EBMT 2024 | Immune-mediated bone marrow failure diseases & their pathophysiology: aplastic anemia, LR-MDS & PNH

Immune-mediated bone marrow failure is a group of diseases in which there’s an immune-mediated attack to hematopoietic stem cells. According to literature, the diseases in which these mechanisms is detectable are acquired idiopathic aplastic anemia, hypocellular or low blast count or low risk MDS, and PNH. The starting point is an immune attack to the hematopoietic stem cells that, for some reasons, become recognizable by the immune systems and then further [inaudible] can develop. In case of aplastic anemia, there was a kind of activation of autoreactive T clones that generate cytokine storms that, in the end hits the hematopoietic stem cells, which gets to apoptosis, thus creating the impoverishment of cells that we see in the empty trephine biopsy of acquired aplastic anemia patients.

In the case of PNH, there was a theory which is called immune escape theory, proposed and confirmed over time by two eminent Italian pathologists, Professor Bruno [inaudible] and Professor Lucio Luzzatto, my mentor years ago in my training here in UK. By which when you have a normal marrow and you get in some hematopoietic stem cells a somatic mutation which hits the PIG-A gene, you get cells that is somehow spared by the immune attack whenever this occur. So if the immune attack hits the normal stem cells, the PIG-A mutated cells is spared. And over time, still continuing the immune attack, these PIG-A cells takes an advantage, proliferating and taking the lead of hematopoiesis. So becoming basically the predominant cells which are populating the bone marrow. So here we have an imperfect event, somatic mutation that generates faulty cells, that takes the lead and somehow generates some hematopoisis that otherwise would not have occurred. Because, I mean, in aplastic anemia we have an empty marrow. And so we have no hematopoietic stem cells.

Finally, in MDS, what are called low risk MDS or hyperplastic MDS, which are also called hypocellular MDS, we have a mutation occurring in hematopoietic stem cells that can generate a proliferative advantage. This may trigger an immune attack reaction that in turn may increase the mutation load, giving further proliferative advantage and so the expansion of the MDS clone. In other cases, the mutation increases because there is a kind of, limited surveillance of the immune system that in the end generates an expansion of MDS clones.

So the bottom line is that in these three diseases, you have these immune-mediated attack to the hematopoietic stem cells. That then is modulated by modulators can either be positive or negative. That generates slightly different phenotypes. But the bottom line is that these diseases can be amenable for treatment in certain conditions with immune suppressive therapy.