Pure red cell aplasia

Pure red cell aplasia (PRCA), a disorder first described in 1922 (Kaznelson, 1922), can be characterized as an anaemia with the almost complete absence of red-cell precursors in the bone marrow, but essentially normal granulopoiesis and megakaryopoiesis. Typical bone marrow findings in PRCA are shown in Fig 1. The reticulocyte count is low while the platelet count, leucocyte count and leucocyte differential are normal. Clinically, the patients present with symptoms of severe anaemia in the absence of haemorrhagic phenomena. Depending on the cause, the course can be acute and self-limiting or chronic with rare spontaneous remissions. Bone marrow histology of a patient with PRCA associated with thymoma. In the aplastic phase (A and B) there is a complete absence of red-cell precursors, as documented by immunohistochemistry using an antibody against haemoglobin with a positive reaction in some partly squashed erythrocytes (A). Most myeloid cells, except for the eosinophils (marked by arrows) stain positive for naphthol-AS-d-chloroacetate esterase (B). Upon recovery of erythropoiesis following removal of the thymoma (C and D), the anti-haemoglobin immunohistochemistry reaction clearly visualizes erythroblasts (C). These cells are also detectable as the naphthol-AS-D-chloroacetate esterase-negative cell clusters (D). (Fig 1A–D, magnification ×370). The pathophysiology of PRCA is heterogeneous, as summarized in Table I. There is a ‘congenital’ form (Diamond–Blackfan anaemia) where most cases appear to be a result of several genetic defects predominantly affecting the erythropoietic lineage. Acquired PRCA induced by parvovirus B19 infection typically produces an acute self-limiting disease, called ‘transient aplastic crisis’ (TAC). In immunosuppressed individuals, B19 infection may result in a more chronic type of bone marrow failure, clinically apparent as PRCA. However, most cases of PRCA are autoimmune-mediated. Various autoimmune mechanisms of PRCA have been described (Table I), such as antibodies against erythroblasts or erythropoietin. T cells or natural killer (NK) cells have been proposed to secrete factors selectively inhibiting erythroid colonies in the bone marrow or directly lysing erythroblasts. Lysis of erythroblasts by T cells could result from ‘classic’ T-cell receptor (TCR)-mediated antigen recognition. In addition, PRCA can be mediated by major histocompatibility complex (MHC) unrestricted effector-target cell recognition, as erythroid progenitors progressively lose expression of MHC class I and, thus, become susceptible to destruction by NK-type cells. This mechanism is similar to NK-mediated lysis of tumour cells following loss of HLA class I by the tumour cells. Autoimmune PRCA can occur as a primary ‘idiopathic’ form or be associated with (i) infections, (ii) autoimmune disease, and (iii) neoplasias such as thymoma, lymphoma or carcinoma. Specific situations under which immune-mediated PRCA has been described are pregnancy and post-allogeneic bone marrow or stem cell transplantation, in which recipient antibody against incompatible donor ABO blood group antigens may inhibit red-cell regeneration. Moreover, most cases of transient erythroblastopenia of childhood (TEC), an acute self-limiting form of PRCA, are probably caused by humoral immune mechanisms, aetiologically induced following infection with an unknown virus that is distinct from B19 parvovirus. Rarely, PRCA may represent the initial manifestation of a preleukaemic syndrome. Finally, PRCA has been associated with several drugs and toxins, documented by the demonstration that the anaemia remits shortly after removal of the causative agent. PRCA has been also studied in cats, either as a rare form occurring spontaneously that resolves following immunosuppressive therapy (Stokol Handgretinger et al, 1999). Diamond–Blackfan anaemia Following the first report on red cell aplasia in infancy (Josephs, 1936), four more cases were presented (Diamond Diamond, 1978). Further haematological findings are increased levels of HbF (Diamond, 1978), erythrocyte adenosine deaminase (an enzyme of the purine salvage pathway) in most patients (Glader et al, 1983) and erythropoietin. Earlier reports, suggesting an immune cell-mediated pathogenesis of DBA (Hoffman et al, 1976), have not been confirmed by others (Freedman Nathan et al, 1978a). Current evidence suggests more than one pathogenic mechanism for the erythroid failure in DBA, suggesting that DBA is composed of more than one disorder (McGuckin et al, 1995; Giri et al, 2000; Willig et al, 2000). It appears that the erythroid progenitor compartment is intrinsically defective in DBA as marrow cultures have shown reduced or absent erythroid blast-forming units (BFU-E) or erythroid colony-forming units (CFU-E) in most, although not in all, DBA patients (Freedman et al, 1976; Nathan et al, 1978a; Tsai et al, 1989; Santucci et al, 1999). Erythroid progenitors in some DBA patients appear to display a reduced sensitivity to erythropoietin that could be corrected by the addition of glucocorticoids in vitro (Chan et al, 1982a). This may provide an explanation for the empirical response of 60–70% of the DBA patients to steroids (Diamond et al, 1976; Chan et al, 1982b; et al, 1996). However, are to occur in of DBA cases (Diamond et al, 1976; et al, for the most in patients with a of DBA that were the of such patients with DBA in are not as red cells et al, et al, 1995; et al, 1996). with an of erythropoiesis in some DBA patients et al, while erythropoietin to be in et al, cell has not been in DBA However, as there is a increased of DBA patients developing haematological as by the of the et al, of DBA with factors are not In patients with or induced there an increased of developing leukaemia et al, 1996). in DBA patients can be by bone marrow et al, a major DBA to on the of (i) the of a in a DBA patient et al, (ii) in different DBA families that documented the of in the of cases et al, and (iii) on associated with a of the cases of the et al, The the at the of the in the DBA and of were documented in of DBA including four of of the cases et al, 1999). There is a that for the in a in some with and may also some of the and of However, in some of the cases the DBA on by the of et al, and the of cases not to have et al, 1999). in DBA in a of but of DBA to be The knowledge on DBA the of a review et al, 2000). erythroblastopenia of childhood erythroblastopenia of childhood is an anaemia in than of the patients are of or at The have a and, the bone marrow erythroblastopenia with normal blood and platelet counts et al, the will be in may be associated with in the blood of and a the bone marrow large proerythroblasts, that appear the of the aplastic phase (Fig These cells large with and by a Some of may cells (Fig the anaemia the and after the from the bone marrow and are by This is as a result of a humoral immune response to the and antibodies to the et al, In such the may be as a chronic PRCA more as et al, 1996). autoimmune mechanism of the anaemia by of the red cell aplasia following of the thymoma in about of cases et al, and the response of some PRCA patients to steroids et al, et al, and et al, In some of the parvovirus B19 have been as a erythropoiesis et al, The mechanism of of erythropoiesis direct lysis of red-cell progenitors and the of immune with erythropoietin that result in and the removal of erythropoietin from the has not been antibodies that are not directly red-cell progenitor by the erythropoietin receptor or another red-cell It be in that cells could a in the of such This humoral factors have been in the of some patients with a T-cell such as patients from thymoma, and diverse autoimmune Moreover, could be some patients with PRCA to et al, donor and recipient following bone marrow or stem cell can result in PRCA with of the incompatible et al, and reticulocyte recovery may occur spontaneously or several as the but there are of of with increased immunosuppressive therapy or et al, et al, PRCA mediated by T cells and cells In patients with PRCA in a of erythropoiesis be of erythropoiesis is the most mechanism of in a patient with T-cell chronic leukaemia that the T lymphocytes erythroid by bone marrow cells (Hoffman et al, 1978). of the bone marrow T cells with and and erythropoiesis in that T cells with for the of the the cells from patients with chronic leukaemia erythroid in vitro et al, an effect of cells or to the of normal T-cell in vitro cultures from patients with et al, However, that removal of the cells by erythroid suggesting that the cells erythropoiesis et al, the cells were large granular lymphocytes (LGLs) and several that expansions of may be the disorder most associated with PRCA (Abkowitz et al, et al, et al, et al, 1996; et al, 1996). These may be of T-cell type or of natural killer type and a T-cell receptor of the of or In are and, not a at the cell not the and typically display MHC unrestricted against HLA class tumour cells, such as the In although not all, patients with of the and the the are directly against cells in vitro et al, et al, Handgretinger et al, 1999). are not against cells, can be induced by antibody the of the with the receptor on cells, or by antibody the receptor on the or with for the antibody on the cells et al, 1987). in vitro by the against cells may be detectable the have been some of the on the of may not have the in most may a that is to erythroblasts in This may be mediated by similar mechanisms as the in vitro et al, Handgretinger et al, 1999). of against erythroblasts could occur (i) the of or of that could unknown by erythroid progenitors (Fig and (ii) antibodies against red-cell progenitors to on the or (iii) by some to on cells et al, mechanisms of PRCA directly mediated by or the may the to directly a red-cell presented by an HLA class I the killer cell by the to an to the killer cells red-cell precursors low levels of HLA class I. a may the to directly a by myeloid and by red cell The myeloid cells normal levels of HLA class I that to the killer cell on the and to the killer cells, while of red-cell precursors low levels of HLA class I is not by and may be against HLA class myeloid precursors, but not the HLA class erythroid not a but may be by antibody against red-cell and of or may mechanism of NK-mediated the not be directly in the of red-cell a of PRCA and a of of has been described where the were shown to MHC class I et al, 1999). These killer cell include several for diverse MHC class I such as the and as as the that are of the 1999). inhibit the of the killer cell the cell the HLA class I antigen to which the particular (Fig tumour cells lose HLA class I antigens as an mechanism to by MHC class T cells, can be by killer cells against cells, another of the on T cells and cells is the of against cells with normal levels of HLA class I expression et al, 2000). This mechanism probably induced the PRCA in the patient with the and expression described et al, 1999). The by the of myeloid cells that normal HLA class I but not the of red-cell progenitors that are in the of progressively HLA class I (Fig In addition to of by HLA class I of an unknown on the red-cell progenitors by the red-cell destruction et al, 2000). In may also be on cell but levels of HLA class I expression such cells from the by T cells (Fig This may for the of as T cells are to by the However, a of of of by be also for that not a but may be antibody against red-cell progenitors or by by erythroid cells (Fig is of the PRCA cases associated with However, as most of the normal of the in cells, the T cells and T be most of the not HLA class I direct such could also inhibit by the such as tumour et al, 1996). PRCA in some patients with associated expansions may not be induced by but by that is not the of the with the as for killer cell-mediated of the with the red-cell progenitors in the bone early that the of erythropoiesis by T cells of the could be et al, suggesting that T cells could erythroblasts by (TCR)-mediated of presented by the MHC (Fig This a distinct for patients although has been However, not be in direct to the pathophysiology of PRCA can also antigen 1999). This that one HLA class I may present an to while class I may inhibit by to the (Fig et al, It is rather to antigen for the antigen and the have been This the of T-cell erythroid progenitor cells and the of the particular as has been for some tumour antigens et al, the expression of a of not by antigen recognition, of T cells may different that may be presented by et al, 1996). Most associated with PRCA are probably although is that expansions of such as following an immune response against an unknown may be associated with The demonstration of in some patients may of one or a a of In addition, most patients with expansions have a chronic course and the demonstration of by not T-cell expansions have been described following and in et al, 1999). there have been some of that were detectable for although is to in of the of in et al, Some of the were shown to be by of the of the in from patients et al, with leukaemia have been reported to have an acute course and cases to be associated with than the expansions although more acute course not in et al, appears that expansions of are and that patients with chromosomal abnormalities in the and leukaemia were described in the et al, expansions of may be present for and associated with an acute phase may in some of the patients the of patients with and may have expansions that become apparent an or an increased of lymphocytes with an are for et al, the of can be in the of bone marrow histology of PRCA patients may be rather in some patients with documented the for than of the bone marrow cells (Lacy et al, 1996). It is in some patients with increased levels of not erythroblasts are by the and the bone marrow histology reduced but not a PRCA. Finally, be in that not cases of PRCA associated with expansions are mediated but that the associated may some patients to chronic parvovirus B19 infection et al, 1996). In PRCA in expansions may (i) of the by the erythroblasts either the or another that and antibody to of the (ii) by the of a of different that of cells with normal levels of HLA class I but are to erythroblasts with decreased class I (iii) The of the to secrete or direct or particular level of with of the bone levels of expansions that may not the bone marrow will not PRCA, the are against red-cell precursors in The of a chronic parvovirus The PRCA in patients with associated expansions may to against the et al, 1996; et al, 1996). in patients with PRCA associated with types of thymoma and autoimmune disease, be Most patients with mediated PRCA normal or increased in vitro is present et al, 1996). are as the initial immunosuppressive agent. Further include and In patients with normal in one with of a complete is et al, et al, 1996). is to the response to a agent. in some of the & et al, appears to be of in more et al, 1996). in patients with autoimmune PRCA, are normal in the absence of or T cells there is of the stem cells or early red-cell bone marrow patients with PRCA typically have than of red-cell progenitors in to the bone marrow in PRCA not evidence of and In PRCA, the in the is normal and abnormalities be PRCA not be in patients with increased of and abnormalities of the criteria are not and with evidence of erythroid can be as PRCA et al, et al, 1999). The of and in patients with are low and abnormalities may be detectable et al, 1996). such may be of to PRCA from stem cell Acquired PRCA is not a preleukaemic disorder cases with and abnormalities are may in patients with parvovirus infection where bone marrow histology may on the of the disease, in patients with PRCA in are in the of and bone marrow may of & and in patients in erythroid aplasia or the of abnormalities in the et al, PRCA has been reported in with more than but most one or patients & & 1996). PRCA in most, although not all, cases after the been a has not been clearly in most but for and there to be evidence of & 1996). The pathogenesis of PRCA in such cases is but may include direct on the red-cell precursors et al, as as the of et al, In the early of red cell and aplasia associated with has been reported in with severe that to or et al, It is that some of cases could have been caused by parvovirus B19 in that a erythrocyte of severe et al, PRCA could be induced in by a of in the et al, failure can be associated with erythroid to low erythropoietin and a effect of on red-cell progenitors However, not to PRCA. the of PRCA with pregnancy is et al, and to of the to the early in after may in and has not been to the In one such of PRCA that were spontaneously pregnancy and PRCA in different with spontaneous recovery after of pregnancy or normal et al, The mechanisms of PRCA in such cases This review has summarized the knowledge on the pathogenesis of PRCA. It to that PRCA not be with cases of red cell associated with and In addition, acute or chronic parvovirus B19 be in cases of congenital and PRCA. In patients with PRCA, be to the by the antibodies on the red-cell It will be more to the by on erythroblasts. This may provide to the autoimmune aetiology of PRCA as such could be or with of from the bone marrow may to such are or The that for HLA class I are in the pathogenesis of PRCA in some or most cases associated with expansions in the bone marrow be for the expression of such and to be using from such could therapy of PRCA, could MHC class I but to the T-cell immunosuppressive therapy the of inhibiting T-cell This by from the