Review Complement and Lupus: Old Concepts and New Directions Department

of

JOSE MANUEL PORCEL and DIEGO VERGANI Immunology, King’s College Hospital and School of Medicine, Bessemer Road,

London SE5 9PJ, UK

In this review it is our intention to outline briefly the relevance of the complement system in systemic lupus erythematosus. Three main issues will be addressed: the role of complement in handling immune complexes (ICs), the association between complement deficiencies and IC diseases, and the value of measuring complement components and their conversion products in monitoring disease activity.

Key Words: Systemic lupus erythematosus Rheumatic diseases Complement

Complement activation Introduction The complement system involves nearly 40 plasma and cell membrane proteins that play an essential role in defence against infections, immunopathologicaily mediated inflammation and amplification of immune responsiveness. A detailed description of the sequential activation of the proteins may be found ~1~~~~er~ ~ (Figure 1) and is outside the scope of this review. The complement system, triggered by immune complexes (ICs), has a central role in the incitement of inflammation and tissue damage in systemic lupus erythematosus (SLE). Complement participates in this process through the generation of chemotactic peptides (anaphylatoxins), which attract and stimulate neutrophils to release chemical mediators of inflammation at sites of IC deposition. Paradoxically, harmful ICs are rendered innocuous by solubilization, limitation in size and phagocytic clearance from the circulation as a result of binding complement proteins. In fact, impaired handling of I~~ accounts for the unexpectedly high incidence of IC diseases, particularly SLE, in individuals with inherited complement deficiencies. Reduced serum complement levels are hallmarks of active SLE. Thus far, determination of individual complement components (C3 and C4) and haemolytic functional assays (CHso) have been the four assessment of complement activation during the active phases of the disease. In both activation is shown indirectly by detection of a reduction, due to consumption, in the activity or concentration of components of the cascade. These measurements, however, may not reflect accurately the degree of activation Correspondence: Diego Vergani, M.D., Ph.D.,

M.R.C. Path.

and consequently could lead to misleading interpretation of the patient’s true clinical status. New assays, which evaluate fragments or complexes that arise during the activation process, have been recently introduced and represent powerful tools for monitoring activity in SLE

patients 3.

Complement in the pathogenesis of SLE SLE is regarded as the prototype IC disorder. It is widely accepted that the pathogenesis of SLE is intimately related to ICs and complement4. Evidence for participation of complement in this disease has been obtained from immunohistochemical examination of target organs. Demonstration of tissue deposits of complement components and fragments along the glomerular basement membrane and mesangium in lupus nephritis, as well as in the dermal-epidermal junction of skin lesions, has provided persuasive evidence for the requirement of complement for the full expression of tissue damage. However, the role of complement in the pathogenesis of SLE is not limited to local inflammation and tissue injury at 1C deposition sites. Another immunopathological mechanism has been recently recognized, namely the intravascular activation of complement, which leads to the release of active complement split products, such as C3a and C5a, into the circulation~. These split products activate inflammatory cells such as neutrophils, causing them to aggregate adhere to vascular endothelium. This may provoke endothelial damage and ischaemic injury of small vessels at regions remote from sites of IC deposition. In fact, marked elevations of the anaphylatoxins C3a and C5a have been associated with syndromes of reversible pulmonary dysfunction’ and acute neurologic disease in SLE.

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(Figure 1 Complement activation pathways. The complement system can be activated by either the classical or alternative pathway. The classical pathway is typically triggered by IC and proceeds through ~l, C4 and C2. The alternative pathway can be initiated by contact with lipopolysaccharides (LPS) found in the cell walls of microorganisms, and involves factors B, D and P. The two pathways generate enzymes called C3 convertases (C4b2a or classical pathway C3 convertase, and C3bBb or alternative pathway C3 convertase), which cleave C3 to produce C3a and C3b. C3b is both a constituent of the C3 convertase and a product of the action of this enzyme, giving rise to a positive feedback amplification lc~op. Covalent binding of C3b to the C3 convertases changes them to C5 convertases, which initiate the common terminal pathway leading to formation of the membrane attack complex (MAC). This multimolecular complex causes osmotic lysis of cells.

It has long been known that complement exerts a beneficial effect in preventing the formation of large precipitating ICs. The covalent binding of C3b (the activated form of C3) to ICs maintains their solubility and inhibits their precipitation by interfering with lattice formation. In addition, C3b-coated ICs attach to cells bearing C3b receptors (CRI) in the circulation, a phenomenon termed immune adherence 8. Complement receptor type I (CRI) is a polymorphic glycoprotein present on a wide variety of cell types. Despite possessing fewer CRI per cell than other CRI-bearing cell populations, by virtue of their higher numbers in the circulation, erythrocytes express over 83% of circulating CRI9. Once bound, ICs are transported on the red cells to the liver and spleen, where they are released and taken up by hepatic macrophages, thereby reducing the amount of ICs available for tissue deposition. In the transfer step from erythrocyte to proteinase-rich hepatic I~upffer’s cell, some Crits may be stripped by proteolysis ~°, and therefore the red cells returning to the circulation have a reduced number of Crits. The binding of ICs and complement to erythrocyte ~~l accounts for the high frequency of direct positive Coombs’ tests in

SLE patients, in the absence of antibodies to red ~ells&dquo;. In normal subjects, the quantitative expression of CR on erythrocytes is stable and genetically determined by inheritance of two codominant alleles on chromosome l, encoding for either high (H) or low (L) numbers of the receptor. Homozygotes for one allele (HH) express high numbers, those for the other allele (LL) express low numbers, and heterozygotes (HL) express intermediate numbers 12. Surface density of erythrocyte CRI is reduced in patients with SLE by an average of 30% compared to that seen in the normal population 13 , a condition that results in impaired clearance of ICs. Whether the mechanism for this reduction is inherited or acquired has been the subject of controversy 14. While early reports suggested that this alteration was the result of inheritance of genes coding for low expression of the receptor, further studies provided strong evidence that CRI deficiency in SLE was an acquired characteristic. Thus, levels of CRI fluctuate with disease activity, lowering during flares, and CRI loss has been demon-

strated

on erythrocytes transfused into patients with SLE. In addition, pooled findings of several studies show an under-representation of the LL homozygous

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genotype among patients with SLE as compared with normal subjects IS. A recent report suggests that the evaluation of

erythrocyte CR in patients with discoid lupus erythematosus (DLE) may be a useful parameter in detection of potential systemic involvement &dquo;. DLE patients who have mild systemic signs and symptoms, although not conforming to the criteria for the diagnosis of SLE, share the abnormal CR expression on erythrocytes seen in SLE patients. In contrast, those patients with completely asymptomatic DLE have the same surface density of erythrocyte CR 1 as the normal population. Theoretically, measures that increase the numbers of erythrocyte CRI could provide a potential therapeutic approach in patients with IC diseases. In this regard, stimulation of ~r~thropoi~sis - young erythrocytes more CRIs than old red cells9-or transfusion of packed erythrocytes with high CRI 1 a~tivity&dquo; has been suggeste&dquo; a possible method for improving the clearance of circulating ICs.

express

Complement deficiencies and SLE Deficiency of the early-acting components CRI, C4 and C2 is associated with an increased risk of IC diseases, particularly SLE and SLE-like syndromes. The mechanism underlying this association may be related to the important activity of complement in the solubi~zation and catabolism of ICs, and also perhaps with a failure to clear pathogens, especially viruses 18. More than 80Vo of Clq and C4 and over half of C2 homozygous complement-deficient individuals have been found to have SLE&dquo;. Individuals with complete complement deficiencies, however, account for only 1% of SLE patients 20. Measurement of total haemolytic complement activity (CHso) should be undertaken at least once in all patients with SLE to exclude the possibility of a complement deficiency syndrome&dquo;. Although genetic complement deficiencies are still regarded as rare, this notion should be modulated if one considers the frequency of null alleles (or silent genes) for several complement components, such as that for C4. C4 is encoded by two closely linked genes, located

within the major histocompatibility complex (MHC) on the 6th chromosome (Figure 2). These give rise to the isotypic forms of C4: C4A and C4B. In addition, both C4 loci are highly polymorphic, and more than 35 allotypes, including the so-called null alleles (C4AQO, C4BQO) that code for non-synthesis of the protein, have been defined’. Complete C4 deficiency, which requires homozygosity for null alleles at both the C4A and C4B loci (C4AQO, C4AQO; C4BQO, C4BQO), is quite rare, with less than 20 individuals reported, most of whom have presented with severe SLE 19. Although homozygous deficiency of C4A (C4AQO, C4AQO; C4B, C4B) is rare in the general population ~( ~2~1~~, it is found in ll~--15~~ of white lupus patients22; this confers a relative risk to SLE of approximately 17. Heterozygous C4A deficiency (C4AQO, C4A; C4B, C4B) occurs in 20Vo of the white population, but it is found in over half of caucasoid lupus patients (relative risk of 3)23. Of interest, the strong linkage disequilibrium between C4AQO and T-~L~-l~~,l~1~3 makes it difficult to determine which, if either, is the primary genetic marker for SLE. Studies in different racial groups have demonstrated that C4A null alleles per se are critical in the pathogenesis of SLE independent of associated MHC class II genes’. Most studies do not show an increased risk of SLE in C4B deficiency, although some do 25. The mechanisms by which the inheritance of null genes at the C4A rather than C4B locus predisposes to SLE are uncertain, but may be related to differential activity of their products. C4A is more effective than C4B in inhibiting the precipitation of ICs and in enhancing binding to ~l~l on erythrocytes 26. An additional mechanism has recently been suggested, namely the influence of C4A null alleles on the activation of the C4 molecule, a critical event for the clearance of ICs 27. The degree of C4 activation, as indicated by the concentration of C4d, is indeed dependent on C4 null alleles, being reduced in patients with null phenotypes. Lack of C2 is the most common homozygous complement deficiency in caucasoids, with a prevalence of

~.~1-~D.(1~1~5~~ ~~. Heterozygous C2 deficiency has

an

frequency of 0.32-1.2% in the healthy white

Figure 2 MHC gene organization. Grouped together into the class III region of the MHC, between HLA classes I and 11, lie the genes for the complement components C2, C4 and factor B, as well as two genes for the steroidogenic enzyme 21-hydroxylase (21-OHA and 21-OHB) and another recently identified gene called RD. Note that two separate loci code for the isotypic forms of the C4 component, C4A and C4B.

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population, but reaches 3.6% in patients with SLE. Certain features characterize the clinical picture of SLE in C2-deficient individuals’: prominent cutaneous lesions, low incidence of renal involvement, low or absent levels of antinuclear antibodies or anti-doublestranded (ds) DNA antibodies, and high occurrence of anti-Ro/SSA antibodies. Administration of the missing protein to lupus patients with complement deficiencies has the potential risk of enhancing inflammatory tissue damage due to full complement activation. Also, the high turnover of these proteins as well as the formation of antibodies against them might complicate this kind of therapy 30.

Anecdotally, a C2-deficient patient was recently found respond remarkably well to such treatment 31 .

to

Complement in activity

the

monitoring

of

lupus

SLE has a fluctuating course characterized by multiple exacerbations and remissions. Thus, accurate monitoring of disease activity is an extremely important component in the management of the disease. Many of the clinical manifestations of SLE are mediated by IC deposition that leads to complement activation and consequent inflammation and tissue damage. A potential marker of clinical activity should therefore be related to this central pathogenic feature. In this regard, antidsDNA antibodies, circulating ICs and various complement components have been evaluated extensively. It is generally assumed that consumption of complement proteins due to activation of the classical pathway by ICs accounts for the hypocomplementaemia noted in active SLE. A substantial depression of levels of Clq, C4, C3 and Cho frequently parallels periods of disease flare, especially in lupus nephritis, with return to normality occurring as the exacerbation remits 32. Patients with a combination of both active extrarenal and renal disease are more likely to demonstrate the lowest levels of CH50, C4 and C3. Some investigators have been unable, however, to confirm the clinical usefulness of such laboratory parameters. Valentijn et oJ. 33, for example, noted a normal C3 level in 53 ~I~ of patients with active disease as well as low C4 levels in only half of patients with a nephritic relapse. It has become that single-point determinations of complement components in relation to the normal range are less important than the trend of serial measurements -up, down or stable 34 . This allows fluctuations in levels for a particular patient.to be observed, establishing as normal values those found during remission. Swaak ~t ~z~. ~~ observed that all lupus flares with signs of renal involvement were heralded by increasing levels of anti-dsDNA antibodies and falling levels of various complement components (Clq, C3, C4). Once

have not been corroborated in further studies. Thus, Ter Borg et al. 36 found that only half of the exacerbations were preceded by a significant decrease in C3 and/or C4. Serial determinations of serum C3 and C4 have also been claimed as valuable in the management of SLE during pregnancy. Several studies confirm a close association between hypocomplementaemia and poor fetal prognosis in lupus pregnancy 11,31 In addition, while C3 and C4 concentra-tions rise during uncomplicated or pre-eclamptic pregnancy, falling serum C3 or C4 levels associated with the new onset of hypertension and proteinuria during the third trimester of pregnancy suggest a diagnosis of active

again, these results

lupus nephritis 39. Clinical studies comparing the diagnostic sensitivity and specificity of C3 versus C4 have yielded conflicting results regarding their potential usefulness in monitoring disease activity. Whereas some suggest that C4 levels are more useful than C3 levels 32 , other state the opposite 40. In short, at the present time it is not clear whether measurement of C3, C4 or both is best for monitoring SLE disease activity~~. The lack of strong correlation between lupus activity and hypocomplementaemia is not at all surprising. The concentrations of serum complement components that are currently used to assess disease activity in SLE are, in fact, static measurements of the combined effects of complement activation, catabolism and synthesis3. Firstly, complement proteins behave as acute phase reactants, resulting in increased synthesis during the stress of inflammation. Such an increase may exceed the rate of tissue catabolism, thus masking complement consumption. Secondly, there is a wide normal range in the concentration of these components. Patients who in remission have relatively high C3 and/or C4 levels can experience a lupus flare with extensive reduction in these concentrations, which may still fall within the normal range. Thirdly, SLE patients may have decreased complement synthesis, inherited complement deficiencies or increased extravascular distribution of complement. For example, the possession of two null alleles of C4 usually results in reduced C4 concentrations’&dquo;. Finally, additional difficulties complicate the interpretation- of serum C3 and C4 levels. The immunochemical estimation of these proteins involves use of polyclonal antibodies that recognize not only the intact component but its major cleavage fragments. Thus, in the presence of complement activation the assay may overestimate total C3 or C4 concentrations. Occasionally, the presence in SLE patients of either circulating inhibitors of fluidphase amplification ~anverta~e~~ or autoantibodies that stabilize the classical pathway C3-convertase43 may also influence the levels of C3. As for complement functional assays (CHso), they are cumbersome and relatively insensitive, in that a 50%

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decrease in

a component of the cascade is required to compromise the haemolytic activity of serum. The test principally assesses the integrity of the combined classical and terminal complement pathways and con-

tinues to be a useful screening procedure when deficiency states are

suspected.

The limited value of the immunochemical estimation of intact complement proteins and the CHso assay for monitoring clinical activity in SLE has been disappointing, in view of the central rqle of complement in the pathogenesis of this disease. Therefore, the need for the development of new laboratory tests to assess accurately complement activation remains of paramount importance. Metabolic turnover studies provide a direct insight into the dynamics of complement synthesis and catabolism, but they are laborious and make use of radiolabelled reagents and, therefore, cannot be undertaken on a routine basis 44. By contrast, measurement of complement activation products (CAPs) as either fragments or complexes represents an attractive approach that directly documents the activation process 45. Assays have been developed to measure the cleavage products of C2 (C2a), C3 (C3a, iC3b, C3c, C3dg), C4 (C4a, C4b/c, C4d), C5 (C5a, C5b), factor B (Ba, Bb), and the multimolecular complexes ClrClsCl-INH, C3bBbp and SC5b-9 (Figure 3). Radioimmunoassays for the anaphy-

latoxins C3a, C4a and C5a as well as enzyme-linked immunosorbent assay kits for detection of C3a, C4d, Bb, iC3b and SC5b-9 are already available from commercial sources. In the last few years, findings from many studies indicate that the serial measurement of CAPs in plasma will prove extremely valuable in the assessment of lupus activity&dquo;. CAPs from the classical, alternative or common pathways are frequently elevated in active lupus patients whose C3 and C4 values are normal; i.~. abnormally elevated concentrations of these fragments mirror clinical activity more accurately than do abnormal reductions in C3, C4 or ~I°~~~, levels. The alternative pathway in SLE may well be triggered by classical pathway-derived C3b. Of interest to the physician is the clinical outcome of asymptomatic patients with evidence of complement activation. Several reports have shown that raised levels of some CAPs may precede manifest signs of lupus flare 7, and consequently they may be u~~fui for predicting relapses of the disease. That is, the presence of elevated CAPs may allow us to identify those clinically well patients in whom ongoing subclinical damage is occurring and who are at risk of soon developing overt manifestations of SLE. Whether the hypocomplementaemia seen in lupus patients who are pregnant is due to complement

Figure 3 Complement fragments and complexes that provide highly specific evidence of complement activation. Complement activation products that can be measured in human plasma include the anaphylatoxins ~eiiip~i~ai boxes), the split products of C2, C3, C4, C5 and factor B (hexagonal boxes), and the multimolecular complexes (rectangular boxes).

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activation’, decreased synthesis or both is an as yet unresolved question. In addition, while some authors have reported that C3 degradation products are not affected by uncomplicated pregnancy and therefore can be used to monitor disease activity in pregnant SLE patients, others state that C4d concentrations cannot be exploited for this purpose since pregnancy itself leads to C4 activation’. A recent study 50 has found that complement activation, notably of the alternative pathway, is associated with disease flares during lupus pregnancy. Firm conclusions regarding the routine use of CAPs to track lupus activity during pregnancy await further investigations. Biological fluids other than plasma have also been examined for the presence of CAPs. Of interest, detection of some CAPs such as C3d in urine specimens may be a helpful adjunct in the clinical assessment of acute lupus nephritis 51. Moreover, the demonstration of increased levels of SC5b-9 in the cerebrospinal fluid of SLE patients with central nervous system involvement suggests a role for terminal complement activation in the pathophysiology of this condition 52. A major controversy in the management of SLE

2. Abbas

941-7. 7.

8. 9.

10.

11.

12.

involves the use of laboratory tests as a guide to therapy. It has recently been reported that sustained normalization of complement levels by adjustment of immunosuppression in patients with lupus nephritis can successfully stabilize renal function and improve long-term kidney survival&dquo;. This beneficial effect is mainly seen in patients with a low chronicity index on renal biopsy. One issue that remains to be elucidated is whether normalization of plasma CAP levels by treatment will improve outcome in lupus patients. To conclude, considerable evidence exists to support the notion that measurement of CAPs provides a more reliable index of disease activity in SLE and predicts more sensitively an impending flare than conventional determinations of complement components do. Although the relative clinical usefulness of the various CAPs is currently under investigation, it seems reasonable to expect that in future their quantitation will become a routine tool for evaluating and monitoring patients with

13. 14.

15.

16.

&dquo;

lupus.

17.

18. 19. 20.

21.

22. 23.

Acknowledgements

24.

Dr J.M. Porcel is a Research Fellow supported by the C.I.R.I.T (EE91/2-321), Generalitat de Catalunya, Spain. We thank Miss Barbara Panayi for her assistance with the artwork.

25. 26.

References 27. 1. Porcel

JM, Vergani D. El sistema del complemento: una fascinante cascada biológica. Med Clin (Barc) 1992 (in press).

AK, Lichtman AH, Pober JS. Cellular and Molecular

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41. Wilson WA, Armatis PE, Pérez MC. C4 concentrations and C4 deficiency alleles in systemic lupus erythematosus. Ann Rheum Dis 1989; 48: 600-4. 42. Waldo FB, Forristal J, Beischel L, West CD. A circulating inhibitor of fluid-phase amplification C3 convertase formation in systemic lupus erythematosus. J Clin Invest 1985; 75: 1786-95. 43. Morgan BP. Complement. Clinical Aspects and Relevance to Disease. London: Academic Press, 1990: 94. 44. Swaak AJG, van Rooyen A, Vogelaar C, Pillay M, Hack E. Complement (C3) metabolism in systemic lupus erythematosus in relation to the disease course. Rheumatol Int 1986; 6: 221-6. 45. Porcel JM, Peakman M, Senaldi G, Vergani D. Methods for assessing complement activation in the clinical immunology laboratory. (Submitted for publication) 46. Porcel JM, Ordi J. Complemento activado en el lupus eritematoso sistémico. Med Clin (Barc) 1991; 96: 135-7. 47. Levy RA, Qamar T, Lockshin MD. Alternative complement pathway in hypocomplementemic/normal C1s-C1 inhibitor complex patients with SLE. Clin Exp Rheumatol 1990 ; 8: 11-5. 48. Jenkins JS, Powell RJ. C3 degradation products (C3d) in normal Clin Pathol 1987; 40: 1362-3. pregnancy. J 49. Hopkinson ND, Powell RJ. Classical complement activation induced by pregnancy: implications for management of connective tissue diseases. J Clin Pathol 1992 ; 45: 66-7. 50. Buyon JP, Tamerius J, Ordorica S, Young B, Abramson SB. Activation of the alternative complement pathway accompanies disease flares in systemic lupus erythematosus during pregnancy. Arthritis Rheum 1992; 35: 55-61. 51. Manzi S, Kelly RH, Carpenter AB, Jagarlapudi SP, RamseyGoldman R, Medsger TA. Urine complement split product C3d in lupus renal disease. Arthritis Rheum 1991; 34: S96 (abstract

A183). 52. Sanders ME, Alexander EL, Koski CL, Frank MM, Joiner KA. Detection of activated terminal complement (C5b-9) in cerebrospinal fluid from patients with central nervous system involvement of primary Sjögren’s syndrome or systemic lupus erythematosus. J Immunol 1987 ; 138: 2095-9. 53. Laitman RS, Glicklich D, Sablay LB, Grayzel AI, Barland P, Bank N. Effect of long-term normalization of serum complement levels on the course of lupus nephritis. Am J Med 1989; 87: 132-8.

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(Received 13 May 1992) (Accepted I June 1992)

Complement and lupus: old concepts and new directions.

In this review it is our intention to outline briefly the relevance of the complement system in systemic lupus erythematosus. Three main issues will b...
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