Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity
Maxime Hervé, … , Nicholas Chiorazzi, Eric Meffre
Maxime Hervé, … , Nicholas Chiorazzi, Eric Meffre
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1636-1643. https://doi.org/10.1172/JCI24387.
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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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Figure 2

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A majority of CLL B cells express HEp-2 reactive antibodies. (A) Data sh...
A majority of CLL B cells express HEp-2 reactive antibodies. (A) Data shown are from ELISAs for anti–HEp-2 cell reactivity of recombinant antibodies cloned from control CD5+ (left), UM-CLL (middle), and M-CLL (right) B cells. Dotted lines show ED38-positive control antibody (18, 19). The percentage of autoreactive clones for each fraction and their P values are indicated. (B) CLL B cells mostly express anticytoplasmic antibodies. HEp-2–reactive antibodies from CLL B cells show various IFA patterns including rare nucleolar (CLL 261) and nuclear and cytoplasmic patterns (CLLs 266 and RF22) whereas most CLL antibodies recognized different structures in the cytoplasm (CLLs 249, 109, 403, 355, and GO13). (C) Frequency of self-reactive antibodies in UM-CLL (left) and M-CLL (right) with nuclear, nuclear/cytoplasmic, or cytoplasmic staining patterns and frequency of nonreactive antibodies.