A way to “mimic” the pathophysiology of acquired SAA

In this issue of Blood, Ben Hamza and colleagues¹ use unique, state-of-the-art methodologies to demonstrate direct evidence of T cells from patients with acquired severe aplastic anemia (SAA) targeting antigens on hematopoietic stem cells by recognition of viral epitopes and then the subsequent antigenic mimicry of those hematopoietic progenitor cells.

Acquired aplastic anemia has long been considered an immune-mediated blood disease.² In this setting, T cell–mediated hematopoietic stem and progenitor cell destruction in patients with aplastic anemia has been inferred historically from indirect evidence of T-cell clonal expansion and activity in vitro and recovery of hematopoiesis after administration of immunosuppressive therapy in vivo. Viral precipitants to aplastic anemia etiology have also frequently been suggested.³ The study by Ben Hamza and colleagues provides elegant proof-of-concept data of the undisputed role that T cells have in aplastic anemia pathophysiology. This work provides evidence for viral targets as drivers of clonal expansion of T cells using Epstein-Barr virus (EBV) as an exemplar.

The authors demonstrate that T cells in the bone marrow of patients with aplastic anemia (in various stages of disease and treatment with immunosuppression) show oligoclonal expansion and CD8⁺ cytotoxic effector differentiation. They identified a median of 15 expanded T-cell clones per patient, of which the majority of the expanded clones were private to that patient based on single-cell amino acid sequences. They then selected multiple dominant clones for further study and determined 3 key features of these clones: (1) the dominant CD8⁺ T-cell clones can eliminate hematopoietic progenitor cells; (2) these clones persist over time without major changes in relative clone size within the lymphocyte compartment; and (3) these clones can be reactive against virus-related epitopes revealed through recognition of peptide pools from cytomegalovirus and EBV, among other common viruses. Lastly, through complex but stepwise experiments, this group used an expanded clone from an EBV⁺ patient to target CD34⁺ cells from the bone marrow of a healthy EBV⁻ donor. The patient’s expanded T-cell clones eliminated hematopoietic progenitor cells in an antigen-dependent fashion from that healthy donor. This last set of experiments strongly suggests that molecular mimicry of epitopes derived from EBV (as 1 viral example) presented on hematopoietic progenitor cells potentially contributes to immune-mediated bone marrow aplasia.

There are some limitations to the current study. The median age of 56 years for the patients studied in this cohort is old for aplastic anemia, and fewer than half of the samples are from treatment-naive patients. Given that exposure to different viruses varies with age, these data may not be generalizable to newly diagnosed younger patients, particularly pediatric patients. Additionally, the exact target populations among the CD34⁺ expanded cells is not definitely identified, and the prior immunosuppressive treatment of the individual patients at the time of marrow study may have influenced the results.

Both providers and patients seek an explanation for what ails them. We often tell patients that their acquired severe aplastic anemia is idiopathic, but studies like this provide far better mechanistic explanations for the T cell–mediated attack of their bone marrow stem cells, possibly due to an antecedent viral illness. Current aplastic anemia guidelines⁴ continue to suggest viral testing. However, it is less likely that this mechanistic explanation will alter current therapies as both immunosuppressive therapy⁵ as well as bone marrow transplantation⁶ have long had a successful therapeutic role in severe aplastic anemia, regardless of etiology. The current results also do not provide a way of predicting responders from nonresponders to immunosuppressive therapy. One could hypothesize that hematopoiesis-reactive T-cell clones should decrease in frequency or disappear upon successful immunosuppressive therapy. Whether clone frequencies correlate with disease activity and could potentially represent predictive biomarkers could be investigated in larger studies. Lastly, patients with aplastic anemia cured by successful immune system (and thus T cell) replacement via bone marrow transplant (even if the cause was viral) are often exposed again to these same viruses without relapse. Exploring the differences between the donor and the host immune responses (especially in sibling transplants) should expand our understanding of the role of mimicry.

The critical role of T cells in aplastic anemia has already been suggested by previous experimental and clinical evidence.^7,8 Ben Hamza et al elegantly furthered knowledge by systematically studying clonal expansion, associated immune phenotypes, targeted cell populations, and target antigens to demonstrate that epitopes derived from viral infections can potentially drive hematopoiesis-directed T-cell responses by molecular mimicry (see figure). Future studies should include identification of other potential target antigens, for unbiased identification of other T-cell receptor targets causing marrow failure, such as drug-induced aplastic anemia.

Conflict-of-interest disclosure: A.E.D. declares no competing financial interests.