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Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation
Britta Höchsmann, … , Peter M. Krawitz, Taroh Kinoshita
Britta Höchsmann, … , Peter M. Krawitz, Taroh Kinoshita
Published August 20, 2019
Citation Information: J Clin Invest. 2019;129(12):5123-5136. https://doi.org/10.1172/JCI123501.
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Research Article Hematology Inflammation

Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation

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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.

Authors

Britta Höchsmann, Yoshiko Murakami, Makiko Osato, Alexej Knaus, Michi Kawamoto, Norimitsu Inoue, Tetsuya Hirata, Shogo Murata, Markus Anliker, Thomas Eggermann, Marten Jäger, Ricarda Floettmann, Alexander Höllein, Sho Murase, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Nobuo Kohara, Hubert Schrezenmeier, Peter M. Krawitz, Taroh Kinoshita

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Figure 3

Biochemical abnormalities in PIGT-defective cells.

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Biochemical abnormalities in PIGT-defective cells.
(A) Schematic represe...
(A) Schematic representation of binding specificity of T5 mAb. T5 mAb recognizes mammalian free GPI bearing GalNAc-side chain linked to the first mannose (left). T5 mAb does not bind to free GPI when Gal is attached to GalNAc (right). Man, mannose; GlcN, glucosamine; EtNP, ethanolamine phosphate; PI, phosphatidylinositol. (B) Western blotting analysis of PIGT-defective and PIGL-defective CHO cells with T5 mAb for free GPI, anti-CD59, and anti-DAF mAbs, and anti-transferrin receptor (TfR) as loading controls. (C) Flow cytometry of PIGT-defective and PIGL-defective CHO cells with T5 mAb and anti-CD59 mAb. (D) Flow cytometry of erythrocytes from J1, G1, G3, a healthy individual, and 2 patients with PIGA-PNH with T5 mAb and anti-CD59 (top panels) or anti-CD58 (bottom panels). (E) Flow cytometry of blood cells from JI, a healthy individual, and a patient with PIGA-PNH with T5 mAb and FLAER. (F) Granulocytes and monocytes from G1 and G3, and a patient with PIGA-PNH, stained by T5 mAb and FLAER. (G) Determination of the PNH clone size in J1 by qPCR analysis of the break causing 18 Mbp deletion. (Left) Threshold cycle in PCR for the break and exon 3 of PIGL as a reference. #1, DNA from whole blood leukocytes taken in a stage with autoinflammation only (4 months before the onset of recurrent hemolysis); #2, DNA from granulocytes (29% of cells were GPI-AP–defective) taken 1 month after start of eculizumab therapy. (Right) Relative levels of the break in samples #1 and #2 by setting the level in #2 as 1. Data are shown in mean of triplicate samples in 1 experiment. Mean RQ max values for #1 and #2 samples were 0.092 and 1.11, respectively.

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