Insights Into the Emergence of Paroxysmal Nocturnal Hemoglobinuria.

Melissa A Colden,Sushant Kumar,Bolormaa Munkhbileg,Daria V Babushok

doi:10.3389/fimmu.2021.830172

Abstract

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disease as simple as it is complex. PNH patients develop somatic loss-of-function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A gene (PIGA), required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. Ubiquitous in eukaryotes, GPI anchors are a group of conserved glycolipid molecules responsible for attaching nearly 150 distinct proteins to the surface of cell membranes. The loss of two GPI-anchored surface proteins, CD55 and CD59, from red blood cells causes unregulated complement activation and hemolysis in classical PNH disease. In PNH patients, PIGA-mutant, GPI (-) hematopoietic cells clonally expand to make up a large portion of patients’ blood production, yet mechanisms leading to clonal expansion of GPI (-) cells remain enigmatic. Historical models of PNH in mice and the more recent PNH model in rhesus macaques showed that GPI (-) cells reconstitute near-normal hematopoiesis but have no intrinsic growth advantage and do not clonally expand over time. Landmark studies identified several potential mechanisms which can promote PNH clonal expansion. However, to what extent these contribute to PNH cell selection in patients continues to be a matter of active debate. Recent advancements in disease models and immunologic technologies, together with the growing understanding of autoimmune marrow failure, offer new opportunities to evaluate the mechanisms of clonal expansion in PNH. Here, we critically review published data on PNH cell biology and clonal expansion and highlight limitations and opportunities to further our understanding of the emergence of PNH clones.

Highlights

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening blood disease characterized by hemolysis, propensity for blood clotting, and bone marrow failure [1]
In most PNH patients, GPI-anchor deficiency is caused by somatic mutations in phosphatidylinositol glycan anchor biosynthesis class A (PIGA), an X-linked gene required for GPI anchor biosynthesis [4,5,6] (Figure 1)
PIGA mutations occur in early hematopoiesis, and subsequent clonal expansion of PIGAmutant cells lacking GPI-anchored proteins (GPI-APs) leads to clinical PNH disease

Summary

INTRODUCTION

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening blood disease characterized by hemolysis, propensity for blood clotting, and bone marrow failure [1]. PIGA mutations occur in early hematopoiesis, and subsequent clonal expansion of PIGAmutant cells lacking GPI-anchored proteins (GPI-APs) leads to clinical PNH disease. A schematic diagram illustrating the relationship between immune-mediated bone marrow failure (acquired aplastic anemia) and clonal expansion of HSPCs with somatic mutations in the PIGA gene (PNH HSPCs). Mice that escaped embryonal recombination had almost 100% of red cells with partial deficiency of GPI-anchored proteins, and intermediate sensitivity to complement, resembling type II PNH cells. While the early mouse models of PNH were mired by difficulties in achieving complete Piga loss in hematopoietic cells, the ability to track GPI (-) cell populations by flow cytometry allowed studies of competitive advantage in animals mosaic for Piga loss. GPI (-) T cells are competent in response to protein antigens, but have increased proliferation in response

Findings

Main Findings

DISCUSSION

42. Abstract