Infectious Agents and Bone Marrow Failure: A Causal or a Casual Connection?

Valentina Giudice,Carmine Selleri,Antonio M Risitano

doi:10.3389/fmed.2021.757730

Abstract

Acquired bone marrow failure (BMF) syndromes are considered immune-mediated disorders because hematological recovery after immunosuppressive therapies is the strongest indirect evidence of the involvement of immune cells in marrow failure development. Among pathophysiology hypotheses, immune derangement after chronic antigen exposure or cross-reactivity between viral particles and cellular components are the most accepted; however, epitopes against whom these lymphocytes are directed to remain unknown. In this study, we showed that BMF-associated immunodominant clones, namely the most represented T cells carrying an antigen-specific T-cell receptor (TCR) sequence in a random pool, were frequently associated with those described in various infectious diseases, such as cytomegalovirus (CMV) and Mycobacterium tuberculosis infection. We hypothesize that these pathogens might elicit an autoimmune response triggered by cross-reactivity between pathogen-related components and proteins or might be expanded as an unspecific response to a global immune dysregulation during BMF. However, those frequent intracellular pathogens might not only be passengers in marrow failure development, while playing a central role in starting the autoimmune response against hematopoietic stem cells.

Highlights

Bone marrow failure (BMF) syndromes are a heterogeneous group of benign hematological diseases characterized by uni or multilineage marrow and/or peripheral blood cytopenia(s) [1, 3,4,5] and included acquired aplastic anemia (AA), hypoplastic myelodysplastic syndromes (MDS), paroxysmal nocturnal hemoglobinuria (PNH), and large granular lymphocyte (LGL) leukemia [6, 7]
Bone marrow failure-related clonotypes are considered private to each disease because of the unlimited number of possible epitopes [32, 50]; why these clones share similarities with those associated with infectious diseases, especially M. tuberculosis and CMV infection, with this latter predominantly observed in PNH-related clonotypes, is still an open question (Figure 1)
Primary infection occurs in most cases without symptoms, and CMV remains latent in CD34+ stem cells and CD33+ myeloid progenitors; only myeloid dendritic cells and monocytes are productively infected causing viral reactivation under immunosuppression, such as after transplantation and during immunosuppressive therapies (IST) [2, 51]

Summary

INTRODUCTION

Bone marrow failure (BMF) syndromes are a heterogeneous group of benign hematological diseases characterized by uni or multilineage marrow and/or peripheral blood cytopenia(s) [1, 3,4,5] and included acquired aplastic anemia (AA), hypoplastic myelodysplastic syndromes (MDS), paroxysmal nocturnal hemoglobinuria (PNH), and large granular lymphocyte (LGL) leukemia [6, 7]. Seven out of 27 sequences (26%) were found in the database and associated with CDR3 motifs described in infectious diseases, including M. tuberculosis (n = 3), and influenza virus (n = 4), or autoimmune disorders and cancers (n = 4) (Table 1 and Supplementary Figure 1A). Shared between patients with AA and LGL and healthy subjects, and one CDR3 motif between an AA subject (UPN, AA5) and patients with LGL leukemia These sequences were associated with infectious diseases (M. tuberculosis, n = 6 matches; influenza virus, n = 3; CMV, n = 2; and HTLV-1/HIV, n = 2) or autoimmune disorders and cancers (n = 8)

DISCUSSION

Findings

DATA AVAILABILITY STATEMENT