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• W2794274329 abstract "Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease: therefore, Jaroslaw Maciejewski's team must be congratulated on collating longitudinal clinical and haematological data on 70 patients with PNH (Bat et al, 2017) – a significant feat. The Authors regard the notion of a clonal population of PNH cells evading damage to haematopoietic stem cells (HSCs) as key to explaining some of their findings. We felt gratified not only because this notion was formulated together with our dear late colleague Bruno Rotoli, as long ago as 1989 (Rotoli & Luzzatto, 1989a,b), but also because it seems to have now gained such wide acceptance as to be taken for granted. In essence, we hypothesized that whatever causes damage to HSCs in aplastic anaemia (AA) spares those stem cells that lack glycosyl-phosphatidyl-inositol(GPI)-linked proteins: hence the conditional growth advantage of the PNH clone. Thus, this escape, as we originally called it, or evasion, is not a trivial process: it can only operate if the damage is GPI-specific. Now there is evidence that CD1d-restricted GPI-specific T cells are indeed present not only in PNH (Gargiulo et al, 2013), but also in the majority of AA patients (Gargiulo et al, 2017). The work reported by Bat et al (2017) brings into focus the implications of the escape model with respect to the immunosuppressive treatment (IST) of AA, which aims to counter a T cell-mediated auto-immune attack on HSCs. If, in the majority of cases of AA, the target of this attack is GPI (Gargiulo et al, 2017), we can presume that the outcome will depend essentially, in each individual patient, on three important elements: (i) the number and the fitness of surviving HSCs when IST is started, (ii) whether there is at least one bona fide HSC with a PIGA mutation, and (iii) the efficacy of IST in abating the auto-immune process in that particular patient. We cannot discuss here all possible combinations, but several examples are well represented in this patient series. (A) If there are surviving HSCs and IST is highly effective, the patient will recover without PNH, whether or not a PIGA mutant HSC is present, because the condition conferring a growth advantage to the PNH clone no longer exists. (B) If the treatment is not effective, or if it is effective but there are no surviving HSCs except a PIGA-mutant HSC, its progeny will grow and the PNH clone will expand to give clinical PNH. (C) If the treatment is only partially effective or not effective or there are no surviving HSCs and there is no PIGA-mutant HSC, the patient will continue to have AA (and would need HSC transplantation if at all possible). In addition, some specific findings detailed by Bat et al (2017) support the escape model. First, when IST includes anti-thymocyte globulin (ATG), it is in general more effective: indeed, they observed that, after ATG, AA is less likely to be followed by PNH (see A above). Second, cases of AA who have GPI-negative granulocytes on presentation must already have a PIGA mutation, hence the subsequent expansion (see B above). Third, patients developing PNH have higher neutrophil and platelet counts, as though an expanding PIGA-mutant clone that has escaped damage can do better than the original HSCs struggling to recover from damage. The most significant clinical correlate of this finding is the much better survival of PNH patients versus AA patients over a period of some 20 years since diagnosis (fig. S1B in Bat et al, 2017): validating the notion that PNH is ‘a blessing in disguise’ (Luzzatto et al, 1997). In the case of PNH, the escape model is based on GPI being the target: but it appears that the same model may be applicable also to a subset of AA patients who have lost one human leucocyte antigen (HLA) allele either by deletion, i.e. loss of heterozygosity across the HLA locus on chromosome 6p (Afable et al, 2011; Katagiri et al, 2011), or by specific mutations within HLA-B (Zaimoku et al, 2017), which might be the target of major histocompatibility complex-restricted (rather than CD1d-restricted) auto-reactive T cells. Thus, the escape model appears to be versatile: its only uncompromising essence is a binomial combination of (i) a somatic mutation altering a molecule targeted by an auto-immune process and (ii) somatic cell selection favouring the mutant cells. Both authors have jointly conceived, written and reviewed this letter, and have agreed on the final text." @default.
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• W2794274329 date "2018-01-24" @default.
• W2794274329 modified "2023-10-12" @default.
• W2794274329 title "The “escape” model: a versatile mechanism for clonal expansion" @default.
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• W2794274329 doi "https://doi.org/10.1111/bjh.15111" @default.
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