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514 Part VI: The Erythrocyte Chapter 35: Aplastic Anemia: Acquired and Inherited 515

production or release of essential multilineage hematopoietic growth recipients, caused a fatal aplastic anemia. The aplasia could be prevented
factors. There is little experimental evidence for a stromal microenvi- by immunotherapy or with monoclonal antibodies to interferon-γ and
ronmental defect or a deficit of critical hematopoietic growth factors or TNF-α. Another mouse model of aplastic anemia induced by the
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their receptors. Telomerase mutations with consequent telomere short- infusion of lymph node cells histoincompatible for the minor H anti-
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ening may be involved in as many as 40 percent of patients. A suscep- gen, H60, resulted from the expansion of H60-specific CD8 T cells in
tibility to the development of aplastic anemia is present in persons with recipient mice. The result was severe marrow aplasia. The effect of the
certain human leukocyte antigen (HLA) types, such as HLA-DR15. 25 CD8 T cells could be abrogated by either immunosuppressive agents
Deficiencies in telomere repair could predispose to aplastic anemia or administration of CD4+CD25+ regulatory T cells, providing addi-
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by affecting the size of the multipotential hematopoietic cell compart- tional experimental evidence for the role of regulatory T cells in the
ment and by decreasing the multipotential cell’s response to marrow prevention of aplastic anemia.
injury, and could play a role in the evolution of aplastic anemia to a Several putative target antigens on affected hematopoietic cells
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clonal myeloid disease by contributing to genomic instability. Reduced have been identified. Autoantibodies to one putative antigen, kinectin,
hematopoiesis in most cases of aplastic anemia results from cytotoxic have been found in patients with aplastic anemia. T cells, responsive
T-cell–mediated immune suppression of very early CD34+ hematopoi- to kinectin-derived peptides, suppress granulocyte-monocyte colony
etic multipotential progenitor or stem cells. A small fraction of cases growth in vitro. However, in these studies cytotoxic T lymphocytes
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is initiated by a toxic exposure, drug exposure, or viral infection, and in with that specificity were not isolated from patients. Thus, the puta-
these cases the pathogenesis also may relate to autoimmunity as there tive antigen(s) that is the target of the autoreactive T cells has not been
is evidence of immune dysfunction in seronegative hepatitis, after ben- identified.
zene exposure, and many such patients respond to anti–T-cell therapy. 26
Telomere Shortening
Autoreactive Cytotoxic T Lymphocytes A relationship between acquired aplastic anemia and hereditary aplastic
In vitro and clinical observations have resulted in the identification of anemia (Fanconi anemia or dyskeratosis congenita) in some patients has
a cytotoxic T-cell–mediated attack on multipotential hematopoietic been suggested because the defects in telomerase and telomere repair,
cells in the CD34+ cellular compartment as the basis for most cases of characteristic of Fanconi anemia and dyskeratosis congenita are shared
acquired aplastic anemia. Cellular immune injury to the marrow after in some adult patients with aplastic anemia, but in these cases there is no
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drug-, viral-, or toxin-initiated marrow aplasia could result from the family history of such a disorder and no phenotypic abnormalities that
induction of neoantigens that provoke a secondary T-cell-mediated attack characterize the hereditary disorders (see “Fanconi Anemia” and “Dys-
on hematopoietic cells. This mechanism could explain the response to keratosis Congenita” below). Telomeres shorten physiologically with
immunosuppressive treatment in cases that follow exposure to an exoge- age as telomerase becomes less active. T-cell–mediated acquired aplas-
nous agent. Spontaneous or mitogen-induced increases in mononuclear tic anemia is associated with telomere shortening which could reflect
cell production of interferon-γ, 28,29 interleukin (IL)-2, and tumor necrosis an inherited defect in telomerase or a senescent erosion of activity. The
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factor-α (TNF-α) 30,31 occur. These factors are inhibitory to hematopoietic telomerase mechanism consists of a telomerase reverse transcriptase
cell development. Elevated serum levels of interferon-γ are present in 30 (TERT); an RNA template for TERT, the telomerase RNA component
percent of patients with aplastic anemia, and interferon-γ expression (TERC), and other stabilizing proteins. 41,41a Cells with shortened telo-
has been detected in the marrow of most patients with acquired aplastic meres normally undergo apoptosis unless DNA repair mechanisms
anemia. Addition of antibodies to interferon-γ enhances in vitro col- are impaired allowing the development of aneuploidy and neoplastic
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ony growth of marrow cells from affected patients. Long-term marrow transformation.
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cultures manipulated to elaborate exaggerated amounts of interferon-γ,
26
markedly reduced the frequency of long-term culture-initiating cells. Drugs
These observations indicate that acquired aplastic anemia is the result Chloramphenicol is the most notorious drug documented to cause
of cellular immune-induced apoptosis of primitive CD34+ multipoten- aplastic anemia. Although this drug is directly myelosuppressive at
tial hematopoietic progenitors, mediated by cytotoxic T lymphocytes, in very high dose because of its effect on mitochondrial DNA, the occur-
part, through the expression of T-helper type 1 (Th1) inhibitory cytok- rence of aplastic anemia appears to be idiosyncratic, perhaps related to
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ines, interferon-γ, and TNF-α (Fig. 35–1). The secretion of interfer- an inherited sensitivity to the nitroso-containing toxic intermediates.
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on-γ is a result of the upregulation of the regulatory transcription factor This sensitivity may produce immunologic marrow suppression, as a
T-bet, and apoptosis of CD34+ cells is, in part, mediated through substantial proportion of affected patients respond to treatment with
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26
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a FAS-dependent pathway. Because HLA-DR2 is more prevalent immunosuppressive therapy. The risk of developing aplastic anemia
in patients with aplastic anemia, antigen recognition may be a factor in patients treated with chloramphenicol is approximately 1 in 20,000,
in those patients. A variety of other potential factors have been found in or 25 times that of the general population. Although its use as an anti-
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some patients, including nucleotide polymorphisms in cytokine genes, biotic has been largely abandoned in industrialized countries, global
overexpression of perforin in marrow cells, and decreased expression reports of fatal aplastic anemia continue to appear with topical or sys-
of SLAM-associated protein (SAP), a modulator protein that inhibits temic use of the drug.
interferon-γ secretion. 26 Epidemiologic evidence established that quinacrine (Atabrine)
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A decrease in regulatory T cells (CD4+CD25+FoxP3+) con- increased the risk of aplastic anemia. This drug was administered to
tributes to the expansion of an autoreactive CD8+CD28− T-cell all U.S. troops in the South Pacific and Asiatic theaters of operations as
population, which induces apoptosis of autologous hematopoietic prophylaxis for malaria during 1943 and 1944. The incidence of aplastic
multipotential hematopoietic cells. 36–38 T-regulatory cells are a compo- anemia was 7 to 28 cases per 1,000,000 personnel per year in the pro-
nent of the immune system that suppress immune responses of other phylaxis zones, whereas untreated soldiers had 1 to 2 cases per 1,000,000
cells. They provide a “stop” for immune reactions that have achieved personnel per year. The aplasia occurred during administration of the
their purpose. They also play a role in preventing autoimmune reac- offending agent and was preceded by a characteristic rash in nearly half
tions (Chap. 76). One mouse model of immune-related marrow fail- the cases. Many other drugs have been reported to increase the risk of
ure, induced by infusion of parental lymph node cells into F1 hybrid aplastic anemia, but owing to incomplete reporting of information and

Kaushansky_chapter 35_p0513-0538.indd 515 9/19/15 12:23 AM