Elsevier

Clinical Immunology

Volume 108, Issue 3, September 2003, Pages 248-256
Clinical Immunology

Regular article
Defect in the lymphoid compartment might account for CD8+-mediated effects in the pathophysiology of pure red cell aplasia

https://doi.org/10.1016/S1521-6616(03)00139-6Get rights and content

Abstract

Pure red cell aplasia (PRCA) is a rare hematological syndrome characterized by the lack of red cell progenitors in an otherwise normocellular bone marrow. Many agents and mechanisms have been implicated in the pathophysiology of PRCA, including immune-mediated dysfunctions. This report describes three patients with PRCA with unknown underlying cause and showed that for each, increases in CD8+ cells blunted the maturation of early erythroid (BFU-E). Each patient subsequently responded to immunosuppressive therapy. Peripheral blood mononuclear cells from age- and sex-matched healthy controls showed comparable distribution of CD3, CD4 and CD16, but significant increase in CD8 and decreased CD19. The distribution of lymphocyte subsets correlated with mitogen responses, but showed no difference in allogeneic responses when compared to controls. The adherent population in PRCA is important for mediating the hyper-immune state of patients, when IL-2 levels were used as readout. There was a trend for decreased BFU-E in patients, but marked reduction for late erythroid progenitors (CFU-E). CD8+ cells from PRCA blunted the maturation of BFU-E, despite increasing erythropoietin concentrations. These results strongly suggest that there are defects in the lymphoid compartment that feedback on the erythroid lineage of PRCA.

Introduction

Pure red cell aplasia (PRCA) is a hematological syndrome defined by severe normochromic, normocytic anemia with reticulocytopenia and absence of erythroid precursors. Erythroid abnormalities in PRCA are observed in an otherwise normocellular bone marrow (BM) with normal counts of peripheral blood leukocytes and platelets [1], [2]. In some cases of PRCA, there are few proerythroblasts and small numbers of mature erythroblasts, suggesting “maturation arrest” within the erythroid lineage [3].

Mechanisms associated with the pathophysiology of PRCA appear heterogeneous. PRCA has been linked to particular drugs, chemical exposure, autoimmune diseases, viral infection, thymoma, lymphomas, chronic lymphocytic leukemia, predominantly B-cell and, a minor subset including those with T-cell and large granular lymphocytes [1], [2], [4], [5]. PRCA has also been associated with myelodysplasia and human parvovirus B19 infection [4], [6].

Humoral and cellular-mediated mechanisms have been linked to the pathophysiology of PRCA [1], [4], [7], [8], [9], [10], [11]. Immune-mediated mechanisms, such as the development of erythropoietin antibodies during treatment with recombinant erythropoietin [2], [7], or the presence of an inhibitor of erythroid maturation are implicated in PRCA [8], [12], [13].

Patients with PRCA generally respond to immunosuppressive therapies, including corticosteroids, anti-thymocyte globulin, cyclosporine and low-dose cyclophosphamide [14]. Consistent with responses to immunosuppressive treatments are remissions of PRCA during pregnancy [15], [16], [17].

The literature is not clear regarding a link between thymoma and autoimmune diseases as underlying causes of PRCA. This report assumes that these two entities are not mutually exclusive in the development of PRCA. In support of this, is the recent report that showed autoreactive T-cells from thymoma [18]. Since several patients with PRCA develop thymoma, we hypothesized that autoreactive T-cells could have a major role underlying PRCA. We hypothesize that although both CD4+ and CD8+ T-cell subsets could be important in PRCA, CD8+ cells might be the major player due to their increases in PRCA patients [1], [19].

Erythroid progenitors using in vitro cultures indicated that these cells are present in 60% of PRCA patients [1], [4]. Furthermore, these erythroid progenitors show no genetic abnormality [1], [2]. However, these cells appear to be defective in vivo, given the profound anemia in PRCA and morphologic abnormalities in the BM of these patients with regards to erythroid lineage [1].

Use of immunodeficient animals to study human hematopoiesis [20] was valuable in providing insights in the mechanism of PRCA. The mice used in these studies developed thymoma when they were subjected to sublethal irradiation compared to control mice [20]. This finding, in combination to the lack of genetic abnormalities in the erythroid progenitors of PRCA suggest that BM alterations and thymoma are linked. We therefore studied the biology of PRCA by assuming that the development of this disorder could be explained by a pan-dysfunction in the lymphoid compartment and considered the possibility of a disorder in the development of the committed lymphoid cells.

Section snippets

Patients

Three different patients diagnosed with PRCA were studied with age- and sex-matched healthy controls (HC) at the time of diagnosis and after immunosuppressive therapy. This study followed the guidelines outlined by a protocol, approved by Institutional Review Board (IRB) of UMDNJ—New Jersey Medical School (Newark, NJ, USA). All patients underwent routine blood counts and laboratory tests, including Vitamin B12 levels, direct Coombs’s test and Parvovirus B-19 titers. Sera from these patients did

Peripheral distribution of representative lymphocytes

At each hospital visit by patients, immunofluoresence was done for T-cell subsets (CD3, CD4 and CD8), B-cell (CD19) and NK cell (CD16). Each labeling was compared with age- and sex-matched HC. The results, summarized in Table 1, showed no difference in the distribution of CD3, CD4 and CD16 between the two groups. However, there were significant (p < 0.05) differences in the percentages of CD8+ (increase) and CD19+ cells (decrease).

Mitogenic responses of PBMC from PRCA and HC

The distribution of CD4 T-cell subset in PRCA was similar to HC (

Discussion

The main objective of this study was to understand the biology of PRCA by assuming that the cause of this disorder is due to a dysfunction in the lymphoid cells and discusses the possibility that PRCA might involve dysfunctions in the development of the lymphoid compartment. The frequency of PRCA is low with only three patients admitted at University Hospital that spanned the five-year period in which the three study subjects were studied. This study reports that erythroid aplasia in the three

Acknowledgements

This work was supported by the following Public Health Service grants: HL-57675, and CA89868.

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