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J Clin Invest. 2019 Dec 2;129(12):5123-5136. doi: 10.1172/JCI123501.

Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.

Author information

1
Institute of Transfusion Medicine, University of Ulm, Ulm, Germany.
2
Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service and University Hospital Ulm, Ulm, Germany.
3
Research Institute for Microbial Diseases and.
4
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
5
Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.
6
Institute for Genomic Statistics and Bioinformatics, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
7
Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan.
8
Department of Tumor Immunology, Osaka International Cancer Institute, Osaka, Japan.
9
Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.
10
Institute for Human Genetics,Medical Faculty, RWTH University Aachen, Aachen, Germany.
11
Department of Medical Genetics, Charite Hospital, University of Berlin, Berlin, Germany.
12
MLL Muenchner Leukaemielabor GmbH, Munich, Germany.

Abstract

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients' leukocytes and of PIGT-KO THP-1 cells we show that, through increased IL-1β secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.

KEYWORDS:

Complement; Glycobiology; Hematology; Inflammation

PMID:
31430258
PMCID:
PMC6877298
[Available on 2020-03-02]
DOI:
10.1172/JCI123501
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