUS can be C-mediated, but in different ways. The familial pattern of aHUS was known since 1980 but only in 1999 was a mutation of factor H implicated (286). Multiple reports in 2000 and later amply confirmed that finding, and at least a dozen papers on aHUIS appeared in 2009 alone. In brief, gene variants of C factors now implicated in aHUS include those for factors C3, H, I, B, MCP (CD46), and factor H-related proteins (CFHR1, CFHR3, CFHR4). Some 14 mutations of factor I alone are related to aHUS (287). Most recently, a defect in the gene for clusterin (CLU) was associated with aHUS, bringing to 75% the number of aHUS cases accounted for by C-related genetic anomalies (288). It is instructive that such a profusion of defects all predispose to aHUS. Of particular interest in this review is the parallel frequency of AutoAb to C factors in aHUS, such as anti-factor H (289). Skerka et al has identified a subtype, DEAP-HUS, the acronym being "deficiency of CFHR1 and CFHR3 and autoantibody positive" (34, 290); see also (42, 291).

6.13. Thrombotic thrombocytopenic purpura

Fluctuating neurological disturbances are hallmarks of this thrombotic microangiopathy (TMA), which is often discussed along with HUS. The cause of thrombotic thrombocytopenic purpura (TTP) was identified by Moake and colleagues as a defect in the enzyme ADAMTS13 which cleaves von Willebrand factor (vWF) (292, 293). However many have questioned if this is a complete explanation, or if it applies to all cases. Evidence that C is a major culprit of TTP was suggested in 1989 (294), and further supported more recently (295, 296). Rock et al. had reported AutoAb to CD36 in TTP (297), as investigated further by our lab (298). AutoAb to ADAMTS13 has been found in TTP (299), as have antibodies to unspecified antigens on the microvascular endothelium (300).

6.14. Systemic lupus erythematosus

Course and manifestations of systemic lupus erythematosus (SLE) are very diverse, notably including neurological, renal, cutaneous, infectious, and thrombotic. These effects are attributed to a broad array of AutoAb including anti-nuclear and antiphospholipid (aPL), together with their immune complexes (IC) (301, 302). The IC which most strongly activate C are also the most pathogenic (303). The detailed role of C in SLE is highly convoluted and well beyond the scope of this review; (see 156). Of special interest in that review is discussion of the paradox of protective vs. harmful effects of C, as mentioned earlier. Carroll also discusses this paradox (165). More recently, genetic polymorphisms of CR2 were shown to associate with SLE (304), supporting prior reports back to the 1970's, such as familial deficiency of C2 with SLE-like syndromes (305, 306).

Recent reviews of SLE genetics cite evidence for association with deficits of C1q, C2 and C4 (307, 308). The association with deficit of C1q is most persuasive since nearly all with this defect develop SLE-like symptoms, as do mice deficient in C1q. A novel explanation for this, involving interferon-alpha, has been proposed (309). A study of 17 pairs of monozygotic twins, one with SLE the other not, revealed epigenetic differences in 49 genes, including several immune-related (e.g. interferon) but not C factors per se (310). Neuro-psychiatric lupus appears to result from cross-reaction of certain anti-nuclear antibodies with brain NMDA receptors (311). Exposure to Epstein-Barr virus has been proposed as a triggering event for SLE (312); it would be interesting to know if EBV+ SLE have AutoAb to CD46. Impaired opsonization of bacteria in a cohort of SLE patients was reported (313), consistent with high frequency of infections and C deficits. Platelet-bound C4d was found to be a highly specific biomarker for SLE (314).

6.15. Antiphospholipid syndrome and antibodies

The "lupus anticoagulant" was originally thought to be specific for SLE patients, most of whom are antiphospholipid antibodies (aPL⁺). In view of this and other facts, it has been proposed that antiphospholipid syndrome (APS) and SLE lie on the same etiologic spectrum (315). It has been pointed out that APS and MS also often have very similar clinical presentations (316, 317). We have briefly reviewed the role of C in APS (318). Some but not all reviews of APS assign high importance to the role of C (319-321). Munakata et al. found that C-fixing aPL were specifically associated with thrombosis (322). Important work in this area concerns recurrent fetal loss (RFL), which is among the defining criteria of APS. Following suggestive early work and later work by Shoenfeld and colleagues (323), Salmon and colleagues demonstrated an absolute requirement of C for RFL (324, 325). A related advance was establishing the role of C in preeclampsia (326), also by assay of C factor Bb in plasma. APS often has neurological involvement but the role of C in this specific regard has not been extensively investigated.

6.16. Immune thrombocytopenia

Although not considered a neurological disorder, a subgroup of immune thrombocytopenia (ITP) with progressive vascular dementia has been identified (327). Apart from that, ITP is the archetype of autoimmune diseases, first identified as such in the early 1950's (328). Evidence for a role of C in platelet destruction in ITP was widely debated in the 1980s (329-331) but interest in that has since waned. In preliminary studies, we identified two subgroups of ITP, one with evidence of deposition of C, the other not (332)

6.17. Note on detection of C deposition

It has been shown that deposition of C can induce vesiculation, carrying off the C from the parent cell (143, 144, 333). Accordingly, evidence of C-mediated attack may not be detectable on the cell but will be found on the microparticles (MP) released. Biro et al detected elevation of several C fragments on MP from the synovial fluid and plasma of patients with rheumatoid arthritis (RA) (334). These observations suggest that so-called soluble C5b-9 often detected in plasma and CSF may in reality be MP-bound. Relatedly, it is possible that in the work of Lynch et al., who found that elevated Bb levels in plasma correlated with pre-term birth (325) and preeclampsia (326), the Bb may have been bound to MP.

6.18. Progress in gene association studies

Improved methods have revealed gene associations previously missed. Here we mention some other opportunities. One is post-translational editing of RNA transcripts by adenosine deaminases RNA-binding (ADAR's), termed "RNA re-coding". According to Cies and Maas, re-coding effects have been mistaken for SNP's by certain methods, but still show great promise (335). Remarkably, they find sharply different outcomes in different brain regions. Also of potential importance are copy number variations, not commonly tabulated, but recently shown to be major determinants of the phenotype of C factors (336). Another avenue only beginning to be explored are epigenetic marks, which are expected to be most relevant in diseases suspected to have environmental components such as MS.

7. Anti-complement therapies, old and new

A central role of C in many pathologies has long been known or suspected but therapeutic options have been limited. That situation is poised to change (337). This section emphasizes C-targeting therapies that are less well covered in other reviews (337-339), and also serves to introduce the next and final section.

7.1. Recently approved, in trials, or in pipe-line

Already in 1998, about ten C-targeting drugs were listed in commercial development (340, 341). Since this topic is covered in depth by others, only highlights are considered here. Among the first to reach phase 3 clinical trials is a monoclonal antibody, eculizumab (Soliris™, Alexion), which blocks activation of C5; it is FDA-approved for treatment of PNH (342, 343) but is expected to have wide off-label applications. General inhibition of C will increase risk of infection, but blocking C5 should minimally affect activation of C3.

Compstatin is a cyclic tri-decapeptide discovered by J. Lambris using phage display libraries, which binds C3 to inhibit its activation (344, 345). It is in clinical trials for some types of age-related macular degeneration (AMD) and if approved, will also probably find other off-label uses. It has been useful in research to elucidate problems such as the role of the C5a receptor (C5aR) in bacterial killing (346), the role of C in cancers (347), and in the adverse effects of extra-corporeal blood circulation devices (338). Of note, since CR3, together with CR2 (CD21), is important for B cell activation and energy (47, 348, 349), inhibitors such as compstatin may have far-reaching effects not limited to reducing inflammation. Lambris has since found compstatin related peptides which have increased potency. Others are also working with peptidic C inhibitors, such as one targeting C5a (350). For further details, see (339).

FUT-175 is a serine protease inhibitor which has been in use as an anti-thrombotic but is also known to have potent inhibitory actions against several C factors. Therefore, it was tested in the EAE mouse model of MS with promising results (351). That paper also briefly reviews new insights on C production and activation within and between T cells and antigen presenting cells (APC's), in relation to MS. Also of interest is use of cobra venom factor (CVF) for anti-C therapy (352). CVF has long been used to deplete C in laboratory animals, by causing massive C activation. It is remarkable that a single treatment has few ill-effects, hence is continuing consideration for human use.

7.2. Previously established C-targeting therapies

As early as 1980, a partially purified C1 inhibitor (C1-INH) from pooled plasma came into use for treating hereditary angioedema (HAE) in emergencies such as laryngeal edema, and is still used. More recently, C1-INH gave significant protection in acute spinal cord injury, p<0.01 (195). A recombinant C1-INH from transgenic animals is now in development (183). Animal studies also support benefit of C1-INH in sepsis (353). C1-INH therapy has been recently reviewed (354). Like many C components, C1-INH has several actions apart from its best-known role as protease inhibitor (265).

In the 1990's, many reports demonstrated great reduction of I/R injury by a soluble form of CR1 (sCR1), in several organs of animal models of I/R, e.g., (355, 356). In that form, it presumably acts as a "decoy receptor", capturing otherwise injurious products, especially immune complexes. The observed benefits further support the central role of C in I/R injury. Of note, at least one of those reports presented reasonable evidence that neutrophil-mediated I/R injury, (which had been an alternative hypothesis), was secondary to C activation (357), confirmed in the paper cited earlier (280). A glycosylated (sialyl Lewis x) form of sCR1 also proved highly promising for neuronal protection in stroke (358).

7.3. Insights from pathogen evasion strategies

By definition, a pathogen has means of evading or neutralizing immune defenses. A highlight of recent research has been elucidation of the strategies for evading the C system, all pointing to a "next generation" of C inhibitors, as well as new vaccines and other approaches to infection control. For example, the vaccinia complement control protein (VCP) has been termed a "potential wonder drug" (359); see also (360, 361). The smallpox inhibitor of C enzymes (SPICE) is another case in point (362). The authors compared inhibitors from several pox viruses and found SPICE to be most potent and, aside from potential therapies based on SPICE, suggest that mAb against it could be therapeutic against the disease. In other work by the same group, the rhesus rhadinovirus C control protein (RCP) was shown to promote degradation of C3b and C4b by factor I, and to accelerate decay of the C3 convertase (363). The authors state that this is the first known such inhibitor that does not require a heparin binding site (364).

Not only viruses but pathogens of every kind have developed means of evading C-mediated killing. Candida albicans produces an iC3b receptor reminiscent of integrins CD11b,c which is required for its infectivity in mice (365). The Candida strategies are discussed by Zipfel (366), who cites more comprehensive treatments of the many "cloaks and disguises" used by pathogens to evade C.

The tick-borne pathogen Borrelia hermsii acquires factor H as well as plasminogen (367), as does Pseudomonas aeruginosa (368). The latter authors offer several likely reasons for the capture of plasminogen, such as its' ability to degrade vitronectin (S protein). The former authors point out that Staphylococcus aureus activates plasminogen to plasmin, which in turn degrades IgG and C3b at the bacterium's surface, citing Rooijakkers et al. (369). This supports the paradigm that plasmin, an enzyme of fibrinolysis, may have C-suppressing actions. Rossmann et al. list ~10 other bacterial pathogens which also capture factor H, among their tactics (367). Kunert et al. (368) mention several other pathogens known to bind plasminogen (e.g. S. pneumoniae, B. Burgdorferi, S. Pyogenes, and the yeast C. albicans) but the plasminogen binding motif they find on P. aeruginosa is unique. From an evolutionary perspective this is interesting since it implies independent invention (parallel evolution) of the same strategy rather than horizontal gene transmission or common heritage.

Another approach to therapy is suggested by Welsch and Ram, who point out that susceptibility to many diseases (e.g., meningococci) are human-specific, implying that the C systems of resistant mammals, such as rats, have slightly different components - in this case factor H- which might be exploited for our own protection (219). (For a consideration of the role of CFH in human diseases, see refs. 34, 370). These references are only a small sampler of a large and growing literature on this topic, aimed at new therapies.

Note on role of C in viral attack: It is obvious from the above that the C system is an important defense again many viral pathogens. Examples of this include viral influenza (46), Herpes (371), flaviviruses such as West Nile and Dengue (372), and others (361). We mention this because several reviews of innate defenses against viruses fail to mention the C system at all, focusing instead or exclusively on the TLR's and signaling pathways such as the interferon (IFN) response, e.g., (373, 374). This could lead to overlooking the role of C in viral defense, especially among students.

7.4. Vitamin D and the C system

Recent discoveries on the role of vitamin D in immunity may be of great importance to public health. Deficiency of this vitamin has purportedly been linked to neurological disorders, notably MS (375-378). In view of the known latitude gradient in the epidemiology of MS (375), and of cancers, hypertension, and many autoimmune diseases (379), many have suggested a connection. To our knowledge, discovery of the immune benefits of vitamin D3 was by Cannelli (380), after his reading of the role of this vitamin in generating the antimicrobial peptide, cathelicidin (381). This seminal paper was followed by numerous studies, including on the role of this vitamin in autoimmune diseases such as MS, SLE, RA, and others (382, 383). A key link between vitamin D3 and the C system is the vitamin D binding protein (Gc-globulin), a cofactor in the chemotactic activity of C5a (384-387). Mice deficient in vitamin D receptor (VDR) show an increased propensity for autoimmune diseases (388). Conversely, it had been earlier shown that production of C3 in bone marrow stromal cells and osteoblasts is regulated by vitamin D (215); this finding has been extended to monocytes (389). Gene polymorphisms for Gc-globulin and for properdin were found to be in Hardy-Weinberg equilibrium (390). In a proteomic study of autoimmune uveitis, Gc-globulin was down-regulated in parallel with C1q and C4 (391). In pediatric MS, a proteomic study revealed 12 proteins significantly elevated including Gc-globulin together with several C factors, viz., factor I, serum amyloid P (SAP), clusterin (CLU), kininogen-1, and others more distantly involved such as gelsolin and hemopexin (392). As we have noted earlier, plasma gelsolin is a regulator of PAF (115), and PAF, in turn, can be up-regulated via C activation, e.g. (181). According to Roach et al., PAF is syngergistic with C5a signaling (393). In summary, these observations may warrant further study of the relation of C to vitamin D in autoimmune diseases such as MS.

7.5. Heparin and "heparinoids"

This glycosaminoglycan (GAG), heparin, has been known as an inhibitor of the C system since 1929 (394) and some of its pleiotropic benefits doubtless owe to this fact. Heparin is best known as an anticoagulant, acting chiefly by potentiating the inhibition of thrombin by antithrombin III and heparin cofactor II. It also inhibits other serine proteases to varying degrees, as well as von Willebrand factor (395) but it has many other actions as well (396, 397), notably including "immunomodulation" (398), as reviewed more recently (399). This might be expected since heparin binds to some 22% of total plasma protein, while a related polyanion, dermatan sulfate, binds 7%, and chondroitin sulfate, 0.23% (400). Heparin is normally present in plasma in modest amounts (401) but to our knowledge, has not been measured in disease states. The related GAG, heparan sulfate, is also an important constituent of the ECM, (mentioned earlier).

Related GAG's were shown in vitro to inhibit the neurodegenerative effects of the C-related factor, serum amyloid P (SAP), which is thought to contribute to AlzD via binding to Aβ (402). Many studies have documented the efficacy of heparin in reducing C-mediate damage from ischemia-reperfusion (I/R) (403). This effect likely contributes to its benefits in surgical procedures. Spring et al. provide evidence for benefit of the heparinoid, dextran sulfate, for I/R injury, allografts, and immune tolerance by "impeding the link between innate and adaptive immunity" (404). Heparin proved useful for treating C-mediated intravascular hemolysis (405), was more effective than IVIG for recurring APS-related pregnancy loss (406). Its value in obstetrics is attributed in large measure to its passivation of C (407). Although we did not perform a meta-analysis, our readings in the APS literature suggest that heparin was most often the most effective treatment, consistent with a central role of C in APS (321).

Mechanistically, heparin inhibits the C system at several points, notably by potentiating C inhibitors such as factor H (16) and C1-INH (408, 409). The details are complex but are now being elucidated (404). Heparin also inhibits CR4 signaling (CD11c/CD18) (410). Many of the C factors have heparin binding domains, and this has been exploited for assessing mutations in C components that result in reduced heparin binding, e.g. in aHUS (411). Black et al. used acetylated heparin, (which lacks anticoagulant activity), in a canine model of I/R injury, and observed protection as good as native heparin (412). It was also protective in cerebral hemorrhage (413) and reduced neurological deficits induced by thrombin (27). (On the other hand, C1 selectively bound the fraction of heparin with highest anticoagulant activity (414).) The question has been raised if such protection can be entirely attributable to C inhibition since many other actions are known (397). Thourani et al. used a different chemically modified heparin, which in addition to lacking anticoagulant activity had greatly reduced C inhibition (415), yet still observed good protection in canine I/R. However, some technical caveats could be raised about this study, especially the assay method used to show absence of C inhibition. The concentration of native heparin needed for 90% inhibition of lysis (1 mg/mL, ≈ 500 units/mL) in this study was supra-physiological and 100-fold more than needed by other workers (408). Groth et al. has carefully compared the C-inhibiting power of several GAG's, revealing important differences (416). An orally-available pentosan polyphosphate showed good promise as a practical C inhibitor (417).

7.6. Intravenous immunoglobulins

The use of intravenous immunoglobulins (IVIG) for treatment of a wide variety of immune-mediated and inflammatory disorders is growing, including for treatment of MS (418, 419), neurological critical care (420), SLE (421), APS (406), sepsis, and other conditions (422). Many explanations are proposed, the most prominent include C modulation, however the mechanism of benefit remains unsettled (423). One recent hypothesis centers on dendritic cells (DC) (424). The hypothesis that it ameliorates C-mediated inflammation is attractive because this could cooperate with some other putative mechanisms, e.g., correction of "cytokine imbalance". On the other hand, (as reviewed in the next article), the hypothesis that IVIG acts by supplying corrective natural antibodies is increasingly persuasive.

In MS, many reports had shown benefit of IVIG but the large PRIVIG study showed no benefit of monthly treatment over 1 year (418). (Interestingly, the placebo group receiving albumin did show benefit, prompting comments (425).) This negative conclusion provoked letters objecting to the study design, chiefly on the grounds that dosing was too low. Bayry et al. (419), asserting that alternative novel therapies (426) are unrealistic, still advocates IVIG for MS despite that negative report. In other autoimmune disorders such as SLE and APS, results with IVIG are consistently favorable.

7.7. Intravenous IgM and the idiotype hypothesis introduced

If it is true that normal humans naturally harbor many auto-antibodies which are masked by IgM antibodies against them (anti-idiotypes), then we have the hypothesis that autoimmune diseases are often caused by insufficient IgM control. On this hypothesis, here over-simplified, Hurez et al in 1997 prepared IgM-enriched immunoglobulins (IVIgM) and showed that it could suppress auto-antibodies from patients with autoimmune diseases more effectively than IVIG (427). Moreover, rats infused with IVIgM were protected against experimental uveitis. Under this hypothesis, the active agent in IVIG is IgM. If true, this could explain why such a high dose of IVIG is required for effective therapy, e.g., in MS.

More recently, Hoffmann et al., after observing by meta-analyses of literature that IVIgM showed a trend for improved survival in sepsis patients compared to IVIG, demonstrated in hamsters that IVIgM, but not IVIG, significantly reduced leukocyte adhesion in venules and normalized capillary perfusion 24 hours post-endotoxemia induction (428). The discussion in their paper cites further references on IVIG vs. IVIgM. One such report showed that IVIgM was significantly better than IVIG in preventing renal damage in a rat model of inflammation, which was attributed to reduced C activation (429). Another study by that group showed that despite C inhibition by IVIgM, bacterial killing by C was not impaired (430). The next section further explores these important issues.

8. NATURAL ANTIBODIES, COMPLEMENT, AND AUTOIMMUNITY

8.1. Introduction

When we reviewed the antiphospholipid syndrome (APS) (318), two hypotheses for its etiology emerged as the most convincing, (i) C activation, and/or (ii) dysregulation of natural auto-antibodies (NatAb) which are normally suppressed by antibodies against them (anti-idiotypes). Here we summarize recent evidence uniting and further supporting these two hypotheses.

8.2. Background on natural auto-antibodies (auto-Ab)

Compelling evidence accumulated over decades shows that the general population carries a large repertoire of auto-antibodies (auto-Ab) which are normally masked by inhibitory IgM. For example, Adib et al. showed in 1990 that mouse sera reacted only weakly to selected self-antigens but after the IgG was purified, it reacted strongly, indicating the presence of an inhibitor of IgG in plasma, ultimately shown to be IgM (431). When the mouse was infected with Trypanosoma cruzi, the IgM was less inhibitory. The authors concluded that their findings, together with previous work by co-author Ternynck and colleagues, are consistent with an "idiotype-like network" in which self-reactive IgG is normally suppressed by IgM ant-idiotypes.

(The idiotype network theory, first proposed by Jerne in 1974 (432), is beyond the scope of this review. It was widely discussed after Jerne's paper but grew quite complicated and fell out of fashion. However, Behn's review of 2007 refers to a "renaissance" of interest (433). His review is from the perspective of a physicist, who speaks of immunology as a "playground for physicists" because of its daunting complexity. For a succinct review with emphasis on the example of factor VIII inhibitors, see Gilles et al (434); and see Menshikov and Beduleva for the example of autoimmune hemolytic anemia (435).)

We earlier mentioned the report of Hurez et al. (427), the title of which explicitly states the hypothesis. Cheng et al. observed that all normal sera became positive for several aPL after heating (436), and this was repeatedly confirmed by several groups by different methods (437-440). The few negative reports (441) are likely explained by technical issues. For example, as noted by Adib et al. (431), recovery of antibodies from adsorption columns can be impaired by acid elution compared to the gentler method of concentrated MgCl₂ for example. (437). Pan et al. demonstrated SLE IgG AutoAb's in all normal sera, and showed they were masked by IgG anti-Id's (442). Stahl et al. demonstrated that AutoAb's responsible for autoimmune hemolytic anemia (AIHA) are very similar to natural antibodies in the general population. Using methods similar to those above (purification of IgG/M, re-mixing, etc.), they propose that the disease likely results from failure of control by IgM (443).

Some natural antibodies are not masked. The best example of this are those natural antibodies directed against non-self ABO blood group antigens. In such cases, masking is not needed since the antigen is absent. Natural Ab's are part of the humoral innate immune response, encoded in the germ line, and are believed to be important to distinguish self from non-self (434). Work by Gyorgy et al. on Natural Ab in rheumatoid arthritis (RA) shows them to be at least a biomarker of disease activity (444). Interestingly, they report that high levels of IgM against the antigens of interest correlate with mild disease and low IgM with severe disease. Our study of aPL in MS revealed exclusively IgM aPL associated with exacerbations (257).

8.3. The complement connection

Assuming that auto-immune disease can be caused by loss of anti-Id control, a role for the C system may be implied by the observed high frequency of autoimmune diseases associated with defects in the C system. However, it now appears that not only C, but also Natural Ab's are crucial players in adaptive immunity (176). That reference updates Carroll's description of the role of C in the selection and expansion of B-1 cells (171), which are CD5⁺ and the source of Natural Ab (434). Holers and Kulik have review new findings showing relations between CR2, Natural Ab, and autoimmunity in SLE and I/R (175). Those studies include intriguing findings on interferon-Alpha (IFN-alpha), a known ligand of CR2 (40).

The main point in these studies is that C plays a pivotal role in regulating Natural Ab in autoimmune disease, and probably also the regulatory anti-Id's. Moreover, since several auto-immune diseases are linked to HLA haplotypes, it is noteworthy that serum levels of Natural Ab are significant associated with those genotypes (445).

8.4. Remyelination mediated by C and natural antibodies

Warrington et al, building on prior work aimed at MS (446), produced a recombinant IgM from a patient with lymphoproliferative disorder, and demonstrated that it restored remyelination in several EAE mouse models of MS (447). More recently, they reported upcoming clinical trials using this product (448). In view of its source, this antibody is presumably a natural IgM. It did not, however, protect against neurodegeneration, (i.e., of loss of motor neurons). In this regard, it is of great interest to note that axon cell death in EAE results not from MAC deposition but from another pore-forming weapon, perforin (449, 450), wielded by NK cells and cytotoxic T lymphocytes (CTL); i.e., neuron death in EAE was prevented by deletion of the perforin gene, but demyelination was not affected (451, 452). Relatedly, it was shown that MIRL (CD59), which normally protects against autologous MAC attack, provided no protection against the molecularly comparable perforin (453). Some of the same authors have also implicated kallikreins (182). They have discussed their exciting findings in terms of clinical applications (454, 455). Later findings from that group were recently reviewed (448, 456), with a specific emphasis on natural antibodies (457)

Cid et al. attribute failure of remyelination in MS to the depletion of oligodendrocyte precursor cells (OPC's) by AutoAb's to heat-shock protein 90 (HSP90) in CSF of patients. They find that C activation is critical in this mainly by demonstrating that C1-INH could prevent the anti-HSP90-mediated death of OPC's (458). Earlier in this review we cited evidence for the role of C in recruitment of neural stem / progenitor cells. Interestingly, HSP90 is liberated by glucocorticoids (206).

Following work by them and others documenting that sublytic C5b-9 inhibits apoptosis of oligodendrocytes, and that C5 promoted remyelination in EAE (459), Cudrici et al. performed a genetic study of EAE mice with knockout of the C5 gene (147). Their aim was to identify which other genes (proteins) might be associated with the C5-dependent remyelination. About 400 genes were found to be differentially expressed in the C5^-/- mice, and in various pairwise analyses (acute EAE vs. baseline, recovery, chronic, and wild-type C5^+/+). The authors concluded that insulin-like growth factor binding proteins (ILGF-BP) were of greatest interest, (for reasons given in their discussion (147). For further discussion of their findings, see Tegla (141).

8.5. Natural antibodies and ischemia/ reperfusion injury

From similar clues, Zhang et al. were able to identify the target of the natural auto-Ab responsible for ischemia-reperfusion (I/R) injury as a non-muscle myosin heavy chain, which promotes C activation and tissue damage (460, 461); (reviewed in 462). This appears to be a real conceptual breakthrough, since it implies effective treatment using the anti-Id. They documented this mechanism for two different tissues, though it may well apply to I/R of all organs and tissues.

It may be relevant to note early work by Pinckard et al, who demonstrated strong activation of the classical C pathway by mitochondria from human heart in vitro and in coronary surgery patients, in absence of anti-mitochondrial antibodies (463, 464). It is tempting to suggest that this was caused by natural anti-cardiolipin antibodies (since mitochondria are rich in cardiolipin) but the authors convincingly exclude a role of antibodies in this instance, so it more likely innate recognition.

8.6. Natural antibodies, C, and adaptive immunity

The purpose of natural antibodies (NatAb) has been uncertain, but in 1998, an important role for them, particularly IgM, in C-mediated activation of antigen-specific B cells, and in the elimination of self-reactive B cells, was considered (171). More recently, that author (M.C. Carroll) has discussed the broader role of C as a major regulator of multiple pathways in adaptive immunity (465), and in the processing of antigens for antigen-presenting cells (APC's) (466). Gonzalez et al. have shown that natural IgM, acting in concert with C3 and CR1/CR2, are essential for long-term immunological 'memory' (176). They also stated in that study, that IgM and C are in general, essential for normal antibody responses.

The C system might also be involved in the locomotion of leukocytes and formation of immune synapses. It has been shown that the Wiskott-Aldrich syndrome protein (WASP) binds specifically to C5aR (467). It is known that WASP is important to cell locomotion at the level of the actin cytoskeleton, supported by a study of that syndrome in which the WASP protein is defective, entailing recurring infections, a high rate of autoimmune disease, cancers, thrombocytopenic bleeding, and eczema (468, 469). The syndrome also shows reduced C receptors on B cells, low plasma IgM, and an impaired ability to form immune synapses (470, 471). Thus, C5aR may represent a common denominator of these activities that require actin cytoskeletal reorganization: dysregulation of C-mediated control of auto-Ab could be among the consequences.

8.7. Concepts of anti-idiotypes

A now-classic example was the production of a monoclonal antibody from an SLE patient, called idiotype 16/6 (16/6 Id), which occurs commonly in SLE patients, correlates with disease activity, and is deposited in afflicted tissues, (reviewed by Shoenfeld in 1990, 472). Mice immunized with 16/6 Id developed SLE-like disease and a spectrum of antibodies similar to SLE. (Patients with SLE have antibodies to as many as 25 self-targets, many of them intracellular.) Briefly, they explain this by supposing that some of the anti-Id generated in the mouse duplicate the original antigen pattern, which in turn could yield an anti-anti Id to drive the SLE-like response. (For related perspectives, see McGuire and Holmes (473).) The details are complex but generally support this broad concept (472). Similar work had been accomplished earlier by Johnson and Smalley (474), who immunized mice with rheumatoid factor (RF) from RA patients, which is known to react with streptococcal polysaccharides (PS), to obtain antibodies reactive to the original PS; i.e., anti-Id. Implications for autoimmunity are obvious, including potential etiologies attributable to pathogen exposure; but it is equally apparent that mechanisms must normally exist which limit this from happening.

8.8. More roles of natural antibodies

Su et al have demonstrated that natural anti-phosphoryl choline (PC), which can be extracted from pooled normal IVIG, appears to play a protective role in SLE (475). It has been argued that autoimmune hemolytic anemia (AIHA) results from disruption of an idiotype network (435). Quan et al. also made interesting observations on shifts in the repertoire of natural antibodies in treated vs. untreated HIV patients (476). Deliberate construction of anti-idiotypes against pathogenic AutoAb has been proposed for treatment of autoimmune diseases such as ITP (477). The significance of natural antibodies in IVIG therapy was recently reviewed (457).

9. SUMMARY AND PERSPECTIVE

This review clearly shows that the C system can no longer be viewed as in independent arm of the immune system, but is rather intricately connected to many aspects of immunity, including auto-immunity, and self-repair. In addition, the C system is closely connected with the coagulation system, accounting for many otherwise puzzling observations.

From the standpoint of new paradigms leading to potential therapies for several neurological diseases, perhaps most promising is the work reviewed in the last section pertaining to natural antibodies, raising hopes for effective treatments of dymelinating disease, I/R injury, and other immune-mediated disorders, entirely free of generalized immune suppression. Equally exciting is the new insight on the role of C in recruiting neural stem / progenitor cells, and related insights on neuronal repair after injury, e.g. remyelination.

Among the take-home lessons is to proceed with caution on the use of the many C inhibitors now in development because of the numerous beneficial activities of the C system. Another lesson, (a humbling one), concerns our ignorance of the detailed operation of the C system and its relation to other arms of immunity. It seems paradoxical, but true, that the more we learn about biological systems, the less certain we are that we understand them. Ulrich Behn best phrased it this way: "There is a need to better understand the immune system at all temporal and spatial scales and at all levels of complexity" (433).

10. ACKNOWLEDGEMENTS

All authors equally contributed to this article.

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Key Words: Complement, Neurobiology, Multiple Sclerosis, Neuroinflammation, Alzheimer's disease, Review