Differential activation mechanisms of serum C5a in lupus nephritis and neuropsychiatric systemic lupus erythematosus

Sakuma, Yu; Nagai, Tatsuo; Yoshio, Taku; Hirohata, Shunsei

doi:10.1080/14397595.2016.1193965

Cited by 19 publications

(10 citation statements)

References 35 publications

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“…Plasma C5a levels are elevated in patients with systemic lupus erythematosus (22) and rheumatoid arthritis (23). The cancer promotion by the Arthus reaction observed in this study suggests that acceleration of cancer progression may occur via elevated C5a level in patients with an autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that the C5a-C5aR system promotes human cancer. C5a enhances cancer cell activities in a concentration-dependent manner (12) and the plasma C5a level was elevated in patients with autoimmune diseases, such as systemic lupus erythematosus (22) or rheumatoid arthritis (23). Accordingly, cancer promotion by the C5a-C5aR system may be exaggerated in autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of cancer invasion and growth via the C5a‑C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion

et al. 2018

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Autoimmune diseases are caused by immune complex-induced activation of the complement system and subsequent inflammation. Recent studies have revealed an association between autoimmune diseases and worse survival in patients with cancer; however, the underlying mechanism is still unknown. The C5a-C5a receptor (C5aR) system has been shown to enhance cancer activity and recruit myeloid-derived suppressor cells (MDSCs) that suppress the anti-tumor immune response. The Arthus reaction is inflammation caused by complement system activation by the immune complex and thus is a model of autoimmune diseases. To explore the effect of the Arthus reaction on cancer progression, mouse cancer cells were inoculated in syngeneic mouse skin, where the Arthus reaction was induced simultaneously. The Arthus reaction enhanced invasion and tumor growth of C5aR-positive cancer cells, but not control cells, and induced MDSC recruitment. Intravenous injection of C5a-stimulated C5aR-positive cancer cells into nude mice resulted in more lung nodules than injection of nontreated C5aR-positive cells and C5a-stimulated C5aR-negative cells, supporting C5a-C5aR-mediated enhancement of cancer growth. C5aR expression in uterine cervical carcinoma stage I cells, which invade into the deeper tissues, was significantly higher than that in CIN3 cells, which remain in the epithelium. These results indicate that cancer promotion by the C5a-C5aR system may underlie poor prognosis in cancer patients with autoimmune diseases, particularly in patients with C5aR-positive cancer, and may be associated with cervical cancer invasion. The enhancement of cancer cell invasion and growth by the C5a-C5aR system suggests that this system is a possible target of cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancement of cancer invasion and growth via the C5a‑C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion

et al. 2018

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“…However, once the disease is triggered and immune complexes are insufficiently cleared, their deposition in tissue leads to local complement activation, mainly driven by terminal complement components, indicated by decreased systemic levels of C3 and C4, suggesting high inflammatory activity and tissue damage (69)(70)(71)(72)(73). Furthermore, complement has been shown to contribute to the disease by increased C3aR and C5aR activity (74,75), and elevated C5a levels (76). State-ofthe-art clinical management of lupus nephritis consists of nonselective immunosuppressive treatment with corticosteroids (68).…”

Section: Lupus Nephritismentioning

confidence: 99%

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

et al. 2020

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The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

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“…In der Immunpathologie des SLE spielt die Komplementaktivierung eine wesentliche Rolle. Eine Erhöhung der Serumspiegel von C5a (Anaphylatoxin) wurde bei Patienten mit Lupusnephritis und neuropsychiatrischen Lupus beschrieben [45]. Eculizumab ist eine monoklonaler Anti-C5-Antikörper, der die Spaltung von C5 in C5a verhindert.…”

Section: B-zell-hyperaktivitätunclassified

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

Hiepe

2020

Aktuelle Rheumatologie

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ZusammenfassungAutoantikörper sind essentiell in der Pathogenese des SLE. Sie sind das Ergebnis einer Störung des erworbenen (adaptiven) Immunsystems mit fehlender Toleranz gegen Selbst. Eine Typ-I Interferon-Signatur, die im angeborenen (innaten) Immunsystem ihren Ursprung hat, ist ein wesentlicher Treiber dieser Störung. Autoantikörper können sowohl von kurzlebigen, proliferierenden Plasmablasten, die B-Zell-Hyperaktivität widerspiegeln, als auch von langlebigen, nicht-proliferierenden Gedächtnis-Plasmazellen sezerniert werden. Gedächtnis-Plasmazellen, die in Nischen im Knochenmark und im entzündeten Gewebe lokalisiert sind, lassen sich nicht durch konventionelle Immunsuppressiva und Therapien mit B-Zellen als Target eliminieren. Konzepte, die auf die Depletion von Gedächtnis-Plasmazellen abzielen, können im Zusammenspiel mit Targets, die eine Aktivierung von autoreaktiven B-Zellen verhindern, ein kuratives Potenzial haben.

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Differential activation mechanisms of serum C5a in lupus nephritis and neuropsychiatric systemic lupus erythematosus

Abstract: These results disclosed that serum C5a was elevated not only in NPSLE but also in LN through different mechanisms. Moreover, it is suggested that C5a might be consumed during BBB damages.

Cited by 19 publications

References 35 publications

Enhancement of cancer invasion and growth via the C5a‑C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion

Enhancement of cancer invasion and growth via the C5a‑C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

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