Broadly effective metabolic and immune recovery with C5 inhibition in

Abstract

CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

C1 [Ozen, Ahmet; Kasap, Nurhan; Karakoc-Aydiner, Elif; Ogulur, Ismail; Baris, Safa] Marmara Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Istanbul, Turkey.

[Ozen, Ahmet; Kasap, Nurhan; Karakoc-Aydiner, Elif; Akgun, Gamze; Ogulur, Ismail; Eltan, Sevgi Bilgic; Baris, Safa] Istanbul Jeffrey Modell Diagnost Ctr Primary Immu, Istanbul, Turkey.

[Ozen, Ahmet; Kasap, Nurhan; Karakoc-Aydiner, Elif; Akgun, Gamze; Ogulur, Ismail; Eltan, Sevgi Bilgic; Baris, Safa] Isil Berat Barlan Ctr Translat Med, Istanbul, Turkey.

[Vujkovic-Cvijin, Ivan; Belkaid, Yasmine] NIAID, Metaorganism Immun Sect, Lab Immune Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.

[Apps, Richard; Cheung, Foo; Fantoni, Giovanna; Sellers, Brian; Tsang, John; Belkaid, Yasmine] Trans NIH Ctr Human Immunol Autoimmun & Inflammat, NIH, Bethesda, MD USA.

[Akkelle, Bilge; Tutar, Engin; Ertem, Deniz] Marmara Univ, Sch Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Istanbul, Turkey.

[Sari, Sinan; Dalgic, Buket] Gazi Univ, Sch Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Ankara, Turkey.

[Ozcay, Figen; Sezer, Oya Balci] Baskent Univ Hosp, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Ankara, Turkey.

[Uygun, Dilara Kocacik; Bingol, Aysen] Akdeniz Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Antalya, Turkey.

[Islek, Ali] Ataturk Univ, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Erzurum, Turkey.

[Akgun, Gamze; Eltan, Sevgi Bilgic] Marmara Univ, Dept Pediat, Div Allergy & Immunol, Minist Hlth, Istanbul, Turkey.

[Selcuk, Merve] Marmara Univ, Sch Med, Dept Pediat, Istanbul, Turkey.

[Zhang, Yu] NIAID, Human Immunol Dis Sect, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.

[Zhang, Yu; Chauvin, Samuel D.; Lenardo, Michael J.] NIAID, Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.

[Kutluk, Gunsel] Hlth Sci Univ, Kanuni Sultan Suleyman Training & Res Hosp, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Istanbul, Turkey.

[Topal, Erdem] Inonu Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Malatya, Turkey.

[Sayar, Ersin] Alanya Alaaddin Keykubat Univ, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Alanya, Turkey.

[Celikel, Cigdem] Marmara Univ, Sch Med, Dept Pathol, Istanbul, Turkey.

[Houwen, Roderick H. J.] Wilhelmina Childrens Hosp, Dept Pediat Gastroenterol, Univ Med Ctr, Utrecht, Netherlands.

[Snow, Andrew L.; Lake, Camille] Uniformed Serv Univ Hlth Sci, Dept Pharmacol & Mol Therapeut, Bethesda, MD 20814 USA.

[Alba, Camille] Uniformed Serv Univ Hlth Sci, Henry Jackson Fdn, Amer Genome Ctr, Bethesda, MD USA.

[Chauvin, Samuel D.; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.

[Chauvin, Samuel D.; Lenardo, Michael J.] NIAID, NIAID Clin Genom Program, Lab Immune Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.

[Dalgard, Clifton L.] Uniformed Serv Univ Hlth Sci, Amer Genome Ctr, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA.

[Harari, Olivier; Ni, Yan G.; Wang, Ming-Dauh; Devalaraja-Narashimha, Kishor] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA.

[Subramanian, Poorani] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.

[Ergelen, Rabia] Marmara Univ, Sch Med, Dept Radiol, Istanbul, Turkey.

[Artan, Reha] Akdeniz Univ, Sch Med, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Antalya, Turkey.

[Guner, Sukru Nail] Necmettin Erbakan Univ, Meram Med Fac, Div Pediat Allergy & Immunol, Konya, Turkey.