Immunopathogenesis of idiopathic aplastic anemia

The most direct evidence that IAA may be an autoimmune disorder has come from the clinical observation that patients

Table 12.4 Classification of the bone marrow failure (BMF) syndromes.

INHERITED

Disease

Mode of inheritance

Chromosomal locus

Gene

Clinical manifestations

Fanconi's anemia

Autosomal recessive

See Table 12.5

See Table 12.5

See text

Dyskeratosis congenital

X-linked autosomal recessive

Xq283q26

DKC1, hTR

See text

Diamond-Blackfan anemia

Autosomal dominant Autosomal recessive

19q13.2 8p22-p23.31

RPS19 Not known

See text

Shwachman-Diamond syndrome

Autosomal recessive

Not known

Not known

Neutropenia, exocrine pancreatic insufficiency, metaphyseal dysostosis

Amegakaryocytic thrombocytopenia

Autosomal recessive

1p34

c-mpl (thrombopoeitin receptor)

Absent megakaryocytes in bone marrow, late BMF

Thrombocytopenia with absent radii syndrome

Autosomal recessive?

Not known

Not known

Bilateral radial aplasia, lower limb anomalies, cow's milk intolerance, renal and cardiac anomalies

Congenital thrombocytopenia and radio-ulnar synostosis

Autosomal dominant

7p15-p14

HOXA11? (needs confirmation)

Aplastic anemia, proximal radial ulnar synostosis, clinodactyly, syndactyly, hip dysplasia and sensorineural hearing loss

Pearson's marrow-pancreas syndrome

Mitochondrial

Usually from nt 8469 to nt 13447

Contiguous genes deleted

Pancreatic exocrine dysfunction, sideroblastic anemia (see also text)

Familial aplastic anemias There are numerous reports of family clustering of BMF other than the above. They have shown different patterns of inheritance and a variety of associated clinical manifestations (e.g. malformations), suggesting that this group may be genetically heterogeneous.

ACQUIRED

Idiopathic Radiation

Drugs and chemicals Regular: cytotoxic, benzene

Idiosyncratic: chloramphenicol, NSAIDs, antiepileptics, gold Viruses Epstein-Barr virus Hepatitis Parvovirus

Human immunodeficiency virus Immune diseases Thymoma Pregnancy

Paroxysmal nocturnal hemoglobinuria

NSAID, non-steroidal anti-inflammatory drug.

with IAA have complete or partial reversion of their pancytopenia when they are treated with antilymphocyte globulin (ALG). Subsequently, it was shown that patients with IAA often have increased numbers of 'activated' CD8+ CD25+ T

cells in their blood and bone marrow. In addition, T cells from IAA patients can inhibit the growth of autologous in vitro hemopoietic colonies, and the growth of colonies from HLA-identical siblings. Based on these observations, a cur rent model of the pathogenesis of IAA predicts that autoreactive T cells attack HSCs, causing their depletion—hence the reduction of HSCs in severe IAA to about 1% of normal. The primary event that triggers this aberrant immune response remains elusive: a possible viral cause has long been sought but never proved. The identity of the putative autoantigen on HSCs also remains unknown. There is evidence, however, that the inhibitory effect of autoreactive T cells is mediated, at least in part, through interferon-y (IFN-y). In addition, IFN-y up-regulates Fas receptor on the surface of HSCs, thus facilitating activation of the Fas-dependent apoptotic pathways.

As in other autoimmune diseases there is over-representation of specific HLA alleles in IAA patients compared with population controls: the HLA-DR2 allele is over-represented in patients with IAA of European ancestry, whereas another HLA class II haplotype is over-represented in Japanese patients with IAA.

Recently, a pathogenetic link between IAA and myelo-dysplastic syndrome (MDS) has surfaced. Clinically, IAA overlaps with the hypoplastic form of MDS; in fact, the differential diagnosis between the two is often difficult. It is now recognized that 20-30% of patients with MDS, especially those who would otherwise be classified as having refractory anemia with hypocellular marrow, respond to immunosup-pressive therapy with alleviation of their cytopenias, indicating that an immune process, similar to the one operating in IAA, is also involved in the pathogenesis of some forms of MDS. In addition, as in IAA, in 20% of patients with refractory anemia, paroxysmal nocturnal hemoglobinuria (PNH) populations of small size are detected (see below). What is more, their presence is predictive of response to immunosup-pressive therapy, providing further evidence of an immune process in the pathogenesis of MDS in this select group of patients, and linking them to those with IAA.

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