Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity
Maxime Hervé, Kai Xu, Yen-Shing Ng, Hedda Wardemann, Emilia Albesiano, Bradley T. Messmer, Nicholas Chiorazzi, Eric Meffre
Maxime Hervé, Kai Xu, Yen-Shing Ng, Hedda Wardemann, Emilia Albesiano, Bradley T. Messmer, Nicholas Chiorazzi, Eric Meffre
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Research Article Oncology

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

Maxime Hervé, Kai Xu, Yen-Shing Ng, Hedda Wardemann, Emilia Albesiano, Bradley T. Messmer, Nicholas Chiorazzi, Eric Meffre

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IgH CDR3 sequences of unmutated revertant antibodies engineered from M-C...
IgH CDR3 sequences of unmutated revertant antibodies engineered from M-CLL antibodies. (A) The 183 mutated sequence (183) to be reverted according to germline VH, D, and JH counterparts was selected based on the identification of mutations in bold in the IgH CDR3 sequences. Homologous nucleotides to the original germline segment sequences are represented by dots whereas nucleotides to be substituted in the reverted sequence are shown in bold. Deducted amino acids are shown in upper-case letters. 183R, the resulting sequence of the 183 unmutated revertant. (B) IgH amino acid CDR3 sequences of mutated-CLL and engineered unmutated revertants (R). Homologous amino acids to the original mutated CLL sequences (top) are represented by dots whereas substituted amino acids in the reverted sequence (bottom) are shown. IgH CDR3 D and JH gene segments are indicated.