title: Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity.
abstract: B cell chronic lymphocytic leukemia (CLL) is a disease of expanding monoclonal B cells whose B cell receptor (BCR) mutational status defines 2 subgroups; patients with mutated BCRs have a more favorable prognosis than those with unmutated BCRs. CLL B cells express a restricted BCR repertoire including antibodies with quasi-identical complementarity-determining region 3 (CDR3), which suggests specific antigen recognition. The antigens recognized by CLL antibodies may include autoantigens since about half of CLL B cells produce autoreactive antibodies. However, the distribution of autoreactive antibodies between Ig heavy-chain variable-unmutated (IgV-unmutated) CLL (UM-CLL) and IgV-mutated CLL (M-CLL) is unknown. To determine the role of antibody reactivity and the impact of somatic hypermutation (SHM) on CLL antibody specificity, we cloned and expressed in vitro recombinant antibodies from M- and UM-CLL B cells and tested their reactivity by ELISA. We found that UM-CLL B cells expressed highly polyreactive antibodies whereas most M-CLL B cells did not. When mutated nonautoreactive CLL antibody sequences were reverted in vitro to their germline counterparts, they encoded polyreactive and autoreactive antibodies. We concluded that both UM-CLLs and M-CLLs originate from self-reactive B cell precursors and that SHM plays an important role in the development of the disease by altering original BCR autoreactivity.
authors.affiliation: Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, New York 10021, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Hervé
authors.forename: Kai
authors.initials: K
authors.lastname: Xu
authors.forename: Yen-Shing
authors.initials: YS
authors.lastname: Ng
authors.forename: Hedda
authors.initials: H
authors.lastname: Wardemann
authors.forename: Emilia
authors.initials: E
authors.lastname: Albesiano
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Messmer
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D001323:Autoantibodies / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics*; D015331:Cohort Studies; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
chemical_list: D001323:Autoantibodies; D022801:Complementarity Determining Regions; D011947:Receptors, Antigen, B-Cell