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Updated: May 22, 2026
Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
Published on: November 26, 2018
Immunological aspects in chronic lymphocytic leukemia (CLL) development
Ricardo García-Muñoz1, Verónica Roldan Galiacho, Luis Llorente
1Hematology Department, Hospital San Pedro, c/Piqueras 98, Logroño, La Rioja, 26006, Spain. rgmunoz@riojasalud.es
Insights
Chronic lymphocytic leukemia (CLL) originates from self-reactive B cells undergoing tolerogenic processes. These B cells (lymphocytes) are selected through antigen encounters, leading to distinct mutated or unmutated IGVH gene profiles in CLL.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- Chronic lymphocytic leukemia (CLL) is a B cell malignancy characterized by either somatically mutated or unmutated IGVH genes.
- The cellular origin of CLL remains incompletely understood, with differing developmental pathways proposed based on IGVH mutation status.
Purpose of the Study:
- To review immunological aspects of CLL pathogenesis.
- To propose a mechanistic hypothesis for the origin of CLL clones within normal B cell development.
- To provide insights into the complex biology and pathogenesis of CLL.
Main Methods:
- Review of existing literature on B cell development and CLL.
- Formulation of a mechanistic hypothesis integrating immunological processes.
- Analysis of proposed B cell selection and tolerization mechanisms in CLL.
Main Results:
- Unmutated CLL may arise from self-reactive B cells undergoing receptor editing, CD5 expression, and anergy in the bone marrow.
- Mutated CLL may arise from B cells in germinal centers that acquire self-reactivity and undergo tolerization mechanisms like receptor editing and anergy.
- Both CLL types are proposed to be proliferations of B lymphocytes selected through encounters with autoantigens and microbial pathogens, despite differing maturation states.
Conclusions:
- Tolerogenic mechanisms, including receptor editing, anergy, CD5+ expression, and somatic hypermutation, are crucial in shaping CLL B cell clones.
- The resulting CLL clones exhibit similar surface markers and gene expression signatures, potentially reflecting attempts to re-educate self-reactive B cells.
- The proposed hypothesis integrates CLL pathogenesis into the framework of normal B cell development, highlighting the role of antigen selection and immune tolerance evasion.
Abstract:
Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self-reactivity for autoantigens-including apoptotic bodies-in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re-educate self-reactive B cells.
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