Types of acquired neutropenia

Acquired neutropenia is the most common form of the disease. The disorder can be observed following infections, treatment with various medications, malignancies but also in particular cases of auto-immune diseases. These may impact the bone marrow release and/or production of neutrophils or have a direct effect on mature neutrophils present in the peripheral blood (2).

Infectious neutropenia

Neutropenia induced by microorganisms represent a major cause of the acquired neutropenia diagnosed. Viruses such viral hepatitis, influenza, Epstein-Barr virus (EBV), cytomegalovirus (CMV) or Human immunodeficiency virus (HIV) has been described as inductors of neutropenia (8), (9), (10),(11), (12). In the case of EBV, Larochelle et al showed that the virus can infect neutrophils and induce their apoptosis through a Fas/FasL-dependent mechanism (13). Although viruses are the major causes of post-infectious neutropenia, bacterial infections including salmonella typhi, brucella and rickettsia are the second cause of infectious neutropenia (14), (15), (16) . Finally, cases of mycobacterial, fungal and protozoal infections are unusual causes but remain existing (17), (18).

Bone marrow failure disorders associated with neutropenia

Defect of the bone marrow to produce mature neutrophils results in neutropenia. So far, the idiopathic aplastic neutropenia, chronic idiopathic neutropenia and malignancies are the most known bone marrow disorders related to neutropenia. Idiopathic aplastic anemia is defined as a failure of the bone marrow to produce white and red blood cells. Indeed, the disorder is associated with an alteration of stem cells proprieties (proliferation and differentiation) (19), (20). In the case of non-immune chronic idiopathic neutropenia, pro-inflammatory cytokines such as TNF and IL1, chemokines   and the myelopoiesis inhibitor  TGF1 have been suggested to interfere with bone marrow metabolism and functions as well as with cell trafficking  (21). Finally, malignancies such as leukemia and myelodysplastic syndrome are characterized by the presence of immature myeloid cells in peripheral blood (22).

Neutropenia associated with autoimmune disease

Neutropenia has been described to be associated with systemic lupus erythematosus (SLE) and two rheumatoid arthritis (RA) disorders, the Feltys syndrome and large granular lymphocyte leukemia (LGL) (23), (24), (25). While the involvement of anti-neutrophil antibodies has been shown in SLE and Feltys syndrome, a Fas-mediated apoptosis was identified as the major mechanism in LGL associated neutropenia. Fas receptors belongs to the tumor necrosis receptor family and is known to trigger cell apoptosis when bound to Fas ligand (FasL). While Fas is expressed in various cell types, FasL is a transmembrane protein expressed by activated T cells. In addition, the protein

could be cleaved by metalloprotease and therefore be found as a soluble form. In 2000, Liu et al could detect in LGL patients sera a significantly higher level of circulating FasL compared to control samples. In addition, the incubation of LGL patients sera with neutrophils from controls and patients increase cell apoptosis (26).

Chemotherapy drug-induced neutropenia

Treatment with chemotherapy agents are frequently accompanied by neutropenic conditions (27). Indeed, the non-specificity of the cytotoxic drugs results in the killing of cancer cells as well as non-cancer cells, including neutrophils. Bone marrow suppression remains a common side effect of chemotherapy agents. Most drugs are known to cause DNA alterations. Therefore, replication is inhibited and cells undergo apoptosis (28), (29). Moreover, chemotherapeutic agents purpose is to trigger cells with high replication turnover (cancer cells). Since neutrophils and precursors have a high renewal rate, the cells become naturally susceptible to chemotherapeutics.

Non-chemotherapy drug-induced neutropenia

Non-chemotherapy drugs are with infections the predominant causes of neutropenia. Various medications, such as anti-inflammatory drugs, antibiotics, antipsychotic agents or antithyroid drugs (ATD) have been associated with neutropenia (Table 3) (30). The pathogenesis is suggested to be mediated by non-immune (cytotoxic) and / or an immune mechanism (31),(32), (33), (34). On the one hand, the ability of neutrophils and/or precursors to metabolize drugs into toxic reactive metabolites was shown to induce neutrophils / precursors apoptosis (35), (36).

On the other hand, the parent drugs or its metabolites may bind endogenous proteins and be presented following processing as an hapten or may interact directly with immunological receptors (37), (38). In the case of ATD-induced agranulocytosis, both mechanisms have been shown to be implicated. The accumulation of the antithyroid agents propylthiouracil (PTU) and methimazole in phagocytizing neutrophils was demonstrated by Lam and Lindsay to be 8 – 10-fold higher than that observed in resting neutrophils. Interestingly, this phenomenon was associated with an increased concentration of hydrogen peroxide (H202) which may oxidize the drugs in the cells (39). The excessive concentration of both components may lead to neutrophils apoptosis.

In contrast, Guffy et al detected in serum from an PTU-induced agranulocytosis patient specific IgM directed on granulocytes. Granulocytotoxicity was found to be complement-mediated (40). While a type II hypersensitivity reaction was demonstrated by Guffy et al, a delayed-type IV mechanism, implying the involvement of cytotoxic CD8+ T cells, has been suggested through genome-wide association studies (GWAS). Numerous human leukocyte antigen (HLA) variants including HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03, were shown to be susceptible loci associated with ATD-induced agranulocytosis (41), (42), (43).Table 3. Table 3. Most common drugs associated with neutropenia (44). Fig.1:  Mechanisms of ATD-induced neutropenia (45), (43)

Figure 1. Mechanisms of antithyroid drug-induced neutropenia. The mechanism underlying ATD-induced agranulocytosis may be from a non-immune (direct toxicity) or immune mechanism. In the case of a direct toxicity, the drugs are metabolized by neutrophils cytochrome (CYP) or/and myeloperoxidase (MPO) into toxic reactive oxygen species (ROS) that could induce granulocytes and precursors apoptosis. In contrast, the immune-mediated apoptosis is related to the presence of anti-neutrophil cytoplasmic antibodies direct against granulocyte and precursors (45). In addition, the hypothesis of an immune mechanism, more precisely a T-cell mediated process, is supported by the association of specific HLA variants with the disease (43).