Back to Search
Start Over
Upregulation of Checkpoint Ligand Programmed Death-Ligand 1 in Patients with Paroxysmal Nocturnal Hemoglobinuria Explained by Proximal Complement Activation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2022 Mar 01; Vol. 208 (5), pp. 1248-1258. Date of Electronic Publication: 2022 Feb 16. - Publication Year :
- 2022
-
Abstract
- Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic disease driven by impaired complement regulation. Mutations in genes encoding the enzymes that build the GPI anchors are causative, with somatic mutations in the PIG-A gene occurring most frequently. As a result, the important membrane-bound complement regulators CD55 and CD59 are missing on the affected hematopoietic stem cells and their progeny, rendering those cells vulnerable to complement attack. Immune escape mechanisms sparing affected PNH stem cells from removal are suspected in the PNH pathogenesis, but molecular mechanisms have not been elucidated. We hypothesized that exuberant complement activity in PNH results in enhanced immune checkpoint interactions, providing a molecular basis for the potential immune escape in PNH. In a series of PNH patients, we found increased expression levels of the checkpoint ligand programmed death-ligand 1 (PD-L1) on granulocytes and monocytes, as well as in the plasma of PNH patients. Mechanistically, we demonstrate that complement activation leading to the decoration of particles/cells with C3- and/or C4-opsonins increased PD-L1 expression on neutrophils and monocytes as shown for different in vitro models of classical or alternative pathway activation. We further establish in vitro that complement inhibition at the level of C3, but not C5, inhibits the alternative pathway-mediated upregulation of PD-L1 and show by means of soluble PD-L1 that this observation translates into the clinical situation when PNH patients are treated with either C3 or C5 inhibitors. Together, the presented data show that the checkpoint ligand PD-L1 is increased in PNH patients, which correlates with proximal complement activation.<br /> (Copyright © 2022 by The American Association of Immunologists, Inc.)
- Subjects :
- B7-H1 Antigen blood
CD55 Antigens genetics
CD59 Antigens genetics
Complement C3 immunology
Complement C5 immunology
Granulocytes metabolism
Hematopoietic Stem Cells cytology
Hemoglobinuria, Paroxysmal immunology
Humans
Immune Evasion immunology
Membrane Proteins genetics
Monocytes metabolism
B7-H1 Antigen metabolism
Complement Activation immunology
Complement C3 antagonists & inhibitors
Complement C5 antagonists & inhibitors
Hemoglobinuria, Paroxysmal pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 208
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 35173033
- Full Text :
- https://doi.org/10.4049/jimmunol.2100031