GPI-defective monocytes from paroxysmal nocturnal hemoglobinuria patients show impaired in vitro dendritic cell differentiation

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic disorder characterized by a phosphatidylinositol (PI) glycan-A gene mutation, which impairs the synthesis of the glycosyl-PI (GPI) anchor, thus causing the absence of all GPI-linked proteins on the membrane of the clonal-defective cells. The presence of a consistent GPI-defective monocyte compartment is a common feature in PNH patients. To investigate the functional behavior of this population, we analyzed its in vitro differentiation ability toward functional dendritic cells (DCs). Our data indicate that GPI-defective monocytes from PNH patients are unable to undergo full DC differentiation in vitro after granulocyte macrophage-colony stimulating factor and recombinant interleukin (IL)-4 treatment. In this context, the GPI-defective DC population shows mannose receptor expression, high levels of the CD86 molecule, and impaired CD1a up-regulation. The analysis of lipopolysaccharide and CD40-dependent, functional pathways in these DCs revealed a strong decrease in tumor necrosis factor alpha and IL-12 production. Finally, GPI-defective DCs showed a severe impairment in delivering accessory signals for T cell receptor-dependent T cell proliferation.

T cells from paroxysmal nocturnal haemoglobinuria (PNH) patients show an altered CD40-dependent pathway

“…In this regard, the inability of healthy donor monocytes to overcome such impairment strongly supports the occurrence of some defects in the TCR-dependent activation machinery of the GPI-defective T lymphocytes. These data confirm and extend previous reports showing severe dysregulation of the immune system in a pig-a -/Rag Ϫ/Ϫ chimeric murine model [46], impaired lectin-triggered proliferation [31][32][33]35], TCR-dependent signaling in GPI -T cells [36] and defects of the monocyte/granulocyte GPI-defective subsets [47,48] in PNH patients. The divergence with the competence of the GPI-defective T lymphocyte population referred to by Takahama et al [30] could be a result of the inability of the Cre P-lox approach to mimic the PNH pathophysiology [9,13,14].…”

CD157 plays a pivotal role in neutrophil transendothelial migration

“…Indeed, PNH monocytes undergo impaired differentiation to dendritic cells and display severe defects in delivering accessory signals for T-cell receptor-dependent T-cell proliferation. 41 The absence of inhibition of neutrophil adhesion to endothelial cells following ligation of CD157 with specific mAbs and the efficient adhesion of neutrophils from PNH patients suggest that CD157 does not play an obvious role in this interaction. However, the possibility that the redundant involvement of other receptorligand pairs hides a role of CD157 in the adhesion process cannot be ruled out.…”

Biomimetic proteolipid vesicles for reverting GPI deficiency in paroxysmal nocturnal hemoglobinuria

“…However, several studies have described impairment in lymphocyte and monocyte functions in PNH patients, such as increased exhaustion of effector memory CD8 + T cells and ineffective dendritic cell maturation of GPI-deficient monocytes after in vitro stimulation. 32 , 33 Moreover, granulocytes also display dysregulated functions, such as impaired migration abilities, higher pro-inflammatory activities, and likely an increased susceptibility to release granules. 34 Therefore, hemolysis and thrombosis might be only the tip of the iceberg, as impaired immune responses could concur to increase the risk of life-threating infections during complement inhibition therapy, as cells are not lysed while their functions might still be altered.…”