Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation

Abstract

Study approval. This study was approved by the institutional review boards of Osaka University (approval number 681), University of Ulm (approval numbers 279/09 and 188/16), and University of Berlin (approval number EA2/077/12).

PNH phenotypes and their genesis

“…Through this deletion, the loss of the active copy of the two genes L3MBTL1 and SGK2 is a quite different and plausible explanation for the expansion of a PIGT ‐mutant PNH clone. Very recently, in addition to typical haemolytic features responding to eculizumab, Kinoshita’s group have also reported evidence of a chronic auto‐inflammatory syndrome in these patients (Hochsmann et al ., 2019). ‘ PIGT PNH’ can be regarded as a true novel sub‐type of PNH.…”

Paroxysmal nocturnal hemoglobinuria without GPI-anchor deficiency

“…The authors previously reported PNH patients whose GPI anchor protein deficiency was caused by germline and somatic mutations in the PIGT gene localized on chromosome 20q (16). Here, Höchsmann et al describe an additional two patients with germline and somatic mutations affecting PIGT (15). The additional two cases allowed them to recognize clinical manifestations that were distinct from Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by hemolysis, thrombosis, and bone marrow failure caused by defective expression of glycosylphosphatidylinositol-anchored (GPI-anchored) complement inhibitors.…”

“…ric staining using T5 mAb (recognizes free GPI, but not protein-bound GPI), fluorescence-labeled nonlytic aerolysin (FLAER) (recognizes protein-bound GPI), and antibodies to individual GPI-anchored proteins (i.e., CD59) (19). Blood cells from PIGT-PNH patients stained positive for anti-T5 but negative for FLAER and anti-CD59; blood cells from PIGA-PNH patients were negative for all three (anti-T5, FLAER, and anti-CD59), and normal human blood cells stained positive for all three (15).…”

“…In some cases, mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), such as JAK2V617F and CALR, have also been found in PNH patients, which may explain how some patients without a history of acquired aplastic anemia develop PNH (12)(13)(14). In this issue, Höchsmann et al present an elegant study investigating the pathogenic mechanism of an extremely rare subtype of paroxysmal hemoglobinuria, PNH, which is caused by mutations affecting PIGT rather than PIGA (15).…”

Das Komplementsystem: von den Grundlagen zur klinischen Bedeutung

“…Aufgrund der C3-abhängigen extravaskulären Hämolyse, die durch C5-Inhibitoren nicht [53]. In einer kürzlich identifizierten Subgruppe von PNH-Patienten bewirken Mutationen im PIGT-Gen durch eine Lektinwegaktivierung mit vermehrter C5b-9-Ablagerung, verbunden mit einer erhöhten IL-1β-Produktion durch Monozyten, eine Überaktvierung des Inflammasoms [54].…”