- Email: [email protected]
Antibodies Against C1q
29 Antibodies Against C1q Karina de Leeuw and Cees G.M. Kallenberg
OUTLINE Introduction, 372 Antigenic Specificity and Methods of Detection of Anti-C1q, 372 Clinical Associations, 372
Do Levels of Anti-C1q Follow Disease Activity in Lupus (Nephritis)?, 373 Pathogenic Role of Anti-C1q Autoantibodies, 373 Conclusion, 373
INTRODUCTION
CLINICAL ASSOCIATIONS
Antibodies to components of the innate immune system are frequently detected in the sera of patients with systemic lupus erythematosus (SLE). Among these are antibodies against various components of the complement system. Antibodies to C1q have drawn particular attention because they have been suggested to be involved in the pathogenesis of lupus nephritis and to serve as markers of renal disease activity in SLE. This chapter will focus on the clinical associations and pathogenic potential of anti-C1q autoantibodies (anti-C1q) in SLE.
Anti-C1q antibodies have been described in many conditions (Table 29.1).4 Thus, their specificity for SLE is low. Anti-C1q antibodies are invariably present in sera from patients with hypocomplementemic urticarial vasculitis (HUV). This finding suggests that anti-C1q plays a pathogenic role in the latter disease, although this has not been proved experimentally. Studies on subclasses and epitopes of anti-C1q in HUV and SLE suggest almost identity of anti-C1q in both diseases despite many differences in clinical presentation.5 Several studies have demonstrated that anti-C1q antibodies are more prevalent in SLE patients with (proliferative) lupus nephritis than in SLE patients without nephritis. For example, Sinico and colleagues6 observed that 60% of SLE patients with nephritis were positive for anti-C1q in contrast to only 14% of patients without nephritis. During active nephritis, 89% were positive, whereas none of the inactive patients tested positive. Trendelenburg and colleagues7 described anti-C1q in 36 of 38 (97.2%) patients with active lupus nephritis. In contrast, only 35% of patients (8 of 26) with inactive lupus nephritis and 25% (9 of 36) with nonrenal lupus tested positive for anti-C1q. A study from China also described a high prevalence of anti-C1q (58 of 73 patients, 80%) in lupus nephritis with the highest levels detected in patients with class IV nephritis.8 A recent study confirmed this association because high titers of anti-C1q antibodies were an independent predictor that discriminated proliferative from nonproliferative lupus nephritis.9 However, not all series showed such clear-cut results. Marto and colleagues10 found 75% of their 77 patients with active SLE nephritis positive for anti-C1q antibodies compared with 53% of patients with nonactive nephritis. The autoantibodies were present in 33 of 83 patients (39%) without a history of renal disease, but, interestingly, 9 of these 33 patients developed lupus nephritis after a median interval of 10 months, and one developed HUV, demonstrating the possible predictive value of anti-C1q for lupus nephritis in SLE. Comparable prevalences ranging from 50% to 65% of anti-C1q in lupus nephritis were found by others.11-13 Together, anti-C1q antibodies are present in various (auto)immune conditions. They are highly sensitive for HUV. In SLE, anti-C1q antibodies are particularly likely to be present in (diffuse) proliferative lupus
ANTIGENIC SPECIFICITY AND METHODS OF DETECTION OF ANTI-C1q C1q is a complex molecule consisting of collagenous portions ending up with globular heads; one molecule is composed of six copies of three different chains each, giving the impression of a bunch of tulips. Anti-C1q binds mainly to the collagenous portions which, apparently, are the main immunogenic region of the molecule. However, there are also antibodies that specifically target the globular head regions of C1q. In C1q binding assays used for the detection of immune complexes, purified C1q is coated to a solid phase, immune complexes in serum or plasma samples are allowed to bind, and bound complexed IgG is detected with heterologous anti-IgG antibodies. The autoantibodies to C1q bind to neoepitopes only exposed on bound C1q and not present on soluble C1q and, as mentioned previously, map to different regions of the collagenous portions of C1q.1,2 Therefore, tests for measuring anti-C1q are, generally, solid phase enzyme-linked immunosorbent assays (ELISAs) using whole human C1q as a substrate. To inhibit binding of immune complexes, high ionic strength conditions (0.5–1.0 M NaCl) should be used. To eliminate the use of this buffer, assays have been developed that use only the C1q collagen-like region, generated by enzymatic digestion, as antigen.2,3 Today, several commercial assays are available for the detection of anti-C1q antibodies; however, none of these assays has been approved by the Food and Drug Administration (FDA) because of the lack of prospective studies. In addition, systematic studies comparing anti-C1q antibody assays from different companies are lacking.
372
CHAPTER 29 Antibodies Against C1q TABLE 29.1 Autoantibodies to C1q:
Clinical Associations
Hypocomplementemic urticarial vasculitis Felty syndrome Systemic lupus erythematosus Lupus nephritisa Rheumatoid vasculitis Sjögren’s Membranoproliferative glomerulonephritis IgA nephropathy Healthy individuals
100% 76% 33% 63% 77% 13% 54% 31% 5%
(n = 174) (n = 21) (n = 591) (n = 95) (n = 31) (n = 39) (n = 68) (n = 36) (n = 140)
a
More frequently in proliferative lupus nephritis. Adapted from Seelen MA, Trouw LA, Daha MR: Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens 12(6):619–624, 2003.
nephritis strongly associated with active disease. Furthermore, especially striking in all these studies is the strong negative predictive value of anti-C1q testing for lupus nephritis, prompting the statement “there is no lupus nephritis without anti-C1q.”14
DO LEVELS OF ANTI-C1q FOLLOW DISEASE ACTIVITY IN LUPUS (NEPHRITIS)? The previously described data suggested that levels of anti-C1q reflect (renal) disease activity in SLE. Because serologic identification of a flare of lupus nephritis is preferable to repeated renal biopsy, anti-C1q might be a useful biomarker, in addition to anti-dsDNA and complement levels.13 However, there are a few longitudinal studies that confirm this hypothesis. One study of 43 SLE patients related levels of anti-C1q to disease activity, compared with levels of anti-dsDNA and complement C3 and C4, by scoring disease activity and sampling plasma every month.15 No change in autoantibody levels occurred over time in patients with inactive disease. Anti-C1q and anti-dsDNA were both present in 82% of patients with a renal relapse (n = 17) and rose significantly before the relapse in 58% and 65% of patients, respectively. During nonrenal relapses (n = 16) anti-C1q was detected in 38% of patients and levels rose before relapse in only 19%. In contrast, nonrenal relapses were accompanied by anti-dsDNA in 94% of patients and levels rose in 56% of patients before relapse. Thus changes in levels of anti-C1q particularly follow renal disease activity. Another study by Moroni and colleagues16 also observed that changes in anti-C1q levels are strongly associated with renal disease activity in SLE, reaching a sensitivity of 87% and a specificity of 92%. Together with other studies, showing the predictive value of anti-C1q for renal flares,17,18 the current data suggest that anti-C1q are especially involved in the pathogenesis of lupus nephritis but are less evident in nonrenal flares.
PATHOGENIC ROLE OF ANTI-C1q AUTOANTIBODIES Mannik and colleagues19 extracted antibodies from autopsy kidneys from SLE patients and found anti-C1q activity in extracts from 4 of 5 kidneys. In addition, anti-C1q antibodies were strongly enriched in glomeruli compared with serum because the anti-C1q/IgG ratio in the glomerular extract was more than 50 times higher than the ratio in serum. A strong argument for a pathogenic role of anti-C1q in lupus nephritis comes from the study of Trouw and colelagues.20 Injection of a monoclonal antibody to C1q in normal (BALB/c) mice led to the depletion of C1q from the circulation and deposition of both C1q and
373
anti-C1q along the glomerular basement membrane (GBM) with, however, only mild granulocyte influx and no proteinuria. Injection with a subnephritogenic dose of complement-fixing rabbit antimouse GBM antibody together with the anti-C1q monoclonal antibody led to strong granulocyte influx and massive proteinuria. Apparently, the anti-GBM antibody binds to the GBM and fixes C1q, which is followed by binding of anti-C1q and inflammation. They concluded that anti-C1q antibodies are only pathogenic in the context of immune complex renal disease such as occurs in lupus nephritis. This may also explain why renal lesions do not develop in HUV despite the presence of anti-C1q. Bigler and colleagues,21 using the MRL/MpJ+/+ lupus mouse strain, could not demonstrate a correlation between the presence of anti-C1q and overall survival or severity of nephritis in these mice. Finally, anti-C1q may be involved in an inflammatory clearance of apoptotic cells because these antibodies particularly target C1q bound on early apoptotic cells.22 Their uptake by macrophages will involve Fc-receptor engagement resulting in activation of the phagocytic cells.23
CONCLUSION Anti-C1q antibodies are most sensitive for HUV. In SLE, anti-C1q antibodies are strongly associated with proliferative lupus nephritis, and their absence carries a negative predictive value for development of lupus nephritis of close to 100%. The anti-C1q titers correlate with global disease activity scores in patients with renal involvement, and an increase in titers seems to precede renal flares. However, the main obstacle to the inclusion of anti-C1q in the classification criteria and clinical management of SLE is the lack of standardized laboratory assays. Using the new commercially available assays in large well-defined cohorts, preferably in a prospective study design, might confirm the additional value of testing for anti-C1q autoantibodies in clinical situations.
REFERENCES 1. Kallenberg CG. Anti-C1q autoantibodies. Autoimmun Rev. 2008;7(8): 612–615. 2. Mahler M, van Schaarenburg RA, Trouw LA. Anti-C1q autoantibodies, novel tests, and clinical consequences. Front Immunol. 2013;4:117. doi:10.3389/fimmu.2013.00117. 3. Vanhecke D, Roumenina LT, Wan H, et al. Identification of a major linear C1q epitope allows detection of systemic lupus erythematosus anti-C1q antibodies by a specific peptide-based enzyme-linked immunosorbent assay. Arthritis Rheum. 2012;64(11):3706–3714. 4. Seelen MA, Trouw LA, Daha MR. Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens. 2003;12(6):619–624. 5. Wisnieski JJ, Jones SM. Comparison of autoantibodies to the collagen-like region of C1q in hypocomplementemic urticarial vasculitis syndrome and systemic lupus erythematosus. J Immunol. 1992;148(5): 1396–1403. 6. Sinico RA, Radice A, Ikehata M, et al. Anti-C1q autoantibodies in lupus nephritis: prevalence and clinical significance. Ann N Y Acad Sci. 2005;1050:193–200. doi:10.1196/annals.1313.020. 7. Trendelenburg M, Lopez-Trascasa M, Potlukova E, et al. High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis. Nephrol Dial Transplant. 2006;21(11):3115–3121. 8. Cai X, Yang X, Lian F, et al. Correlation between serum anti-C1q antibody levels and renal pathological characteristics and prognostic significance of anti-C1q antibody in lupus nephritis. J Rheumatol. 2010;37(4):759–765. 9. Moroni G, Quaglini S, Radice A, et al. The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. J Immunol Res. 2015;2015:106904. doi:10.1155/2015/106904. 10. Marto N, Bertolaccini ML, Calabuig E, et al. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive
374
SECTION 4 Autoantibodies
predictive value in systemic lupus erythematosus. Ann Rheum Dis. 2005;64(3):444–448. 11. Grootscholten C, Dieker JW, McGrath FD, et al. A prospective study of anti-chromatin and anti-C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/ methylprednisolone. Ann Rheum Dis. 2007;66(5):693–696. 12. Fang QY, Yu F, Tan Y, et al. Anti-C1q antibodies and IgG subclass distribution in sera from Chinese patients with lupus nephritis. Nephrol Dial Transplant. 2009;24(1):172–178. 13. Orbai AM, Truedsson L, Sturfelt G, et al. Anti-C1q antibodies in systemic lupus erythematosus. Lupus. 2015;24(1):42–49. 14. Fremeaux-Bacchi V, Noel LH, Schifferli JA. No lupus nephritis in the absence of antiC1q autoantibodies? Nephrol Dial Transplant. 2002;17(12):2041–2043. 15. Coremans IE, Spronk PE, Bootsma H, et al. Changes in antibodies to C1q predict renal relapses in systemic lupus erythematosus. Am J Kidney Dis. 1995;26(4):595–601. 16. Moroni G, Trendelenburg M, Del Papa N, et al. Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis. Am J Kidney Dis. 2001;37(3):490–498. 17. Matrat A, Veysseyre-Balter C, Trolliet P, et al. Simultaneous detection of anti-C1q and anti-double stranded DNA autoantibodies in lupus nephritis: predictive value for renal flares. Lupus. 2011;20(1):28–34.
18. Bock M, Heijnen I, Trendelenburg M. Anti-C1q antibodies as a follow-up marker in SLE patients. PLoS ONE. 2015;10(4):e0123572. 19. Mannik M, Wener MH. Deposition of antibodies to the collagen-like region of C1q in renal glomeruli of patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 1997;40(8):1504–1511. 20. Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest. 2004;114(5):679–688. 21. Bigler C, Hopfer H, Danner D, et al. Anti-C1q autoantibodies do not correlate with the occurrence or severity of experimental lupus nephritis. Nephrol Dial Transplant. 2011;26(4):1220–1228. 22. Bigler C, Schaller M, Perahud I, et al. Autoantibodies against complement C1q specifically target C1q bound on early apoptotic cells. J Immunol. 2009;183(5):3512–3521. 23. Reefman E, Dijstelbloem HM, Limburg PC, et al. Fcgamma receptors in the initiation and progression of systemic lupus erythematosus. Immunol Cell Biol. 2003;81(5):382–389.
OUTLINE Introduction, 372 Antigenic Specificity and Methods of Detection of Anti-C1q, 372 Clinical Associations, 372
Do Levels of Anti-C1q Follow Disease Activity in Lupus (Nephritis)?, 373 Pathogenic Role of Anti-C1q Autoantibodies, 373 Conclusion, 373
INTRODUCTION
CLINICAL ASSOCIATIONS
Antibodies to components of the innate immune system are frequently detected in the sera of patients with systemic lupus erythematosus (SLE). Among these are antibodies against various components of the complement system. Antibodies to C1q have drawn particular attention because they have been suggested to be involved in the pathogenesis of lupus nephritis and to serve as markers of renal disease activity in SLE. This chapter will focus on the clinical associations and pathogenic potential of anti-C1q autoantibodies (anti-C1q) in SLE.
Anti-C1q antibodies have been described in many conditions (Table 29.1).4 Thus, their specificity for SLE is low. Anti-C1q antibodies are invariably present in sera from patients with hypocomplementemic urticarial vasculitis (HUV). This finding suggests that anti-C1q plays a pathogenic role in the latter disease, although this has not been proved experimentally. Studies on subclasses and epitopes of anti-C1q in HUV and SLE suggest almost identity of anti-C1q in both diseases despite many differences in clinical presentation.5 Several studies have demonstrated that anti-C1q antibodies are more prevalent in SLE patients with (proliferative) lupus nephritis than in SLE patients without nephritis. For example, Sinico and colleagues6 observed that 60% of SLE patients with nephritis were positive for anti-C1q in contrast to only 14% of patients without nephritis. During active nephritis, 89% were positive, whereas none of the inactive patients tested positive. Trendelenburg and colleagues7 described anti-C1q in 36 of 38 (97.2%) patients with active lupus nephritis. In contrast, only 35% of patients (8 of 26) with inactive lupus nephritis and 25% (9 of 36) with nonrenal lupus tested positive for anti-C1q. A study from China also described a high prevalence of anti-C1q (58 of 73 patients, 80%) in lupus nephritis with the highest levels detected in patients with class IV nephritis.8 A recent study confirmed this association because high titers of anti-C1q antibodies were an independent predictor that discriminated proliferative from nonproliferative lupus nephritis.9 However, not all series showed such clear-cut results. Marto and colleagues10 found 75% of their 77 patients with active SLE nephritis positive for anti-C1q antibodies compared with 53% of patients with nonactive nephritis. The autoantibodies were present in 33 of 83 patients (39%) without a history of renal disease, but, interestingly, 9 of these 33 patients developed lupus nephritis after a median interval of 10 months, and one developed HUV, demonstrating the possible predictive value of anti-C1q for lupus nephritis in SLE. Comparable prevalences ranging from 50% to 65% of anti-C1q in lupus nephritis were found by others.11-13 Together, anti-C1q antibodies are present in various (auto)immune conditions. They are highly sensitive for HUV. In SLE, anti-C1q antibodies are particularly likely to be present in (diffuse) proliferative lupus
ANTIGENIC SPECIFICITY AND METHODS OF DETECTION OF ANTI-C1q C1q is a complex molecule consisting of collagenous portions ending up with globular heads; one molecule is composed of six copies of three different chains each, giving the impression of a bunch of tulips. Anti-C1q binds mainly to the collagenous portions which, apparently, are the main immunogenic region of the molecule. However, there are also antibodies that specifically target the globular head regions of C1q. In C1q binding assays used for the detection of immune complexes, purified C1q is coated to a solid phase, immune complexes in serum or plasma samples are allowed to bind, and bound complexed IgG is detected with heterologous anti-IgG antibodies. The autoantibodies to C1q bind to neoepitopes only exposed on bound C1q and not present on soluble C1q and, as mentioned previously, map to different regions of the collagenous portions of C1q.1,2 Therefore, tests for measuring anti-C1q are, generally, solid phase enzyme-linked immunosorbent assays (ELISAs) using whole human C1q as a substrate. To inhibit binding of immune complexes, high ionic strength conditions (0.5–1.0 M NaCl) should be used. To eliminate the use of this buffer, assays have been developed that use only the C1q collagen-like region, generated by enzymatic digestion, as antigen.2,3 Today, several commercial assays are available for the detection of anti-C1q antibodies; however, none of these assays has been approved by the Food and Drug Administration (FDA) because of the lack of prospective studies. In addition, systematic studies comparing anti-C1q antibody assays from different companies are lacking.
372
CHAPTER 29 Antibodies Against C1q TABLE 29.1 Autoantibodies to C1q:
Clinical Associations
Hypocomplementemic urticarial vasculitis Felty syndrome Systemic lupus erythematosus Lupus nephritisa Rheumatoid vasculitis Sjögren’s Membranoproliferative glomerulonephritis IgA nephropathy Healthy individuals
100% 76% 33% 63% 77% 13% 54% 31% 5%
(n = 174) (n = 21) (n = 591) (n = 95) (n = 31) (n = 39) (n = 68) (n = 36) (n = 140)
a
More frequently in proliferative lupus nephritis. Adapted from Seelen MA, Trouw LA, Daha MR: Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens 12(6):619–624, 2003.
nephritis strongly associated with active disease. Furthermore, especially striking in all these studies is the strong negative predictive value of anti-C1q testing for lupus nephritis, prompting the statement “there is no lupus nephritis without anti-C1q.”14
DO LEVELS OF ANTI-C1q FOLLOW DISEASE ACTIVITY IN LUPUS (NEPHRITIS)? The previously described data suggested that levels of anti-C1q reflect (renal) disease activity in SLE. Because serologic identification of a flare of lupus nephritis is preferable to repeated renal biopsy, anti-C1q might be a useful biomarker, in addition to anti-dsDNA and complement levels.13 However, there are a few longitudinal studies that confirm this hypothesis. One study of 43 SLE patients related levels of anti-C1q to disease activity, compared with levels of anti-dsDNA and complement C3 and C4, by scoring disease activity and sampling plasma every month.15 No change in autoantibody levels occurred over time in patients with inactive disease. Anti-C1q and anti-dsDNA were both present in 82% of patients with a renal relapse (n = 17) and rose significantly before the relapse in 58% and 65% of patients, respectively. During nonrenal relapses (n = 16) anti-C1q was detected in 38% of patients and levels rose before relapse in only 19%. In contrast, nonrenal relapses were accompanied by anti-dsDNA in 94% of patients and levels rose in 56% of patients before relapse. Thus changes in levels of anti-C1q particularly follow renal disease activity. Another study by Moroni and colleagues16 also observed that changes in anti-C1q levels are strongly associated with renal disease activity in SLE, reaching a sensitivity of 87% and a specificity of 92%. Together with other studies, showing the predictive value of anti-C1q for renal flares,17,18 the current data suggest that anti-C1q are especially involved in the pathogenesis of lupus nephritis but are less evident in nonrenal flares.
PATHOGENIC ROLE OF ANTI-C1q AUTOANTIBODIES Mannik and colleagues19 extracted antibodies from autopsy kidneys from SLE patients and found anti-C1q activity in extracts from 4 of 5 kidneys. In addition, anti-C1q antibodies were strongly enriched in glomeruli compared with serum because the anti-C1q/IgG ratio in the glomerular extract was more than 50 times higher than the ratio in serum. A strong argument for a pathogenic role of anti-C1q in lupus nephritis comes from the study of Trouw and colelagues.20 Injection of a monoclonal antibody to C1q in normal (BALB/c) mice led to the depletion of C1q from the circulation and deposition of both C1q and
373
anti-C1q along the glomerular basement membrane (GBM) with, however, only mild granulocyte influx and no proteinuria. Injection with a subnephritogenic dose of complement-fixing rabbit antimouse GBM antibody together with the anti-C1q monoclonal antibody led to strong granulocyte influx and massive proteinuria. Apparently, the anti-GBM antibody binds to the GBM and fixes C1q, which is followed by binding of anti-C1q and inflammation. They concluded that anti-C1q antibodies are only pathogenic in the context of immune complex renal disease such as occurs in lupus nephritis. This may also explain why renal lesions do not develop in HUV despite the presence of anti-C1q. Bigler and colleagues,21 using the MRL/MpJ+/+ lupus mouse strain, could not demonstrate a correlation between the presence of anti-C1q and overall survival or severity of nephritis in these mice. Finally, anti-C1q may be involved in an inflammatory clearance of apoptotic cells because these antibodies particularly target C1q bound on early apoptotic cells.22 Their uptake by macrophages will involve Fc-receptor engagement resulting in activation of the phagocytic cells.23
CONCLUSION Anti-C1q antibodies are most sensitive for HUV. In SLE, anti-C1q antibodies are strongly associated with proliferative lupus nephritis, and their absence carries a negative predictive value for development of lupus nephritis of close to 100%. The anti-C1q titers correlate with global disease activity scores in patients with renal involvement, and an increase in titers seems to precede renal flares. However, the main obstacle to the inclusion of anti-C1q in the classification criteria and clinical management of SLE is the lack of standardized laboratory assays. Using the new commercially available assays in large well-defined cohorts, preferably in a prospective study design, might confirm the additional value of testing for anti-C1q autoantibodies in clinical situations.
REFERENCES 1. Kallenberg CG. Anti-C1q autoantibodies. Autoimmun Rev. 2008;7(8): 612–615. 2. Mahler M, van Schaarenburg RA, Trouw LA. Anti-C1q autoantibodies, novel tests, and clinical consequences. Front Immunol. 2013;4:117. doi:10.3389/fimmu.2013.00117. 3. Vanhecke D, Roumenina LT, Wan H, et al. Identification of a major linear C1q epitope allows detection of systemic lupus erythematosus anti-C1q antibodies by a specific peptide-based enzyme-linked immunosorbent assay. Arthritis Rheum. 2012;64(11):3706–3714. 4. Seelen MA, Trouw LA, Daha MR. Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens. 2003;12(6):619–624. 5. Wisnieski JJ, Jones SM. Comparison of autoantibodies to the collagen-like region of C1q in hypocomplementemic urticarial vasculitis syndrome and systemic lupus erythematosus. J Immunol. 1992;148(5): 1396–1403. 6. Sinico RA, Radice A, Ikehata M, et al. Anti-C1q autoantibodies in lupus nephritis: prevalence and clinical significance. Ann N Y Acad Sci. 2005;1050:193–200. doi:10.1196/annals.1313.020. 7. Trendelenburg M, Lopez-Trascasa M, Potlukova E, et al. High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis. Nephrol Dial Transplant. 2006;21(11):3115–3121. 8. Cai X, Yang X, Lian F, et al. Correlation between serum anti-C1q antibody levels and renal pathological characteristics and prognostic significance of anti-C1q antibody in lupus nephritis. J Rheumatol. 2010;37(4):759–765. 9. Moroni G, Quaglini S, Radice A, et al. The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. J Immunol Res. 2015;2015:106904. doi:10.1155/2015/106904. 10. Marto N, Bertolaccini ML, Calabuig E, et al. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive
374
SECTION 4 Autoantibodies
predictive value in systemic lupus erythematosus. Ann Rheum Dis. 2005;64(3):444–448. 11. Grootscholten C, Dieker JW, McGrath FD, et al. A prospective study of anti-chromatin and anti-C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/ methylprednisolone. Ann Rheum Dis. 2007;66(5):693–696. 12. Fang QY, Yu F, Tan Y, et al. Anti-C1q antibodies and IgG subclass distribution in sera from Chinese patients with lupus nephritis. Nephrol Dial Transplant. 2009;24(1):172–178. 13. Orbai AM, Truedsson L, Sturfelt G, et al. Anti-C1q antibodies in systemic lupus erythematosus. Lupus. 2015;24(1):42–49. 14. Fremeaux-Bacchi V, Noel LH, Schifferli JA. No lupus nephritis in the absence of antiC1q autoantibodies? Nephrol Dial Transplant. 2002;17(12):2041–2043. 15. Coremans IE, Spronk PE, Bootsma H, et al. Changes in antibodies to C1q predict renal relapses in systemic lupus erythematosus. Am J Kidney Dis. 1995;26(4):595–601. 16. Moroni G, Trendelenburg M, Del Papa N, et al. Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis. Am J Kidney Dis. 2001;37(3):490–498. 17. Matrat A, Veysseyre-Balter C, Trolliet P, et al. Simultaneous detection of anti-C1q and anti-double stranded DNA autoantibodies in lupus nephritis: predictive value for renal flares. Lupus. 2011;20(1):28–34.
18. Bock M, Heijnen I, Trendelenburg M. Anti-C1q antibodies as a follow-up marker in SLE patients. PLoS ONE. 2015;10(4):e0123572. 19. Mannik M, Wener MH. Deposition of antibodies to the collagen-like region of C1q in renal glomeruli of patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 1997;40(8):1504–1511. 20. Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest. 2004;114(5):679–688. 21. Bigler C, Hopfer H, Danner D, et al. Anti-C1q autoantibodies do not correlate with the occurrence or severity of experimental lupus nephritis. Nephrol Dial Transplant. 2011;26(4):1220–1228. 22. Bigler C, Schaller M, Perahud I, et al. Autoantibodies against complement C1q specifically target C1q bound on early apoptotic cells. J Immunol. 2009;183(5):3512–3521. 23. Reefman E, Dijstelbloem HM, Limburg PC, et al. Fcgamma receptors in the initiation and progression of systemic lupus erythematosus. Immunol Cell Biol. 2003;81(5):382–389.