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- Title
Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity.
- Authors
Hervé, Maxime; Kal Xu; Yen-Shing Ng; Wardemann, Hedda; Albesiano, Emilia; Messmer, Bradley T.; Chiorazzi, Nicholas; Meffre, Eric; Hervé, Maxime; Xu, Kai; Ng, Yen-Shing
- 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.
- Subjects
ANTIGEN presenting cells; IMMUNOGLOBULINS; CELLS; CHRONIC diseases; LEUCOCYTOSIS; PRELEUKEMIA; IMMUNE recognition; RECOMBINANT antibodies; AUTOANTIBODIES; B cells; CELL differentiation; CHRONIC lymphocytic leukemia; CLINICAL trials; COMPARATIVE studies; DOCUMENTATION; IMMUNOLOGICAL adjuvants; LONGITUDINAL method; RESEARCH methodology; MEDICAL cooperation; GENETIC mutation; NUCLEOTIDES; RESEARCH; RESEARCH funding; STEM cells; EVALUATION research; RANDOMIZED controlled trials
- Publication
Journal of Clinical Investigation, 2005, Vol 115, Issue 6, p1636
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI24387