The complex pathophysiology of acquired aplastic anaemia

Abstract

Immune-mediated destruction of haematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired aplastic anaemia (aAA). Dysregulated CD8(+) cytotoxic T cells, CD4(+) T cells including T helper type 1 (Th1), Th2, regulatory T cells and Th17 cells, natural killer (NK) cells and NK T cells, along with the abnormal production of cytokines including interferon (IFN)-γ, tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β, induce apoptosis of HSPCs, constituting a consistent and defining feature of severe aAA. Alterations in the polymorphisms of TGF-β, IFN-γ and TNF-α genes, as well as certain human leucocyte antigen (HLA) alleles, may account for the propensity to immune-mediated killing of HSPCs and/or ineffective haematopoiesis. Although the inciting autoantigens remain elusive, autoantibodies are often detected in the serum. In addition, recent studies provide genetic and molecular evidence that intrinsic and/or secondary deficits in HSPCs and bone marrow mesenchymal stem cells may underlie the development of bone marrow failure.

Keywords: aplastic anemia; bone marrow mesenchymal stem cell; hematopoietic stem/progenitor cell, immune dysregulation.

Fig 1

Immune-mediated destruction of haematopoietic stem/progenitor cells. Following exposure to environmental insults, patients with acquired aplastic anaemia (aAA) develop aberrant immune responses that include oligoclonal expansion of T cells and abnormal production of myelosuppressive cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α, leading to apoptosis of haematopoietic stem/progenitor cells (HSPCs). Deficient regulatory T cells (T_reg), natural killer (NK) cells and mesenchymal stem cells (MSC) fail to suppress the dysregulated immune responses. Intrinsic deficits in HSPCs contribute further to the development of bone marrow failure. *Conflicting data exist.