Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare disease that has been investigated for over one century and has revealed unique aspects of the pathogenesis and pathophysiology of a hemolytic anemia. PNH results from expansion of a clone of hematopoietic cells that, as a consequence of an in...
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F1000Research
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765720/ |
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pubmed-47657202016-03-08 Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria Luzzatto, Lucio Review Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare disease that has been investigated for over one century and has revealed unique aspects of the pathogenesis and pathophysiology of a hemolytic anemia. PNH results from expansion of a clone of hematopoietic cells that, as a consequence of an inactivating mutation of the X-linked gene PIG-A, are deficient in glycosylphosphatidylinositol (GPI)-linked proteins: since these include the surface membrane complement-regulatory proteins CD55 and CD59, the red cells arising from this clone are exquisitely sensitive to lysis by activated complement. Until a decade ago, the treatment options for PNH were either supportive treatment – often including blood transfusion, anti-thrombosis prophylaxis, and sometimes thrombolytic therapy – or allogeneic bone marrow transplantation. Since 2007, PNH has received renewed and much wider attention because a new form of treatment has become available, namely complement blockade through the anti-C5 monoclonal antibody eculizumab. This brief review focuses on two specific aspects of PNH: (1) response to eculizumab, variability of response, and how this new agent has impacted favorably on the outlook and on the quality of life of patients; and (2) with respect to pathogenesis, new evidence supports the notion that expansion of the PNH clone results from T-cell-mediated auto-immune damage to hematopoietic stem cells, with the GPI molecule as target. Indeed, GPI-specific CD8+ T cells – which have been identified in PNH patients – would spare selectively GPI-negative stem cells, thus enabling them to re-populate the marrow of a patient who would otherwise have aplastic anemia. F1000Research 2016-02-23 /pmc/articles/PMC4765720/ /pubmed/26962442 http://dx.doi.org/10.12688/f1000research.7288.1 Text en Copyright: © 2016 Luzzatto L http://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Luzzatto, Lucio |
| spellingShingle |
Luzzatto, Lucio Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| author_facet |
Luzzatto, Lucio |
| author_sort |
Luzzatto, Lucio |
| title |
Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| title_short |
Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| title_full |
Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| title_fullStr |
Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| title_full_unstemmed |
Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| title_sort |
recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria |
| description |
Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare disease that has been investigated for over one century and has revealed unique aspects of the pathogenesis and pathophysiology of a hemolytic anemia. PNH results from expansion of a clone of hematopoietic cells that, as a consequence of an inactivating mutation of the X-linked gene
PIG-A, are deficient in glycosylphosphatidylinositol (GPI)-linked proteins: since these include the surface membrane complement-regulatory proteins CD55 and CD59, the red cells arising from this clone are exquisitely sensitive to lysis by activated complement. Until a decade ago, the treatment options for PNH were either supportive treatment – often including blood transfusion, anti-thrombosis prophylaxis, and sometimes thrombolytic therapy – or allogeneic bone marrow transplantation. Since 2007, PNH has received renewed and much wider attention because a new form of treatment has become available, namely complement blockade through the anti-C5 monoclonal antibody eculizumab. This brief review focuses on two specific aspects of PNH: (1) response to eculizumab, variability of response, and how this new agent has impacted favorably on the outlook and on the quality of life of patients; and (2) with respect to pathogenesis, new evidence supports the notion that expansion of the PNH clone results from T-cell-mediated auto-immune damage to hematopoietic stem cells, with the GPI molecule as target. Indeed, GPI-specific CD8+ T cells – which have been identified in PNH patients – would spare selectively GPI-negative stem cells, thus enabling them to re-populate the marrow of a patient who would otherwise have aplastic anemia. |
| publisher |
F1000Research |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765720/ |
| _version_ |
1613542754118270976 |