Complement in autoimmune diseases

Clinica Chimica Acta 465 (2017) 123–130

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Review

Complement in autoimmune diseases Pandiarajan Vignesh, Amit Rawat ⁎, Madhubala Sharma, Surjit Singh Pediatric Allergy and Immunology Unit, Dept. of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India

a r t i c l e

i n f o

Article history: Received 18 November 2016 Received in revised form 15 December 2016 Accepted 17 December 2016 Available online 28 December 2016 Keywords: Complement Autoimmunity Classical pathway Alternative pathway Systemic lupus erythematosus Henoch Schonlein purpura Antiphospholipid syndrome ANCA-associated vasculitides

a b s t r a c t The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli. However, all the 3 pathways converge on Complement C3. Cleavage of C3 and C5 successively leads to the production of the membrane attack complex which is final common effector. Excessive and uncontrolled activation of the complement has been implicated in the host of autoimmune diseases. But the complement has also been bemusedly described as the proverbial “double edged sword”. On one hand, complement is the final effector of tissue injury in autoimmune diseases and on the other, deficiencies of some components of the complement can result in autoimmune diseases. Currently available tools such as enzyme based immunoassays for functional assessment of complement pathways, flow cytometry, next generation sequencing and proteomics-based approaches provide an exciting opportunity to study this ancient yet mysterious element of innate immunity. © 2017 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism of complement system activation and its functions . . . . . . . Inherent deficiencies of complement components . . . . . . . . . . . . . 3.1. C1q deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. C1s and C1r deficiencies . . . . . . . . . . . . . . . . . . . . . 3.3. C4 deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. C2 deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. C3 deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Mannose-binding lectin deficiency/polymorphisms in MBL2 gene. . . 3.7. Deficiencies of alternate complement pathway regulators . . . . . . Acquired deficiencies of complement components . . . . . . . . . . . . . 4.1. Anti-C1 antibodies . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Anti-C1 inhibitor antibodies . . . . . . . . . . . . . . . . . . . . 4.3. C3 and C4 nephritic factors . . . . . . . . . . . . . . . . . . . . Autoimmune diseases and complements . . . . . . . . . . . . . . . . . 5.1. Systemic lupus erythematosus . . . . . . . . . . . . . . . . . . 5.2. Antiphospholipid antibody syndrome . . . . . . . . . . . . . . . 5.3. Henoch Schonlein purpura nephritis/IgA nephropathy . . . . . . . . 5.4. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides . 5.5. Inflammatory myopathies. . . . . . . . . . . . . . . . . . . . . 5.6. Rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . Laboratory assessment . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh 160012, India. E-mail address: [email protected] (A. Rawat).

http://dx.doi.org/10.1016/j.cca.2016.12.017 0009-8981/© 2017 Elsevier B.V. All rights reserved.

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7. Therapeutic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The complement system is a part of the innate immunological armamentarium that comprises of effector molecules and receptors that help in both fighting against the invasion of pathogens and regulation of the immune system. Paul Ehrlich, in the year 1899, introduced the term ‘complements’ for heat labile substances in sera that were responsible for antimicrobial immunity in addition to antibodies [1,2]. Ever since its first description, a number of complement components were subsequently discovered and were numbered according to the order of discovery. Extensive research has been done till date to understand various aspects and functions of the complement system and its role in the pathogenesis of autoimmune diseases. One of the most important reasons for tissue insults and end organ damage in autoimmune diseases is the excessive activation of the complement pathway [3,4]. Paradoxically, deficiencies of certain components of complement pathways also result in manifestations of autoimmune diseases such as systemic lupus erythematosus (SLE) [3,4]. This topical review focuses on the role of complement system in the pathogenesis of various systemic autoimmune disorders and its therapeutic implications. (See Fig. 1.) (See Table 1.) 2. Mechanism of complement system activation and its functions Activation of complement pathway can occur by three different mechanisms. All the three mechanisms converge at the activation of C3 and C5, and finally result in the formation of the membrane attack

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complex (MAC). MAC disrupts the cell membrane, by forming pores on the cell membrane, and causing osmotic cell lysis [2]. The first mechanism is the activation of classical pathway by immune complex deposits (IgG or IgM). The complement binding site in the Fc portion of the antibody gets exposed during formation of antigen-antibody complexes. C1q, a component of C1 complex will attach to the antibody site and this initiates a conformational change in the C1 complex. This, in turn, leads to the activation of C1r and then C1s which are the serine protease units. Activated C1s subsequently activates C4 and then C2 to form C3 convertase (C4b2a). C3 convertase furthers forms activated C3 (C3a) and leads to the formation of C5 convertase (C3bBbC3b) that finally leads to the formation of membrane attack complex (MAC) [5]. The second mechanism is an antibody-independent pathway termed as ‘alternative pathway’ that involves proteins such as factor B, factor D, factor H, and properdin. A ‘tick over’ process that involves spontaneous hydrolysis of C3 in the circulation to form C3(H2O) initiates the process. Factor B binds to C3(H2O), which on further activation by factor D forms a labile C3 convertase (C3(H2O)Bb) which in turn initiates cleavage of C3. The short-lived C3 convertase (C3(H2O)Bb) is stabilized by properdin to form a C5 convertase (C3bBbP), which activates C5 to form C5a and helps in the formation of MAC [6]. The third mechanism, also called ‘lectin pathway’, is activated by recognition of specific carbohydrate moieties in the microbes by the mannose-binding lectin (MBL) or ficolin. With the help of MBL-associated serine proteases, activation of C2 and C4 would occur, which further initiates the cascade for MAC formation [5].

Fig. 1. Flowchart of the complement activation by classical, alternative and lectin pathways. In the classical pathway upon antigen-antibody binding, C1 gets activated and cleaves C4 and C2 complement components. The active components bind on the cell surface forming classical pathway C3 convertase (C4b2a). Lectin pathway has Mannose binding lectin (MBL) and ficolin instead of C1q. MBL associated serine proteases (MASP) cleave C4 and C2 to form C4b2a (C3 convertase). C3 convertase cleaves C3 into C3a and C3b, and forms C5 convertase (C4b2a3b). C5 convertase cleaves C5 into C5a and C5b which combines with the other terminal components to form membrane attack complex. Alternative pathway depends on the spontaneous hydrolysis of C3 to C3b. C3b binds to factor B to form C3bBb that act as C3 convertase. C3bBbC3b forms C5 convertase which is stabilized by properdin. C5b finally then forms a complex with 1 molecule of C6, C7, C8 forming C5b.6.7.8 complex (membrane attack complex). *Ag-Ab: Antigen antibody complex; CRP-C reactive protein; Man: Mannose; GlcNAC: N-acetylglucosamine.

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Table 1 Classical component pathway deficiencies and autoimmune manifestations. Deficiency Genes C1q

C1r/C1s

C4

C2

Mode of inheritance

Clinical characteristics

C1qA, C1qB, C1qC Autosomal recessive Lupus-like manifestations: 90% Renal involvement: 42% CNS involvement: 18% Pyogenic infections: 40% ANA-IF: positive in 75% (typically speckled pattern on IIF with anti-Ro/La specificity) [32]. C1s, C1r Autosomal recessive Cutaneous lupus: 60% Glomerulonephritis: 50% Positivity for Ro, La, Sm, RNP: 70% [34–41] C4 (C4A, C4B) Autosomal recessive Partial C4 deficiency N Complete C4 deficiency Partial C4 deficiency: 1–3% of Causcasians Lupus-like manifestation: 75% in complete C4 deficiency with renal involvement in 50% & high titres of anti-Ro [45–48]. Low C4A gene copy numbers associated with various autoimmune diseases including lupus. C2 Autosomal recessive Lupus-like manifestations: 10% Milder disease compared to other complement deficiencies [59].

ANA - antinuclear antibodies; Sm - Smith antigen; RNP - ribonucleoprotein antigen. CNS: central nervous system.

The products of complement activation - C3a and C5a act as potent chemoattractants and anaphylatoxins. Deposition of C3 fragments (C3b and iC3b) in tissues helps in opsonization and phagocytosis (through complement receptors - CR1 and CR3 on phagocytic cells), enhanced cytokine production, and clearance of immune complex deposits and apoptotic debris [7]. Complement component C3d in interaction with complement receptor 2 (CR2) and B cell receptor in B cells helps in the activation and proliferation of B cells and production of specific antibodies. Clearance of immune complex deposits occurs by erythrocyte-CR1 interaction with the complement fragments C3b and C4b that are covalently bound to the immune complexes. The immune complexes are then removed in liver and spleen. C1q, C3b, and C4b also assists in clearance of clearance of dead cells (apoptotic debris) by macrophages [8,9]. In order to prevent excess complement activation and tissue injury, regulatory mechanisms operate in our body to balance the complement activation. Activated complement components can also spontaneously decay unless they are stabilized by other components or factors. C1 inhibitor forms a complex with C1 or MBL/ficolin complex and prevents its activation. CR1, C4 binding protein, and membrane co-factor protein (MCP) assists in factor I mediated destruction of C4b. Factor H, CR1, and MCP also assists factor I-mediated degradation of C3b [4]. CD 55 and CD59 that are membrane bound also prevents the attachment of MAC and prevents its action from causing cellular damage. 3. Inherent deficiencies of complement components Deficiencies of early complement components are known to predispose to various autoimmune conditions, especially early-onset SLE or a lupus-like disease [10]. One of the mechanisms hypothesized for the development of autoimmunity in complement-deficient patients is a defective disposal of apoptotic debris and immune complex deposits. The mechanism is also called ‘waste-disposal’ hypothesis [11]. Inefficient clearance of apoptotic leftovers act as a source of autoantigens and probably triggers an autoimmune phenomenon [8,12]. The uptake of auto-antigens by dendritic cells and further activation of T cells result in the production of autoreactive B cells and autoantibodies. Moreover, a reduced clearance of immune-complex deposits also results in persistent inflammation and damage [12,13]. Though various complement pathways assist in clearance mechanism, classical pathway mediated through C1, C4, and C2 appears to be essential for this process. Another hypothesis to explain the autoimmunity is a defective selftolerance that might occur in the setting of complement deficiency [14]. Mouse model studies have demonstrated that during maturation of immune system, complements have a role in the elimination of self-reactive lymphocytes [15]. In the follicular dendritic cells of the peripheral lymphoid tissues such as spleen and lymph nodes, the complement

receptors CR1 (CD 35) and CR2 (CD 21) assists to anergize the autoreactive B cell clones by binding and presenting the self-antigens to these B cells [16]. Thus complement system also functions as a cross-talk between innate and adaptive immune system responses. In general, the clinical manifestation of lupus-like disease in complement deficiencies differs from that of classical SLE. Younger age of onset, the predominance of mucocutaneous manifestations in form of oral ulcers, photosensitivity and annular rashes, a relatively low frequency of kidneys, lungs, and pericardial involvement, positive anti-nuclear antibodies with high titres of anti-SSA (anti-Ro) and a low or absent antidsDNA titres usually characterize the lupus manifestation in complement deficiencies [10,17]. Clinical manifestations in C1 and complete C4 deficiencies are more severe whereas the disease severity is much less in C2 deficiencies. It is also interesting to note that around 93%, 65%, 75%, and 10% of persons with C1q deficiency, C1s-C1r deficiency, C4 deficiency, and C2 deficiency respectively develop autoimmune manifestations [17]. Recent studies from Brazil and India report around 8% and 20% of juvenile SLE patients are complement-deficient [18,19]. 3.1. C1q deficiency C1q protein is coded by three different genes (C1qA, C1qB, C1qC) in the short arm of chromosome 1. Bone-marrow derived monocytes are the major source for production of C1q. C1q concentration in plasma is around 80 mg/L. The protein has a tulip-like structure composed of three hexameric structures with a total of 18 polypeptide chains. Each hexameric structure comprises of two heterodimers of one A chain and one B chain (A–B), and a homodimer of C chain (C–C). Binding of the collagenous region of C1q to calreticulin in the apoptotic blebs and CD91 of phagocytes helps in clearance of residual debris without activation of complements. C1q by binding to C-reactive protein (CRP) attached to the phosphatidylserine or to serum amyloid protein attached to distorted fragmented chromatin from the apoptosis, generates C3b, C4b, iC3b, C3d by complement activation, which in turn act as ligands for complement receptors (CR3 and CR4) on phagocytes to generate phagocytosis [20,21]. Recent studies have demonstrated that C1q has an important role in the regulation of dendritic cell maturation and function [22]. Membrane C1q and C1q receptor (C1qR) on monocytes function as sensors and are reported to assist in switching process from monocytes to dendritic cells or macrophages. Various ligands, pathogen-associated molecular patterns (PAMP), and damage-associated molecular patterns (DAMP) are also recognized by C1q. Tolerance induction by dendritic cells in the presence of cytokine milieu, membrane C1q, and C1qR is also hypothesized. C1q has also been reported to regulate T cell function and proliferation. C1q is also reported to regulate immune-complex mediated type-1 interferon production by the plasmacytic dendritic cells and

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probably a deficient state of C1q would lead to excess type-1 interferon production that could explain the disease severity in C1q deficient patients [22–24]. Homozygous deficiency of C1q has been reported in around 75 cases till date [4,19,21,25–32]. Various mutations have been described that result in the lack of synthesis of one of the three chains of C1q (C1qA, C1qB, C1qC). Mutations are commonly found in C1qA gene. In a report of 64 patients with C1q deficiency by Schejbel et al., lupus-like manifestations are noted in around 88% of patients and recurrent infections due to encapsulated organisms occurred in around 41% of patients [32]. Photosensitivity was the predominant manifestation noted in 84% of individuals, followed by oral ulcers and arthralgia in 22% and 16%, respectively. Around 30% and 19% of patients developed glomerulonephritis and neurological diseases respectively [32]. Intractable oral ulcers and rashes such as discoid lupus can be sometimes troublesome. Most of the patients have a normal C3 and C4 levels, elevated ANA titers (predominantly anti-Ro), and a relatively lower frequency of anti-ds DNA antibodies [4,10,32].

that total GCN of C4A is not an independent risk factor for the development of SLE [53]. C4A/C4B deficiencies are also linked with the development of juvenile idiopathic arthritis in a report from Romania [54]. Anecdotal reports suggest that C4 deficiency is also possibly related to the development and pathogenesis of vasculitic illness such as Henoch-Schonlein purpura, and Wegener's granulomatosis, and immune complex glomerulonephritis [55,56]. 3.4. C2 deficiency

C1s and C1r are the complement proteins that exist as pro-enzymes in the circulation. They are arranged in form of a tetramer C1s-C1r-C1rC1s, which on combination with C1q and ionized calcium forms a multimeric C1 complex. After attachment of globular heads of C1q to the Fc portion of IgG, C1q gets activated and it further leads to activation of C1r and C1s which further propagates the pathway to activate C4 and C2. The proteins C1s and C1r are coded by the genes located in the short arm of chromosome 12 [33]. A total of 12 cases of C1r deficiency and eight cases of C1s deficiency have been reported [34–41]. Most of the patients had elevated levels of complement components - C2, C4, C3, and C1 inhibitor. Recurrent infections were noted predominantly (85%), and 13 patients (65%) had clinical manifestations of lupus. Predominant lupus-like manifestations are severe skin lesions and nephritis (40%). Many subjects had succumbed at an earlier age because of severe infections [4]. Autoimmune thyroiditis, autoimmune hepatitis, and hemophagocytic syndrome are the other manifestations reported with C1s/C1r deficiencies [38,41].

Complement C2 is a common link between lectin and classical pathway which on attaching to activated C1 forms a serine protease - C2a that helps in the formation of C3 convertase [8]. Prevalence of C2 deficiency is estimated to be 1 in 20,000 individuals among the Caucasian population and C2 deficiency is considered to be the most common deficiency of the complement pathway [25]. C2 is coded in the HLA class III locus of the short arm of chromosome 6. Type 1 C2 deficiency is the most common form (90%) and it occurs due to nonsense mutations leading to 28-base pair deletion in C2 gene that results in absent protein synthesis [57]. Type 2 deficiency is due to defective secretion of C2 that are normally synthesized [58]. Manifestations of C2 deficiency are relatively milder compared to C1q, C1s, C1r, or a complete C4 deficiency. Only 10–20% of individuals with C2 deficiency develop lupus [59]. A C2 bypass mechanism that involves activation of terminal complement components by C1q and MBL bypassing the C2 pathway could explain a relatively milder disease manifestations in C2 deficiency [60]. Age of development of manifestations is around 30–50 years, and it usually manifests in females. Mucocutaneous and musculoskeletal manifestations of SLE are more prominent. Major organ involvement such as kidneys and central nervous system are rare [59]. Individuals with C2 deficiency are also prone to develop infections due to encapsulated bacteria. C2 deficiency is also known to be associated with deficiencies of IgG subclasses - IgG2 and IgG4 [61]. Jonsson et al. reported 57% of the 40 C2 deficient patients had an invasive Streptococcus pneumoniae infections [59]. When compared with classical SLE patients, patients with C2 deficiency are more prone to develop cutaneous and cardiovascular damage on long-term follow-up [59].

3.3. C4 deficiency

3.5. C3 deficiency

Complement component C4 synthesized in the liver is encoded by C2 gene located in the HLA class III locus on the short arm of chromosome 6 [42]. Inter-individual copy number variations (CNV) of C4 gene are extensive and it varies from two copies to eight copies [43]. C4 exists in two isotype forms- C4A and C4B. C4A stands for an acidic protein that preferentially binds to amino-containing groups such as immune complexes. C4B is a basic protein that selectively binds to hydroxyl or a carbohydrate group [44]. A complete deficiency of C4 is very rare and it manifests as early onset of lupus-like illness with the equal prevalence observed among males and females. Severe photosensitivity, renal involvement, and high titers of ANA and anti-SSA are common [45–48]. However, a more common form of C4 deficiencies are the isotype deficiencies of either C4A or C4B. A study done among 233 European American SLE patients demonstrated that gene copy numbers (GCN) of C4B did not show a significant variation among cases and controls [49]. However, a significant reduction in GCN of total C4 and C4A were observed among SLE patients compared to control (9.3% of patients with SLE had only 2 GCN of C4 compared to 1.5% in control). 6.5% of patients with SLE had no copies of C4A (homozygous deficiency) while 26.4% patients had one copy of C4A (heterozygous deficiency). This is in contrast to 1.3% and 18.2% in the healthy controls who had homozygous and heterozygous deficiencies of C4A [49]. Studies were done in East-Asian countries which revealed a lower GCN of total C4 and C4A, a risk factor for the development of SLE [50–52]. However, a study done by Boteva et al., in 501 SLE patients among British population showed

C3 deficiency is usually linked with the development of recurrent bacterial infections and glomerulonephritis. The incidence of SLE is very rare in C3 deficiency [8].

3.2. C1s and C1r deficiencies

3.6. Mannose-binding lectin deficiency/polymorphisms in MBL2 gene Mannose-binding lectin (MBL) is a component of lectin pathway that recognizes carbohydrate moieties in the pathogen and associates with MASP1 and MASP2 which further activates C4 and C2. It also has a role in the clearance of apoptotic debris as described in C1q [62]. A deficiency status of MBL, though believed as an important risk factor for infections, is also considered a predisposing risk factor for the development of autoimmune conditions such as SLE [62]. Polymorphisms of MBL2 gene is considered as a risk factor for SLE [63,64]. Allele B and promoter region polymorphisms (especially at positions −221 and −550) are considered risk factors in SLE in a meta-analysis done including populations from Europe, Africa, and Asia [63]. MBL2 gene variants are also reported to be associated with the development of clinical nephritis in a Danish cohort of SLE [65]. Recently, a study from Brazil involving 286 adult patients with lupus, have shown a higher frequency of MBL deficiency in lupus nephritis patients [66]. Polymorphisms in MBL have also been studied in relation to rheumatoid arthritis and a metaanalysis have suggested that polymorphisms at codon 54 of MBL2 gene in East Asian population may be more vulnerable to development of a seropositive rheumatoid arthritis [67]. Deficiency of MASP-2 is also

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Antibodies directed against the complement components are detected in patients with SLE. These auto-antibodies are generally directed at the neoepitopes of the complement components that are exposed in the activated state. The presence of these auto-antibodies might potentially result in a complement-deficient state that would further enhance the propagation of autoimmune process.

evidence that complements cause tissue damage in SLE. Immunofluorescence studies have shown deposits of immunoglobulins and complements in the glomeruli and the blood vessel walls of skin. Immune complex deposits in the kidneys mediate excess complement activation and deposition of complement components [78,79]. Patients with SLE have also shown to have reduced levels of erythrocyte complement receptor - CR1 that serves to clear the circulating immune complexes [80]. Diminished expression of Fc gamma receptors FcγRII and FcγRIII in monocytes that contribute to the clearance of apoptotic debris have also been demonstrated in patients with SLE [81]. Acquired deficiency of CD55 and CD59 have been demonstrated in erythrocytes and lymphocytes of patients with SLE, that might contribute to the development of hemolytic anemia and lymphopenia [82]. Elevated MBL levels have been reported in patients with active SLE and this could contribute to excess complement activation and tissue damage [83]. Presence of anti-MBL antibodies in patients with SLE can cause a functional deficiency of MBL and could predispose to development of infections in lupus patients [84]. However, exact significance of these antibodies is still not yet known completely. A high concentration of ficolin-3 concentrations have been found in patients with SLE when compared to controls. A negative correlation of ficolin-1 concentrations with SLE disease activity (SLEDAI) index and a positive correlation with SLE damage index (SDI) and presence of arterial thrombosis have also been demonstrated in patients with SLE [85].

4.1. Anti-C1 antibodies

5.2. Antiphospholipid antibody syndrome

Antibodies to C1q are detected in around 30% of patients with SLE. The presence of anti-C1q antibodies is strongly correlated with the presence of low complements C3, C4, anti-dsDNA antibodies, and nephritis [72]. Anti-C1q antibodies are also reported to contribute to a nephritis flare and it is noted in around 68% of patients with lupus nephritis [72, 73]. Anti-C1s antibodies have also been demonstrated in some patients with SLE and they are believed to be augment C4 activity [74].

Antiphospholipid antibody syndrome (APS) is a clinical entity that encompasses thrombosis, recurrent miscarriages, and pregnancy-related complications, mediated by anti-phospholipid antibodies (APLA). One of the important mechanisms in the initiation and formation of thrombus in APS is by complement activation [86,87]. Excessive complement consumption is suggested by reduced serum levels of complements in primary APS. Levels of C3a and C4a are also higher in patients with primary APS when compared to normal controls [87]. Activated complement fragments induce endothelial cell activation and a prothrombotic phenotype through MAC or C5a-receptor (CD 88) [88]. Mice studies have suggested that fetal regulation of complement system is essential for embryo and fetal survival [89]. A membranebound protein, CR-1 related protein y (Crry) in fetus that blocks the activation of C3 and C4 is found to be very essential for continuation of normal pregnancy in mice. A deficiency of Crry resulted in embryonic death [90,91]. Blocking complement pathway at the level of C3 activation and monoclonal antibody against C5 prevented fetal loss and thrombophilia in mice studies, respectively [92,93]. Mice deficient in C3 and C5 were also found to be resistant to endothelial cell activation and thrombosis [89]. It is also postulated that heparin by inhibiting the complement activation, may play a role in reducing miscarriages in APS [94].

suggested to have an important role in the development of rheumatoid arthritis [68]. 3.7. Deficiencies of alternate complement pathway regulators Factor H, MCP, and factor I deficiency states result in excess uncontrolled activation of alternate complement pathway and result in clinical manifestations of the atypical hemolytic syndrome [69]. Mutations in CFHR (complement factor H-related) genes and deficiency of CFH are known to be associated with C3 glomerulopathy and the pathogenesis is excess alternate pathway activation and deposition of C3 in the glomeruli [70]. Deficiency of CD55 and CD59 on erythrocyte membranes is known to predispose to paroxysmal nocturnal hemoglobinuria. Deficiencies of terminal complement pathways (C5–C8) predisposes mainly to infections by Neisseria [71]. 4. Acquired deficiencies of complement components

4.2. Anti-C1 inhibitor antibodies Acquired antibodies to C1 inhibitor result in a condition called ‘acquired angioedema’, that clinically manifests similar to hereditary angioedema [75]. Some lupus patients exhibiting features of angioedema were reported to have anti-C1 inhibitor antibodies. These auto-antibodies reduces the binding of C1 inhibitor to the C1 complex that would lead to excess activation of classical pathway culminating in excess production of bradykinin [76]. 4.3. C3 and C4 nephritic factors Immunoglobulin G antibodies that bind to alternative pathway C3 convertase is called C3 nephritic factor, while IgG auto-antibodies to classical pathway C3 convertase is called C4 nephritic factor. By prolonging the half-life of C3 convertase, these antibodies result in excess activation of complement pathway. Clinical manifestations associated with C3 and C4 nephritic factors are membranoproliferative glomerulonephritis, partial lipodystrophy, and post-infectious glomerulonephritis [77]. 5. Autoimmune diseases and complements Complement-mediated tissue damage is described in multitude of autoimmune conditions. Most common of it are SLE, various vasculitic conditions, dermatomyositis, and rheumatoid arthritis. 5.1. Systemic lupus erythematosus Excess complement activation in SLE is mediated by high concentrations of immune complex deposits. There are enough histologic

5.3. Henoch Schonlein purpura nephritis/IgA nephropathy Thought the renal histology of Henoch Schonlein purpura (HSP) nephritis and IgA nephropathy is same, presentation is usually acute in HSP nephritis whereas the manifestations are more indolent and progressive renal dysfunction in IgA nephropathy. Recovery is also usually complete in cases of HSP nephritis [95]. Histopathological and immunofluorescence studies of renal tissue in HSP nephritis and IgA nephropathy predominantly demonstrate the deposition of L-ficolin, MBL, MASP, and C4d. Absence of demonstration of C1q in IgA nephropathy speculate the view that lectin pathway is predominantly involved in the pathogenesis [96]. Glomerular MBL deposition in IgA nephropathy is also considered to be a predictor of poor disease prognosis in form of severe renal histopathological changes, and lower remission rates [97]. Regulation of alternate complement pathway have also shown to reduce the severity of clinical manifestations in HSP nephritis [96].

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5.4. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides are necrotizing small vessel vasculitic conditions that usually involves major organs such as lungs and kidneys. It encompasses granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg Strauss syndrome), microscopic polyangiitis, and renallimited vasculitis. The antibodies are directed against a cytoplasmic component proteinase-3 (PR3) (otherwise called cANCA) and a perinuclear component myeloperoxidase (MPO) (otherwise called pANCA) [98]. Murine models and human studies have shown that excessive neutrophil infiltration and alternate complement pathway activation are the main immune response seen in the tissues. Classical complement components have not been detected in the tissues, whereas alternate complement components such as C3d, MAC, and factor B were detected in the affected renal glomeruli [99–101]. 5.5. Inflammatory myopathies Dermatomyositis (DM), polymyositis, and inclusion body myositis are the three usual forms of inflammatory myopathies. Complement mediated damage is predominantly studied in dermatomyositis [102]. Endomysial capillaries are the main antigenic target in DM. Autoantibodies along with complements mediate the immunological damage that are manifested by deposition of C3b, C4b, and MAC in the capillaries early in the course of disease [103]. As the inflammation progresses, damage ensues resulting in necrosis of capillaries and muscle ischemia that are seen as perifascicular atrophy in the histopathology [104]. Skin lesions in DM also show deposits of MAC, while non-affected skin does not show it [105]. DM was reported to occur in a case of C2 deficiency [106]. Presence of C4A deficiency and HLA-DR3 together confer a significantly higher risk for development of juvenile dermatomysositis (JDMS) [107]. A patient with C9 deficiency has been reported to develop dermatomyositis and this suggest that MAC mediated damage may not be responsible for the disease pathogenesis in dermatomyositis [108].

CH50 (Complement hemolysis 50%). Cell bound levels of processed complement activation products (CBCAPS) such as erythrocyte bound C4d is recently reported as an important biomarker of complement activation [116]. CBCAPS on B cells and erythrocytes are also found to have increased sensitivity to assess disease activity in SLE when compared to other serological markers such as C3, C4, and anti-ds DNA [117].

7. Therapeutic strategies As it is evident that complements play a major role in the tissue damage in autoimmune diseases, targeting complement components could serve as a potential therapeutic regimen in autoimmune disorders. Suppressing excess complement activation could theoretically decrease the inflammatory damage. Monoclonal antibody directed against C5 (eculizumab) serve as an effective therapeutic option in the management of atypical hemolytic uremic syndrome caused by uncontrolled activation of alternate complement pathway [118]. A soluble CR1 that potentially inhibited excessive activation of C3 convertase in a patient with dense deposit disease has also been documented [119]. In autoimmune conditions like lupus, anti-complement therapy may also be detrimental as it not only is linked to the development of infections but also to the development of autoimmunity and immune dysregulation. A second option would be supplementing the missing complements in hereditary complement deficiencies. Whole plasma preparations have been used in a patient with C2 deficiency [120]. Fresh frozen plasma infusions efficiently supplements the complement components [121]. However, the activity lasts not more than 2 weeks and needs repeated transfusions that have its inherent complications of infections and thrombosis. Recombinant C2 concentrate has been developed and tested in vitro [122]. However, a purified or a recombinant complement concentrate is not available till date for use in vivo use. C1q is secreted predominantly from bone marrow derived monocytes and a hematopoietic stem cell transplant (HSCT) is an effective therapeutic option theoretically that could help combat the deficiency status. HSCT has been successful in the two patients with C1q deficiency [123,124]. However, larger cohort studies in HSCT and longer follow-up would reveal the pros and cons of this modality of treatment.

5.6. Rheumatoid arthritis Serum concentrations of C3 and C4 are found to be either normal or high in cases of rheumatoid arthritis (RA) [109]. However, synovial concentrations of complements were reported to be low, thereby implying the role of complements in inducing synovial inflammation in RA. Similarly, the levels of complement cleavage products such as C3a, C5a, C5b9 are elevated in the synovial fluid [110,111]. Interestingly patients with C1q or C2 deficiency, and recently C4B deficiency was reported to be associated with the development of RA [112–114]. However, further studies are needed to confirm whether it is a mere association or a casual entity. 6. Laboratory assessment Most commonly tested complement components in serum are C3 and C4. In order to prevent in vitro activation of complements, plasma should be separated immediately the collected samples and stored at − 80 °C. Nephelometry, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and western blots are the various techniques used for the measurement of complement components such as C1q, C1r, C1s, C2, C3, C4, and various complement split products [3]. ELISA tests have also been developed to test for various complement regulating factors such as factor B, factor H, factor I, factor D, and various split products of the complement pathways [115]. ELISA-based kits are also available for the functional assessment of the classical, alternate and lectin pathways of the complement. The whole pathway from activation of classical component pathway to formation of MAC could be assessed by

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