CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis

Özen, Ahmet; Comrie, William A.; Ardy, Rico Chandra; Conde, Cecilia Domínguez; Dalgıç, Buket; Beşer, Ömer Faruk; Morawski, Aaron; Karakoç-Aydıner, Elif; Tutar, Engin; Barış, Safa; Özçay, Figen; Serwas, Nina K.; Zhang, Yu; Matthews, Helen; Pittaluga, Stefania; Folio, Les; Aksu, Aysel Ünlüsoy; McElwee, Joshua; Krolo, Ana; Kıykım, Ayça; Barış, Zeren; Gülşan, Meltem; Öğülür, İsmail; Snapper, Scott B.; Houwen, Roderick H. J.; Leavis, Helen L.; Ertem, Deniz; Kain, Renate; Sarı, Sinan; Erkan, Tülay; Su, Helen C.; Boztuğ, Kaan; Lenardo, Michael J.

doi:10.1056/nejmoa1615887

Cited by 152 publications

(147 citation statements)

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“…Hypoalbuminemia appears to be the most common finding in CHAPLE disease, which can be quite profound (serum values below 1 g/dl are possible). Patients may present to emergency care due to incapacitating pain, abdominal tenderness, and gastrointestinal discomfort, often correlating with the worsening hypoalbuminemia, which is often relieved by albumin infusion temporarily . The symptoms mimicking acute abdomen or abdominal mass are common, which is in line with previous reports of IL cases …”

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

confidence: 84%

“…CHAPLE disease (OMIM# 226300) is an autosomal recessive disorder caused by loss of function mutations in CD55 (also known as decay accelerating factor, DAF) . The cardinal features of CHAPLE disease include:…”

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

confidence: 99%

“…The discovery of CHAPLE syndrome has opened a new avenue in the management of these individuals. In vitro data has demonstrated that the complement‐inhibitory monoclonal antibody, eculizumab, can reverse dysregulated complement activation in the patient cells, which encouraged clinical use of this drug in the patients . Kurolap et al's report on three cases from a large kindred with six affected individuals and the preliminary results of an ongoing trial led by the author (being prepared for publication) reveals that eculizumab has a significant impact in the treatment of CHAPLE disease.…”

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

confidence: 99%

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

confidence: 84%

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

confidence: 99%

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

confidence: 99%

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

Özen

2018

Immunological Reviews

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“…118 Most patients present in the first 2 years of life with PLE due to primary intestinal lymphangiectasia, abdominal pain, thromboembolic disease, recurrent infections, and various degrees of bowel inflammation. Mutations in the gene encoding CD55, a complement regulator, lead to hyperactivation of complement.…”

Section: Immune Dysregulation-associated Enteropathiesmentioning

confidence: 99%

Advances in Evaluation of Chronic Diarrhea in Infants

et al. 2018

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Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

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“…Factor H (FH) is an abundant plasma protein that prevents formation of and dissociates converteases via decay accelerating activity and cofactor activity (Fig 1B). Absence of these normal regulators of the AP are the cause of a number of human diseases, including atypical hemolytic uremic syndrome (aHUS) 1–6 , C3 glomerulopathies (C3GN) 1–6 , age-related macular degeneration (AMD) 7–11 and protein-losing enteropathy 12 .…”

Section: Introductionmentioning

confidence: 99%

Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse

Triebwasser

Bertram

et al. 2018

American J Rep Immunol

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ProblemCrry is a widely expressed type 1 transmembrane complement regulatory protein in rodents which protects self‐tissue by downregulating C3 activation. Crry −/− concepti produced by Crry +/− × Crry +/− matings are attacked by maternal complement system leading to loss before day 10. The membrane attack complex is not the mediator of this death. We hypothesized that the ability of C3b to engage the alternative pathway's feedback loop relatively unchecked on placental membranes induces the lesion yielding the demise of the Crry−/− mouse.Method of StudyWe investigated the basis of Crry −/− conceptus demise by depleting maternal complement with cobra venom factor and blocking antibodies. We monitored their effects primarily by genotyping and histologic analyses.ResultsWe narrowed the critical period of the complement effect from 6.5 to 8.5 days post‐coitus (dpc), which is immediately after the conceptus is exposed to maternal blood. Deposition by 5.5 dpc of maternal C3b on the placental vasculature lacking Crry−/− yielded loss of the conceptus by 8.5 dpc. Fusion of the allantois to the chorion during placental assembly did not occur, fetal vessels originating in the allantois did not infiltrate the chorioallantoic placenta, the chorionic plate failed to develop, and the labyrinthine component of the placenta did not mature.ConclusionOur data are most consistent with the deposition of C3b being responsible for the failure of the allantois to fuse to the chorion leading to subsequent conceptus demise.

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CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis

Cited by 152 publications

References 40 publications

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

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

Advances in Evaluation of Chronic Diarrhea in Infants

Timing and mechanism of conceptus demise in a complement regulatory membrane protein deficient mouse

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