Releasing the complement brakes: is myeloperoxidase the missing link between factor H and C5a in anti-neutrophil cytoplasmic antibody vasculitis?

Releasing the complement brakes: is myeloperoxidase the missing link between factor H and C5a in... This editorial refers to Myeloperoxidase influences the complement regulatory activity of complement factor H, Su-Fang Chen et al. doi:10.1093/rheumatology/kex529. Evidence for a crucial role for activation of the alternative pathway of complement in ANCA-associated vasculitis (AAV) was initially provided by observations in a myeloperoxidase (MPO)-ANCA mouse model induced by the transfer of anti-MPO IgG. This demonstrated complete protection from disease by ablation of C5 and factor B, and systemic depletion of C3, whereas ablation of C4 had no effect [1]. Follow-up studies implicated the induced C5a–C5aR axis as a strong amplifier of the AAV inflammatory response [2]. Studies of human AAV kidney tissue revealed deposition of factor B, properdin, C3d and the membrane attack complex [3, 4]. Following from this, urinary levels of C3a, C5a and soluble C5b-9 are higher during active AAV than during remission [5]. Normally, activation of the complement cascade is confined to microbial surfaces and tightly controlled to prevent tissue damage. This is mediated by several circulating and membrane-bound proteins, collectively termed regulators of complement activation (RCA). Decreased RCA activity may cause uncontrolled complement activation and lead to extensive tissue damage. In a recent histopathological study, Cheng et al. [6] demonstrated that expression of several RCA was downregulated in biopsies of AAV patients, suggesting that not only is complement activated in AAV, it may also not be adequately controlled. Among the RCA, complement factor H (CFH) is a key regulator of the alternative complement pathway, both in solution and on cell surfaces: it competes with factor B for binding to C3b, thereby preventing the formation and accelerating the breakdown of the alternative pathway C3 convertases and serves as a cofactor for the factor I-mediated proteolytic inactivation of C3b [7]. The crucial role of CFH is further emphasized by the association of mutations and/or polymorphisms in the CFH gene, and disorders such as haemolytic uraemic syndrome and dense deposit disease. In this issue of the Journal, Chen et al. [8] have built upon their previous work to illustrate a potential mechanism for the observed CFH dysfunction in AAV. This follows on from previous work from the Beijing lab that demonstrated that, in AAV, the level of CFH is lower, and its function is impaired [9]. This may be mediated by disruption of the binding of membrane-bound CRP to CFH. The current study explores the role of one of the autoantigens in AAV, MPO, which was co-localized with CFH in neutrophil extracellular traps. Although not co-localized, MPO was also found in close proximity to CFH in glomeruli injured by AAV. To examine more closely the interaction between MPO and CFH, the authors used ELISA and surface plasmon resonance to ascertain that the two proteins bind very tightly to each other, with the short consensus repeats (SCR) 1–4 domain of CFH being the main determinant of this. This led the investigators to assess the impact of MPO binding on the ability of CFH to perform its normal role of damping down the alternative complement pathway. Using both fluid-phase and membrane-bound C3b binding as the readout, MPO inhibited CFH function, resulting in reduction of its decay accelerating activity. Interestingly, MPO had no effect on CFH-mediated protection from complement-induced red cell lysis, suggesting that the principal effect is on production of soluble inflammatory mediators such as C3a and C5a, rather than through the membrane attack complex. This is consistent with current hypotheses regarding the role of these mediators in AAV, particularly of C5a. The current work serves to add to the complexity of an already complex system, and raises some important questions. Firstly, although MPO is an autoantigen in AAV, release of MPO from neutrophils and monocytes occurs in many inflammatory diseases, and is not currently considered the principal mechanism by which these cells induce endothelial injury in AAV. Secondly, if the MPO autoantigen itself is proposed as a key regulator of the immune response, it raises the question as to what effect autoantibodies to this antigen (ANCA) have on the observed features, which were studied in an anti-MPO free system. Enzymatic MPO has many effects on the immune response. For example, MPO can perpetuate inflammation by activating macrophages and MPO-deficient mice are protected from experimental glomerulonephritis [10]. Additionally, enzymatically active MPO is required for the observed reduction by MPO-ANCA of anti-inflammatory IL10 and IL6 from monocytes, which occurs through its oxidation of phospholipids [11]. It is not clear whether these many enzymatic effects of MPO were required for the observed effect on CFH, or indeed whether they arose as a result of simple electrostatic interaction between CFH and MPO. In this respect, it would be interesting to compare the impact of a different highly cationic protein (rather than the gelatin that was used as the control). The source of the CFH used in the current work is not clear; presumably it was purified from donor plasma as in their previous work, raising an issue of how many donors were used, and whether known CFH polymorphisms may have exerted differential effects. It would also be fascinating to consider why quantitative and functional deficiency of CFH is associated with an AAV phenotype, as opposed to a thrombotic microangiopathic phenotype observed with other disorders associated with CFH dysfunction. On this note, when thrombotic microangiopathy does occur in AAV it is associated with worse histopathological characteristics and clinical outcome. As AAV therapeutics take brave steps into the complement field, with recent completion of a phase 2 trial of a C5aR antagonist, mechanistic work that seeks to understand in detail how the complement system leads to AAV pathology is welcome. We propose that the key question to be addressed now is whether the influence of MPO on CFH function is specific to AAV. For example, factor H levels are tightly associated with glomerular filtration rate [8]. Are at least some of the observed characteristics merely a manifestation of illness, of impaired kidney function in the context of an inflammatory state? Future studies must include adequate disease controls, including those with similar non-ANCA-mediated multi-system autoimmune disorders characterized by kidney dysfunction (such as anti-GBM disease), and those receiving immunosuppressive medication. Future work should also examine whether the observed CFH dysfunction occurs in PR3 ANCA vasculitis. This is a call that must be answered by other research groups around the world as this is rarely encountered in China. Acknowledgement M.A.L. was funded by the Meath Foundation, grant number 205229. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Xiao H , Schreiber A , Heeringa P , Falk RJ , Jennette JC. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies . Am J Pathol 2007 ; 170 : 52 – 64 . Google Scholar CrossRef Search ADS PubMed 2 Huugen D, , van Esch A, , Xiao H et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice . Kidney Int 2007 ; 71 : 646 – 54 . Google Scholar CrossRef Search ADS PubMed 3 Xing GQ , Chen M , Liu G et al. Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis . J Clin Immunol 2009 ; 29 : 282 – 91 . Google Scholar CrossRef Search ADS PubMed 4 Hilhorst M , van Paassen P , van Rie H et al. Complement in ANCA-associated glomerulonephritis . Nephrol Dial Transplant 2017 ; 32 : 1302 – 13 . Google Scholar CrossRef Search ADS PubMed 5 Gou SJ , Yuan J , Wang C , Zhao MH , Chen M. Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN . Clin J Am Soc Nephrol 2013 ; 8 : 1884 – 91 . Google Scholar CrossRef Search ADS PubMed 6 Cheng L , Gou SJ , Qiu HY , Ma L , Fu P. Complement regulatory proteins in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis . Clin Exp Immunol 2018 ; 191 : 116 – 24 . Google Scholar CrossRef Search ADS PubMed 7 Parente R , Clark SJ , Inforzato A , Day AJ. Complement factor H in host defense and immune evasion . Cell Mol Life Sci 2017 ; 74 : 1605 – 24 . Google Scholar CrossRef Search ADS PubMed 8 Chen S-F , Wang F-M , Li Z-Y et al. Myeloperoxidase influences the complement regulatory activity of complement factor H . Rheumatology 2018 ; doi:10.1093/rheumatology/kex529. 9 Chen SF, , Wang FM, , Li ZY et al. Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis . Arthritis Res Ther 2015 ; 17 : 129 . Google Scholar CrossRef Search ADS PubMed 10 Odobasic D , Kitching AR , Semple TJ , Holdsworth SR. Endogenous myeloperoxidase promotes neutrophil-mediated renal injury, but attenuates T cell immunity inducing crescentic glomerulonephritis . J Am Soc Nephrol 2007 ; 18 : 760 – 70 . Google Scholar CrossRef Search ADS PubMed 11 Popat RJ, , Hakki S, , Thakker A et al. Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development . JCI Insight 2017 ; 2 : e87379 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Releasing the complement brakes: is myeloperoxidase the missing link between factor H and C5a in anti-neutrophil cytoplasmic antibody vasculitis?

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1462-0324
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10.1093/rheumatology/key126
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Abstract

This editorial refers to Myeloperoxidase influences the complement regulatory activity of complement factor H, Su-Fang Chen et al. doi:10.1093/rheumatology/kex529. Evidence for a crucial role for activation of the alternative pathway of complement in ANCA-associated vasculitis (AAV) was initially provided by observations in a myeloperoxidase (MPO)-ANCA mouse model induced by the transfer of anti-MPO IgG. This demonstrated complete protection from disease by ablation of C5 and factor B, and systemic depletion of C3, whereas ablation of C4 had no effect [1]. Follow-up studies implicated the induced C5a–C5aR axis as a strong amplifier of the AAV inflammatory response [2]. Studies of human AAV kidney tissue revealed deposition of factor B, properdin, C3d and the membrane attack complex [3, 4]. Following from this, urinary levels of C3a, C5a and soluble C5b-9 are higher during active AAV than during remission [5]. Normally, activation of the complement cascade is confined to microbial surfaces and tightly controlled to prevent tissue damage. This is mediated by several circulating and membrane-bound proteins, collectively termed regulators of complement activation (RCA). Decreased RCA activity may cause uncontrolled complement activation and lead to extensive tissue damage. In a recent histopathological study, Cheng et al. [6] demonstrated that expression of several RCA was downregulated in biopsies of AAV patients, suggesting that not only is complement activated in AAV, it may also not be adequately controlled. Among the RCA, complement factor H (CFH) is a key regulator of the alternative complement pathway, both in solution and on cell surfaces: it competes with factor B for binding to C3b, thereby preventing the formation and accelerating the breakdown of the alternative pathway C3 convertases and serves as a cofactor for the factor I-mediated proteolytic inactivation of C3b [7]. The crucial role of CFH is further emphasized by the association of mutations and/or polymorphisms in the CFH gene, and disorders such as haemolytic uraemic syndrome and dense deposit disease. In this issue of the Journal, Chen et al. [8] have built upon their previous work to illustrate a potential mechanism for the observed CFH dysfunction in AAV. This follows on from previous work from the Beijing lab that demonstrated that, in AAV, the level of CFH is lower, and its function is impaired [9]. This may be mediated by disruption of the binding of membrane-bound CRP to CFH. The current study explores the role of one of the autoantigens in AAV, MPO, which was co-localized with CFH in neutrophil extracellular traps. Although not co-localized, MPO was also found in close proximity to CFH in glomeruli injured by AAV. To examine more closely the interaction between MPO and CFH, the authors used ELISA and surface plasmon resonance to ascertain that the two proteins bind very tightly to each other, with the short consensus repeats (SCR) 1–4 domain of CFH being the main determinant of this. This led the investigators to assess the impact of MPO binding on the ability of CFH to perform its normal role of damping down the alternative complement pathway. Using both fluid-phase and membrane-bound C3b binding as the readout, MPO inhibited CFH function, resulting in reduction of its decay accelerating activity. Interestingly, MPO had no effect on CFH-mediated protection from complement-induced red cell lysis, suggesting that the principal effect is on production of soluble inflammatory mediators such as C3a and C5a, rather than through the membrane attack complex. This is consistent with current hypotheses regarding the role of these mediators in AAV, particularly of C5a. The current work serves to add to the complexity of an already complex system, and raises some important questions. Firstly, although MPO is an autoantigen in AAV, release of MPO from neutrophils and monocytes occurs in many inflammatory diseases, and is not currently considered the principal mechanism by which these cells induce endothelial injury in AAV. Secondly, if the MPO autoantigen itself is proposed as a key regulator of the immune response, it raises the question as to what effect autoantibodies to this antigen (ANCA) have on the observed features, which were studied in an anti-MPO free system. Enzymatic MPO has many effects on the immune response. For example, MPO can perpetuate inflammation by activating macrophages and MPO-deficient mice are protected from experimental glomerulonephritis [10]. Additionally, enzymatically active MPO is required for the observed reduction by MPO-ANCA of anti-inflammatory IL10 and IL6 from monocytes, which occurs through its oxidation of phospholipids [11]. It is not clear whether these many enzymatic effects of MPO were required for the observed effect on CFH, or indeed whether they arose as a result of simple electrostatic interaction between CFH and MPO. In this respect, it would be interesting to compare the impact of a different highly cationic protein (rather than the gelatin that was used as the control). The source of the CFH used in the current work is not clear; presumably it was purified from donor plasma as in their previous work, raising an issue of how many donors were used, and whether known CFH polymorphisms may have exerted differential effects. It would also be fascinating to consider why quantitative and functional deficiency of CFH is associated with an AAV phenotype, as opposed to a thrombotic microangiopathic phenotype observed with other disorders associated with CFH dysfunction. On this note, when thrombotic microangiopathy does occur in AAV it is associated with worse histopathological characteristics and clinical outcome. As AAV therapeutics take brave steps into the complement field, with recent completion of a phase 2 trial of a C5aR antagonist, mechanistic work that seeks to understand in detail how the complement system leads to AAV pathology is welcome. We propose that the key question to be addressed now is whether the influence of MPO on CFH function is specific to AAV. For example, factor H levels are tightly associated with glomerular filtration rate [8]. Are at least some of the observed characteristics merely a manifestation of illness, of impaired kidney function in the context of an inflammatory state? Future studies must include adequate disease controls, including those with similar non-ANCA-mediated multi-system autoimmune disorders characterized by kidney dysfunction (such as anti-GBM disease), and those receiving immunosuppressive medication. Future work should also examine whether the observed CFH dysfunction occurs in PR3 ANCA vasculitis. This is a call that must be answered by other research groups around the world as this is rarely encountered in China. Acknowledgement M.A.L. was funded by the Meath Foundation, grant number 205229. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Xiao H , Schreiber A , Heeringa P , Falk RJ , Jennette JC. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies . Am J Pathol 2007 ; 170 : 52 – 64 . Google Scholar CrossRef Search ADS PubMed 2 Huugen D, , van Esch A, , Xiao H et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice . Kidney Int 2007 ; 71 : 646 – 54 . Google Scholar CrossRef Search ADS PubMed 3 Xing GQ , Chen M , Liu G et al. Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis . J Clin Immunol 2009 ; 29 : 282 – 91 . Google Scholar CrossRef Search ADS PubMed 4 Hilhorst M , van Paassen P , van Rie H et al. Complement in ANCA-associated glomerulonephritis . Nephrol Dial Transplant 2017 ; 32 : 1302 – 13 . Google Scholar CrossRef Search ADS PubMed 5 Gou SJ , Yuan J , Wang C , Zhao MH , Chen M. Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN . Clin J Am Soc Nephrol 2013 ; 8 : 1884 – 91 . Google Scholar CrossRef Search ADS PubMed 6 Cheng L , Gou SJ , Qiu HY , Ma L , Fu P. Complement regulatory proteins in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis . Clin Exp Immunol 2018 ; 191 : 116 – 24 . Google Scholar CrossRef Search ADS PubMed 7 Parente R , Clark SJ , Inforzato A , Day AJ. Complement factor H in host defense and immune evasion . Cell Mol Life Sci 2017 ; 74 : 1605 – 24 . Google Scholar CrossRef Search ADS PubMed 8 Chen S-F , Wang F-M , Li Z-Y et al. Myeloperoxidase influences the complement regulatory activity of complement factor H . Rheumatology 2018 ; doi:10.1093/rheumatology/kex529. 9 Chen SF, , Wang FM, , Li ZY et al. Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis . Arthritis Res Ther 2015 ; 17 : 129 . Google Scholar CrossRef Search ADS PubMed 10 Odobasic D , Kitching AR , Semple TJ , Holdsworth SR. Endogenous myeloperoxidase promotes neutrophil-mediated renal injury, but attenuates T cell immunity inducing crescentic glomerulonephritis . J Am Soc Nephrol 2007 ; 18 : 760 – 70 . Google Scholar CrossRef Search ADS PubMed 11 Popat RJ, , Hakki S, , Thakker A et al. Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development . JCI Insight 2017 ; 2 : e87379 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

RheumatologyOxford University Press

Published: May 10, 2018

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