Distinguishing immunorelated haemocytopenia from idiopathic cytopenia of undetermined significance (ICUS): a bone marrow abnormality mediated by autoantibodies

Abstract

In recent years we have observed that some patients with idiopathic cytopenia of undetermined significance (ICUS) responded well to corticosteroid and high-dose intravenous immunoglobulin treatment, indicating that some cytopenia in ICUS might be mediated by autoantibodies. In this study, we analysed 166 ICUS cases retrospectively, some of which were autoantibodies detected on haemopoietic cells in bone marrow (BM) by BM mononuclear cell (BMMNC)-Coombs test, flow cytometry (FCM), Western blot and immunofluorescence (IF). We found that 25·9% (43 of 166) of the cases had autoantibodies positive verified with BMMNC-Coombs test or FCM analysis, 72·1% (31 of 43) of whom had immunoglobulin (Ig)G autoantibody positive by Western blot. IgG could be detected in the erythroblastic islands on the BM smear of nine (32·1%, nine of 28) ICUS patients with autoantibodies by IF. Of these 43 patients, the median percentage of reticulocytes was 1·79%. More than half the patients had hyper-BM cellularity with a higher percentage of nucleated erythroid cells in the sternum. Total response rates to immunosuppressive therapy at 6, 12, 24 and > 36 months were 46·5% (20 of 43), 75% (30 of 40), 77·4% (24 of 31) and 66·7% (16 of 24), respectively. We termed this group of ICUS cases with autoantibodies as immunorelated haemocytopenia (or BMMNC-Coombs test-positive haemocytopenia).

Keywords: Coombs test; ICUS; autoantibody; cytopenia.

Fig. 1

Autoantibodies detected in some of idiopathic cytopenia of undetermined significance (ICUS) patients. (a) Bone marrow mononuclear cell (BMMNC)-Coombs tests. (b) Flow cytometry (FCM) tests. Autoantibodies were detected on granulocytes (CD15⁺), nucleated erythrocytes (GlyCoA⁺) and stem cells (CD34⁺). (c) Erythrophagocytosis by macrophages was easily observed in bone marrow (BM) smears in some ICUS patients with autoantibodies. (d) Immunoglobulin (Ig)G autoantibodies were detected in the erythroblastic islands (EI), and deposited at the edge between macrophages and erythroblasts by immunofluorescence (IF): IgG(+) in some ICUS patients with autoantibodies as arrow shown (d₁); IgG(–) in ICUS patients without autoantibodies (d₂); IgG(–) in normal controls (d₃). (e) The IgG against autoantigens on BM cell membrane were identified by Western blot. (1) Membrane proteins were reacted with autologous BM supernatant samples of ICUS patients with autoantibodies; (2) membrane proteins were reacted with autologous BM supernatant samples of healthy controls; (3) membrane proteins were reacted with TBST in ICUS patients with autoantibodies; (4) membrane proteins were reacted with autologous BM supernatant samples of ICUS patients without autoantibodies.

Fig. 2

Age distributions in two groups. (a) Idiopathic cytopenia of undetermined significance (ICUS) patients with autoantibodies. (b) ICUS patient without autoantibodies.