title: Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation.
abstract: Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5(+) B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar. Therefore, antigen binding and stimulation could contribute to clonal selection and expansion as well as disease promotion. Initial studies suggest that CLL mAbs bind autoantigens. Since apoptosis can make autoantigens accessible for recognition by antibodies, and also create neo-epitopes by chemical modifications occurring naturally during this process, we sought to determine if CLL mAbs recognize autoantigens associated with apoptosis. In general, ~60% of CLL mAbs bound the surfaces of apoptotic cells, were polyreactive, and expressed unmutated IGHV. mAbs recognized two types of antigens: native molecules located within healthy cells, which relocated to the external cell surface during apoptosis; and/or neoantigens, generated by oxidation during the apoptotic process. Some of the latter epitopes are similar to those on bacteria and other microbes. Although most of the reactive mAbs were not mutated, the use of unmutated IGHV did not bestow autoreactivity automatically, since several such mAbs were not reactive. Particular IGHV and IGHV/D/J rearrangements contributed to autoantigen binding, although the presence and degree of reactivity varied based on specific structural elements. Thus, clonal expansion in CLL may be stimulated by autoantigens occurring naturally during apoptosis. These data suggest that CLL may derive from normal B cells whose function is to remove cellular debris, and also to provide a first line of defense against pathogens.
authors.affiliation: Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York 11030, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Catera
authors.forename: Gregg J
authors.initials: GJ
authors.lastname: Silverman
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.forename: Till
authors.initials: T
authors.lastname: Seiler
authors.forename: Sebastien
authors.initials: S
authors.lastname: Didier
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Maxime
authors.initials: M
authors.lastname: Hervé
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
authors.forename: R Hal
authors.initials: RH
authors.lastname: Scofield
authors.forename: Yifang
authors.initials: Y
authors.lastname: Chen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kolitz
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007124:Immunoenzyme Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D000939:Epitopes