Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation

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


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Complement System Proteins / immunology*
  • Female
  • Gene Deletion
  • Genes, X-Linked
  • Germany
  • Glycosylphosphatidylinositols / metabolism
  • Hemoglobinuria, Paroxysmal / immunology*
  • Hemolysis / drug effects
  • Humans
  • Inflammasomes / immunology*
  • Inflammation / immunology*
  • Japan
  • Leukocytes / immunology
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation
  • Point Mutation
  • THP-1 Cells


  • Antibodies, Monoclonal, Humanized
  • Glycosylphosphatidylinositols
  • Inflammasomes
  • Membrane Proteins
  • phosphatidylinositol glycan-class A protein
  • Complement System Proteins
  • eculizumab