Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy

Kurolap, Alina; Eshach-Adiv, Orly; Hershkovitz, Tova; Paperna, Tamar; Mory, Adi; Oz-Levi, Danit; Zohar, Yaniv; Mandel, Hanna; Chezar, Judith; Azoulay, David; Peleg, Sarit; Half, Elizabeth E.; Yahalom, Vered; Finkel, Lilach; Weissbrod, Omer; Geiger, Dan; Tabib, Adi; Shaoul, Ron; Magen, Daniella; Bonstein, Lilach; Mevorach, Dror; Baris, Hagit N.

doi:10.1056/nejmc1707173

Cited by 47 publications

(51 citation statements)

References 5 publications

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“…Interestingly, some patients develop thrombotic events, a clinical manifestation of many complementopathies. Patients responded well to the eculizumab treatment, with immediate effects seen in the GI protein loss clinical manifestation. However, more data need to be obtained to see if eculizumab proves to be efficacious in relieving bowel inflammation in CD55‐deficient patients.…”

Section: Monogenic Forms Of Inflammatory Bowel Diseasementioning

confidence: 97%

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Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Pázmándi

Kalinichenko

Ardy

et al. 2018

Immunological Reviews

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Summary Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.

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Section: Monogenic Forms Of Inflammatory Bowel Diseasementioning

confidence: 97%

“…Interestingly, some patients develop thrombotic events, a clinical manifestation of many complementopathies. Patients responded well to the eculizumab treatment,170 with immediate effects seen in the GI protein loss clinical manifestation.…”

mentioning

confidence: 94%

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Pázmándi

Kalinichenko

Ardy

et al. 2018

Immunological Reviews

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“…DAF/CD55 (Decay Accelerating Factor: DAF), ein weitgehend auf hämatopoetischen, stromalen, endothelialen und epithelialen Zellen exprimierter Komplementregulator [55,56], schützt Wirtszellen vor einer Komplementattacke durch Beschleunigung des Zerfalls der C3-und C5-Konvertasen des klassischen und alternativen Wegs [15]. Kürzlich wurde ein homozygoter Defekt des CD55-Gens als molekulare Ursache eines seltenen autosomal-rezessiven Syndroms identifiziert, das durch Komplementhyperaktivierung, angiopathische Thrombose und früh einsetzende Proteinverlustenteropathie (Complement Hyperactivation, angiopathic Thrombosis, and early-onset Protein-losing Enteropathy: CHAPLE-Syndrom) gekennzeichnet ist [13,14]. Die Enteropathie mit Proteinverlust ist wahrscheinlich auf eine primäre Lymphangiektasie zurückzuführen und bei einigen Patienten mit einer Schleimhautentzündung verbunden.…”

Section: Chaple-syndromunclassified

“…Die bei den Patienten fehlende CD55-Proteinexpression führt zu einer verstärkten Ablagerung von C3d und C5b-9 auf peripheren Blutleukozyten bzw. submukosalen Arteriolen [13,14]. Dass die Komplementaktivierung einen signifikanten Beitrag zur Pathogenese der Erkrankung leistet, zeigt eine Off-Label-Behandlung von CD55-defizienten Patienten mit Eculizumab, die zu einer deutlichen Verbesserung der klinischen Symptome führte [13].…”

Section: Chaple-syndromunclassified

Das Komplementsystem: von den Grundlagen zur klinischen Bedeutung

Schröder‐Braunstein

Kirschfink

2020

Transfusionsmedizin - Immunhämatologie, Hämotherapie, Immungene

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ZusammenfassungAls Teil der unspezifischen Abwehr ist das Komplementsystem jederzeit verfügbar und somit bereits in der Frühphase von Infektionen von unschätzbarem Wert, bevor nach Bereitstellung spezifischer Antikörper und T-Zellen das adaptive Immunsystem zielgerichtet seine volle Wirkung entfaltet. Aufgrund seiner Rolle in der Pathophysiologie verschiedener Krankheitsbilder besitzt das Komplement eine besondere Bedeutung für die Klinik. Sowohl für die Aufklärung von Komplementdefekten und -fehlregulationen als auch zur Früherkennung lebensbedrohlicher Prozesse, wie z. B. der Entwicklung eines Multiorganversagens nach schwerem Trauma, Verbrennungen oder Sepsis sowie zur Einschätzung der Wirksamkeit neuer Therapieansätze, ist eine moderne Komplementdiagnostik heutzutage unabdingbar. Mit diesem Übersichtsartikel wollen wir einen Bogen spannen von den Grundlagen des Komplementsystems über dessen klinische Relevanz und diagnostische Maßnahmen bis hin zu aktuellen Möglichkeiten einer zielgerichteten Therapie.

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“…The causality that this cellular phenotype is caused by loss of CD55 is established by either genetic reconstitution of T cells with the wildtype CD55 or treatment by a monoclonal antibody directed against complement C5, eculizumab, in vitro. The gastrointestinal biopsies of CHAPLE patients demonstrate an increased deposition of complement by‐products in the gut, providing an in vivo evidence of complement hyperactivation Therapeutic use of eculizumab provides a dramatic clinical relief to the patients (ongoing clinical trial led by the author and reference) and reverses abnormal features of CHAPLE syndrome. …”

Section: Chaple Disease: a Familial Form Of Isolated Pil Variably Asmentioning

confidence: 99%

CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease

Özen

2018

Immunological Reviews

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Summary Primary intestinal lymphangiectasia (PIL) or Waldmann's disease was described in 1961 as an important cause of protein‐losing enteropathy (PLE). PIL can be the sole finding in rare individuals or occur as part of a multisystemic genetic syndrome. Although genetic etiologies of many lymphatic dysplasia syndromes associated with PIL have been identified, the pathogenesis of isolated PIL (with no associated syndromic features) remains unknown. Familial cases and occurrence at birth suggest genetic etiologies in certain cases. Recently, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (the CHAPLE syndrome) has been identified as a monogenic form of PIL. Surprisingly, loss of CD55, a key regulator of complement system leads to a predominantly gut condition. Similarly to other complement disorders, namely paroxysmal nocturnal and hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), CHAPLE disease involves pathogenic cross‐activation of the coagulation system, predisposing individuals to severe thrombosis. The observation that complement system is overly active in CHAPLE disease introduced a novel concept into the management of PLE; anti‐complement therapy. While CD55 deficiency constitutes a treatable subgroup in the larger pool of patients with isolated PIL, the etiology remains to be identified in the remaining patients with intact CD55.

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Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy

Cited by 47 publications

References 5 publications

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Das Komplementsystem: von den Grundlagen zur klinischen Bedeutung

CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann's disease

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