PT  - JOURNAL ARTICLE
AU  - Britta Hoechsmann
AU  - Yoshiko Murakami
AU  - Makiko Osato
AU  - Alexej Knaus
AU  - Michi Kawamoto
AU  - Norimitsu Inoue
AU  - Tetsuya Hirata
AU  - Shogo Murata
AU  - Markus Anliker
AU  - Thomas Eggerman
AU  - Marten Jaeger
AU  - Ricarda Floettmann
AU  - Alexander Hoellein
AU  - Sho Murase
AU  - Yasutaka Ueda
AU  - Jun-ichi Nishimura
AU  - Yuzuru Kanakura
AU  - Nobuo Kohara
AU  - Hubert Schrezenmeier
AU  - Peter M. Krawitz
AU  - Taroh Kinoshita
TI  - Complement- and inflammasome-mediated autoinflammation-paroxysmal nocturnal hemoglobinuria
AID  - 10.1101/635573
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 635573
4099  - http://biorxiv.org/content/early/2019/05/13/635573.short
4100  - http://biorxiv.org/content/early/2019/05/13/635573.full
AB  - Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by complement-mediated hemolysis and thrombosis, and bone marrow failure. Affected cells harbor somatic mutation in X-linked PIGA gene, essential for the initial step in glycosylphosphatidylinositol (GPI) biosynthesis. Loss of GPI biosynthesis results in defective cell-surface expression of GPI-anchored complement regulators CD59 and DAF. The affected stem cells generate many abnormal blood cells after clonal expansion, which occurs under bone marrow failure. Here, we report the mechanistic basis of a disease entity, autoinflammation-paroxysmal nocturnal hemoglobinuria (AIF-PNH), caused by germline mutation plus somatic loss of PIGT on chromosome 20q. A region containing maternally imprinted genes implicated in clonal expansion in 20q-myeloproliferative syndromes was lost together with normal PIGT from paternal chromosome 20. Taking these findings together with a lack of bone marrow failure, the mechanisms of clonal expansion in AIF-PNH appear to differ from those in PNH. AIF-PNH is characterized by intravascular hemolysis and recurrent autoinflammation, such as urticaria, arthralgia, fever and aseptic meningitis. Consistent with PIGT’s essential role in synthesized GPI’s attachment to precursor proteins, non-protein-linked free GPIs appeared on the surface of PIGT-defective cells. PIGT-defective THP-1 cells accumulated higher levels of C3 fragments and C5b-9 complexes, and secreted more IL-1β than PIGA-defective cells after activation of the complement alternative pathway. IL-1β secretion was dependent upon C5b-9 complexes, accounting for the effectiveness of the anti-C5 drug eculizumab for both intravascular hemolysis and autoinflammation. These results suggest that free GPIs enhance complement activation and inflammasome-mediated IL-1β secretion.