Mechanism of autoimmune hemolytic anemia in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is a malignant clonal expansion of CD5+B lymphocytes. The CD5+B lymphocytes have been postulated to produce autoantibodies. CLL patients may demonstrate features of autoimmunity including autoimmune hemolytic anemia. However, the origin of the autoantibodies causing the hemolysis is not clear. The present studies were performed to determine whether these autoantibodies are the products of the neoplastic B-CLL clones. Immunoglobulins (Ig) were eluted from washed red blood cells (RBC) obtained from two CLL patients at the time they had autoimmune (DAT-direct antiglobulin test-positive) hemolytic anemia. The light chain phenotypes of these eluted autoantibodies were determined and found to be monotypic with exact correlation to the light chain expressed on the surface of the B-CLL clones. Elutions from RBC of DAT negative patients or normal volunteers failed to demonstrate measurable amounts of Ig. In contrast, Ig eluted from RBC obtained from SLE patients with DAT positive hemolytic anemia found to be polyclonal autoantibodies exhibiting both light chain types. Furthermore, CD5+B lymphocytes obtained from the same two CLL patients (DAT+) produce, in vitro understimulation with phorbal myristate acetate (PMA), monoclonal antibodies which react and bind to RBC. Thus these studies provide direct evidence demonstrating that the antibodies causing the autoimmune hemolytic anemia in our two CLL patients are the products of the B-CLL neoplastic clones.

A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies

“…31 CD5 ϩ CLL B lymphocytes have previously been reported to produce natural autoAbs. 11,19,32,33 Although less well defined in humans compared with mice, CD5 ϩ B cells are considered to constitute a self-replenishing B-cell subset producing "natural IgM Abs" characterized by lack of somatic hypermutation, low affinity for microbes (eg, S pneumoniae), and autoreactivity. The unmutated CLL mAbs found in this study are polyreactive, thus resembling natural Abs.…”

Examples of in vivo isotype class switching in IgM+ chronic lymphocytic leukemia B cells.

“…Several previous studies support such a hypothesis. For example, antibodies eluted from erythrocytes in some AIHA patients may be of restricted heterogeneity, as defined by serologic markers (44), Ig L chain type (45,46), and electrophoretic mobility (47). In addition, murine CD5 ϩ B cells frequently react with red blood cell antigens (48) and can cause hemolysis in vivo (49).…”

Chronic lymphocytic leukemia preceded by cold agglutinin disease: intraclonal immunoglobulin light-chain diversity inVH4-34 expressing single leukemic B cells

“…1 However, it remains uncertain whether these phenomena arise from the malignant cells or from residual B cells. 2,3 In both possibilities, autoimmunity should develop in association with or following malignancy. On the other hand, autoimmune dysregulation is a well-known risk factor of the development of lymphoid malignancies.…”