Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin

Abstract

Many B-cell chronic lymphocytic leukemia (CLL) monoclonal antibodies (mAbs) can be grouped into subsets based on nearly identical stereotyped sequences. Subset 6 CLL mAbs recognize nonmuscle myosin heavy chain IIA (MYHIIA). Herein, we report that during apoptosis, MYHIIA becomes exposed on the cell surface of a subgroup of apoptotic cells, allowing subset 6 CLL mAbs to bind with it. Because other non-subset 6 CLL mAbs interact with apoptotic cells, 26 CLL mAbs, including 24 not belonging to subset 6, were tested for reactivity with MYHIIA-exposed apoptotic cells (MEACs

Antigens in CLL: themes and variations

“…Treatment of patients who relapse with leukemia, lymphoma, or multiple myeloma after allogeneic transplantation with donor T cells has illustrated that cellular immunotherapy can lead to complete eradication of cancer cells, resulting in cure of the disease. 1 In the nontransplantation situation, an immune response from donor T cells recognizing alloantigens on hematopoietic cells from the patient will lead to destruction of the patient's hematopoietic system. If the malignant counterpart of these cells also expresses these alloantigens on their cell membrane, this immune response will also eradicate hematopoietic cancer cells.…”

“…1 First, MEAC binding inversely correlated with IGHV gene mutational status. Indeed, 15 of 16 MEAC-reactive CLL mAbs carried unmutated IGHV genes.…”

“…6 mAbs in vitro recognize a distinctive subset of apoptotic cells with exposed MYHIIA, which they termed MYHIIA-exposed apoptotic cells (MEACs), and not apoptotic cells without exposed MY-HIIA or live cells. 1 They also show that MEACs could derive from multiple sources, includinLL cell turnover, normal cell turnover, or induction of damage in vivo. Furthermore, prompted by the finding that recognition of apoptotic cells and autoantigens can also be exposed during apoptosis is a relatively common property of CLL cells, they have examined for MEAC binding a number of non-subset no.…”

Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia

“…It is worthy of note that these structures may also share molecular identity with epitopes on infectious pathogens (molecular mimicry). 2,11,25 In mice and men, natural germ-line Abs bind to these oxidation-specific epitopes and IgM anti-oxLDL Abs are frequently found in the circulation of healthy persons. 1 For this reason, we have proposed that CLL cells may be derived from self-reactive natural Ab-producing B cells that are part of the innate first-line defence.…”

Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence

“…In addition, by using recombinant DNA technologies, the role of antigenic reactivity and the impact of somatic hypermutation (SHM) on CLL mAb specificity have been investigated and revealed that CLL cells likely derive from B cells producing polyreactive, natural antibodies encoded by germline IG genes which either retain or lose polyreactivity due to SHM (26)(27)(28). Although the accumulated data on antigen reactivity does not provide the definitive agent driving CLL, they do provide a framework from which comparisons between other entities, most notably autoimmune diseases, can be drawn.…”