Chronic Lymphocytic Leukemia Cells Bind and Present the Erythrocyte Protein Band 3: Possible Role as Initiators of Autoimmune Hemolytic Anemia

Abstract

The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4+ T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.

Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance

“…[18][19][20][21][22] In addition, treatmenttriggered autoimmune cytopenia was recognized in the first comprehensive descriptions of CLL. 15,17 In the early 1990s, however, there was concern that treatment with purine analogs could, through their potent immunosuppressive effect, be associated with a higher frequency of AIHA that in some instances could eventually be fatal.…”

Lymphoma-associated dysimmune polyneuropathies

“…T reg -cells are ineffective in CLL, and may result in activation of the autoreactive T-cells. While the capacity of CLL cells to function as antigen-presenting cells is suppressed, autoimmunity may include aberrant antigen processing by the malignant B-cells with presentation of cryptic peptides that are seen as foreign by T H -cells i.e., lack of immune tolerance [161,162]. Against this background dysimmune neuropathies may occur in patients with CLL, but the precise mechanisms linking neoplastic disease and the immune components of nerve injury have not been studied [163], and may vary between patients.…”

Chronic lymphocytic leukemia and autoimmunity: a systematic review

“…55 An alternative red cell antigen, B3, has also been demonstrated to be processed by CLL cells, which are then able to provoke a T-cell response. 56 It has been noted that AIHA is more common in advanced CLL, where the spleen is heavily infiltrated by leukemic cells, 12 which brings CLL cells in close proximity to damaged red blood cells. 56 In this regard, the spleen also contains CD40 ligand-expressing T cells which in vitro are able to induce activation of CLL cells and improve antigen presentation.…”

“…56 It has been noted that AIHA is more common in advanced CLL, where the spleen is heavily infiltrated by leukemic cells, 12 which brings CLL cells in close proximity to damaged red blood cells. 56 In this regard, the spleen also contains CD40 ligand-expressing T cells which in vitro are able to induce activation of CLL cells and improve antigen presentation. 57 On the other hand, CLL cells interact with T cells to modulate the immune environment, which may be important in permitting the development of autoimmunity.…”