IGHV1-69-Encoded Antibodies Expressed in Chronic Lymphocytic Leukemia React with Malondialdehyde–Acetaldehyde Adduct, an Immunodominant Oxidation-Specific Epitope

Xuchu Que,Thomas J Kipps,Joseph L Witztum,Douglas Woelkers,Sotirios Tsimikas,Christoph J Binder,Karsten Hartvigsen,Lotte F Hansen,George F Widhopf Ii,Shahzada Amir,Deyu Fang

doi:10.1371/journal.pone.0065203

IGHV1-69-Encoded Antibodies Expressed in Chronic Lymphocytic Leukemia React with Malondialdehyde–Acetaldehyde Adduct, an Immunodominant Oxidation-Specific Epitope

Xuchu Que, Thomas J Kipps + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0065203

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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.

Highlights

Chronic lymphocytic leukemia (CLL) is a malignancy of monoclonal CD5+ B cells, which accumulate in the blood, marrow, and lymphoid tissues [1]
Each of the four IGHV1-69 recombinant antibody (rAb) bound to MAA and MDA epitopes, CLL69C rAb had by far the greatest binding activity, for example, binding to MAA-epitopes (MAALDL and MAA-BSA) eight-fold higher than that of any of the other CLL69 subsets
The results revealed that the recombinant CLL69C Ig heavy chain paired with its native IGLV3-9-encoded Ig light chain bound MAAepitopes more effectively than the CLL69C Ig heavy chains (IgH) paired with nonnative Ig light chains of CLL69A, B, or D (Fig. 2, left panel)

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a malignancy of monoclonal CD5+ B cells, which accumulate in the blood, marrow, and lymphoid tissues [1]. CLL patients that express unmutated Ig heavy chain (IGHV) genes have a worse prognosis than those who express mutated IGHV genes [3,7]. One particular IGHV gene, IGHV1-69, generally is expressed with little or no somatic mutation and is used by CLL cells of approximately 15% of all patients [3,8,9]. The IGHV169-encoded Ig heavy chains (IgH) expressed in CLL commonly have stereotypic motifs in the third complementarity determining region (HCDR3), resulting from the rearrangement and restricted reading-frame-use of certain IGHD and IGHJ gene segments [4,10,11]. The prevalent use of unmutated IGHV1-69 and nonstochastic pairing with light chains suggests that self- and/or common-environmental antigen(s) plays a role in the development and/or progression of CLL [12,13]

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