Immune pathophysiology of acquired aplastic anaemia

Clinical observations and laboratory studies have supported an immune basis for most acquired aplastic anaemias, with the majority of patients responding to immunosuppressive therapy. In vitro, interferon (IFN) and tumour necrosis factor (TNF) inhibit haematopoiesis, including colony formation by early and late progenitor cells and the generation of long-term culture initiating cells (LTCIC). These lymphokines induce Fas antigen expression on CD34+ cells and apoptosis within the haematopoietic cell compartment. Local secretion of cytokines is far more potent than addition to long-term bone marrow cultures. Activated cytotoxic lymphocytes, high levels of INF gamma and TNF alpha, and increased Fas expression on CD34+ marrow cells are present in patients. Haematopoiesis is severely diminished in severe aplastic anaemia on presentation: CD34+ cell numbers, colony forming cells and LTCIC are all markedly decreased. LTCIC numbers do not predict recovery. Blood cell counts increase in some cases in the absence of changed numbers of LTCIC, but recovered patients have higher and sometimes normal LTCIC numbers. The mechanism by which chemical and biological agents incite altered immunity remains unclear. Drug associations have been inferred from case reports and formal epidemiological studies, but have remained refractory to systematic laboratory study. Whatever the initial events, immune system destruction of haematopoiesis plays a central role in the development of acquired aplastic anaemia.