title: IGHV1-69-encoded antibodies expressed in chronic lymphocytic leukemia react with malondialdehyde-acetaldehyde adduct, an immunodominant oxidation-specific epitope.
abstract: The immunoglobulins expressed by chronic lymphocytic leukemia (CLL) B cells are highly restricted, suggesting they are selected for binding either self or foreign antigen. Of the immunoglobulin heavy-chain variable (IGHV) genes expressed in CLL, IGHV1-69 is the most common, and often is expressed with little or no somatic mutation, and restricted IGHD and IGHJ gene usage. We found that antibodies encoded by one particular IGHV1-69 subset, designated CLL69C, with the HCDR3 encoded by the IGHD3-3 gene in reading frame 2 and IGHJ6, specifically bound to oxidation-specific epitopes (OSE), which are products of enhanced lipid peroxidation and a major target of innate natural antibodies. Specifically, CLL69C bound immunodominant OSE adducts termed MAA (malondialdehyde-acetaldehyde-adducts), which are found on apoptotic cells, inflammatory tissues, and atherosclerotic lesions. It also reacted specifically with MAA-specific peptide mimotopes. Light chain shuffling indicated that non-stochastically paired L chain of IGLV3-9 contributes to the antigen binding of CLL69C. A nearly identical CLL69C Ig heavy chain was identified from an MAA-enriched umbilical cord phage displayed Fab library, and a derived Fab with the same HCDR3 rearrangement displayed identical MAA-binding properties. These data support the concept that OSE (MAA-epitopes), which are ubiquitous products of inflammation, may play a role in clonal selection and expansion of CLL B cells.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA. xque@ucsd.edu
authors.forename: Xuchu
authors.initials: X
authors.lastname: Que
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.forename: Shahzada
authors.initials: S
authors.lastname: Amir
authors.forename: Karsten
authors.initials: K
authors.lastname: Hartvigsen
authors.forename: Lotte F
authors.initials: LF
authors.lastname: Hansen
authors.forename: Douglas
authors.initials: D
authors.lastname: Woelkers
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
mesh_terms: D000079:Acetaldehyde / Q000276:immunology*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D000918:Antibody Specificity; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000378:metabolism*; D007147:Immunoglobulin Light Chains / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000276:immunology; D008315:Malondialdehyde / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011817:Rabbits
chemical_list: D000912:Antibodies, Neoplasm; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde; D000079:Acetaldehyde