Abstract
A diverse B-cell receptor (BCR) repertoire is required to bind a wide range of antigens. BCRs are generated through genetic recombination and can be diversified through somatic hypermutation (SHM) or class-switch recombination (CSR). Patterns of repertoire diversity can vary substantially between different health conditions. We use isotype-resolved BCR sequencing to compare B-cell evolution and class-switch fate in healthy individuals and in patients with chronic lymphocytic leukemia (CLL). We show that the patterns of SHM and CSR in B-cells from healthy individuals are distinct from CLL. We identify distinct properties of clonal expansion that lead to the generation of antibodies of different classes in healthy, malignant, and non-malignant CLL BCR repertoires. We further demonstrate that BCR diversity is affected by relationships between antibody variable and constant regions leading to isotype-specific signatures of variable gene usage. This study provides powerful insights into the mechanisms underlying the evolution of the adaptive immune responses in health and their aberration during disease.
Highlights
The adaptive immune system possesses mechanisms for generating diverse repertoires of B-cell receptor (BCRs), which enable the specific recognition of a vast number of encountered antigens [1]
We identify distinct properties of clonal expansion that lead to the generation of antibodies of different classes in healthy and malignant BCR repertoires
Capturing the full complexity of BCR repertoires by high-throughput sequencing poses substantial technical challenges, including PCR and sequencing errors, biased transcript amplification and insufficient transcript capture efficiency, which can affect the estimation of true somatic hypermutation (SHM) rate and repertoire diversity [34,35,36]
Summary
The adaptive immune system possesses mechanisms for generating diverse repertoires of B-cell receptor (BCRs), which enable the specific recognition of a vast number of encountered antigens (estimated unique BCRs in an individual ≈1011–13) [1]. B-cells originate from hematopoietic stem cell progenitors in the bone marrow They contain multiple distinct variable (V), diversity (D) (for the heavy chain only), joining (J), and constant (C) gene segments within the immunoglobulin gene loci [2, 3]. These genes are highly polymorphic and constitute the basis for the germline BCR allelic diversity of an individual. The germline allelic diversity, together with the combinatorial V-(D)-J diversity and imprecise joining of the V-(D)-J gene segments generates a highly diverse pre-immune (naïve) B-cell repertoire [1]
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