1. Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation
- Author
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Junichi Nishimura, Yuzuru Kanakura, Michi Kawamoto, Shogo Murata, Hubert Schrezenmeier, Britta Höchsmann, Marten Jäger, Yasutaka Ueda, Taroh Kinoshita, Alexander Höllein, Alexej Knaus, Tetsuya Hirata, Thomas Eggermann, Makiko Osato, Norimitsu Inoue, Ricarda Floettmann, Markus Anliker, Nobuo Kohara, Yoshiko Murakami, Sho Murase, and Peter Krawitz
- Subjects
0301 basic medicine ,Biallelic Mutation ,Male ,medicine.medical_specialty ,Glycosylphosphatidylinositols ,Inflammasomes ,THP-1 Cells ,Hemoglobinuria, Paroxysmal ,Biology ,medicine.disease_cause ,Antibodies, Monoclonal, Humanized ,Hemolysis ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Genes, X-Linked ,Internal medicine ,hemic and lymphatic diseases ,Germany ,medicine ,Leukocytes ,Humans ,Point Mutation ,Alleles ,Aged ,Inflammation ,Mutation ,Hematology ,Point mutation ,Membrane Proteins ,General Medicine ,Complement System Proteins ,Eculizumab ,Middle Aged ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Lectin pathway ,Immunology ,Paroxysmal nocturnal hemoglobinuria ,Commentary ,Female ,Genomic imprinting ,Gene Deletion ,medicine.drug - 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.
- Published
- 2018