Intravascular hemolytic crisis (IVH) triggered by infection and inflammation is a classical clinical feature of Paroxysmal Nocturnal Hemoglobinuria (PNH) and it is an unmet clinical need of PNH patients on complement (C) inhibitors. We have confirmed in a large international study that half of patients on C inhibitors achieve a partial/minor response that impairs their quality of life; moreover, 14% of them experiences IVH triggered by inflammatory/infectious noxae, including SARS-CoV-2 infection. However, the mechanism by which infection/inflammation trigger the lysis of PNH erythrocytes (E) is still unknown. We hypothesize that fluid phase C fragments generated by the activation of Classical, Lectin and Alternative C pathway could bind PNH-E and cause bystander lysis. Alternatively, pathogens could, upon binding to PNH-E, activate C on PNH-E surface and cause their lysis. To verify these hypotheses, we will undertake in vitro studies by using normal human sera, PNH-E and bacteria (E. coli); we will define the relative contribution of each C pathway evaluating the effects of Mg ++ and MgEGTA. We will also assess whether the interaction of factor H with the pentraxin system could be involved in inflammation-triggered PNH-E lysis. The hemolytic mechanisms identified by this study could provide a rationale for more effective strategies of C inhibition aiming to improve the clinical outcome of PNH patients.
Barone, F. (2022). "A translational investigastion on unmet clinical needs in PNH" [10.25434/federica-barone_phd2022].
"A translational investigastion on unmet clinical needs in PNH"
Federica Barone
2022-01-01
Abstract
Intravascular hemolytic crisis (IVH) triggered by infection and inflammation is a classical clinical feature of Paroxysmal Nocturnal Hemoglobinuria (PNH) and it is an unmet clinical need of PNH patients on complement (C) inhibitors. We have confirmed in a large international study that half of patients on C inhibitors achieve a partial/minor response that impairs their quality of life; moreover, 14% of them experiences IVH triggered by inflammatory/infectious noxae, including SARS-CoV-2 infection. However, the mechanism by which infection/inflammation trigger the lysis of PNH erythrocytes (E) is still unknown. We hypothesize that fluid phase C fragments generated by the activation of Classical, Lectin and Alternative C pathway could bind PNH-E and cause bystander lysis. Alternatively, pathogens could, upon binding to PNH-E, activate C on PNH-E surface and cause their lysis. To verify these hypotheses, we will undertake in vitro studies by using normal human sera, PNH-E and bacteria (E. coli); we will define the relative contribution of each C pathway evaluating the effects of Mg ++ and MgEGTA. We will also assess whether the interaction of factor H with the pentraxin system could be involved in inflammation-triggered PNH-E lysis. The hemolytic mechanisms identified by this study could provide a rationale for more effective strategies of C inhibition aiming to improve the clinical outcome of PNH patients.File | Dimensione | Formato | |
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https://hdl.handle.net/11365/1222295