Immunological aspects in chronic lymphocytic leukemia (CLL) development

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.

Humoral immune responses toward tumor-derived antigens in previously untreated patients with chronic lymphocytic leukemia

“…Deficiencies or reduced levels in one or more complement components have already been reported in CLL patients [35, 36]. However, we demonstrated that CLL sera behave as proper source of complement, in inducing alemtuzumab-mediated CDC as effectively as HD sera.…”

HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway

“…1, 2, 3 Most patients with MLs in clinical course are aggressive and soon after diagnosis require intensive treatment. 4, 5 Both the defective balance between pro- and anti-apoptotic molecules, and aberrant upregulation of prosurvival mechanism have been shown to be related to resistance of ML cells to radiation therapy and chemotherapy.…”

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

“…Chiorazzi and Ferrarini suggested that CLL may derive from marginal zone B-cell clonal expansion [25]. Human B-1 cells have been recently also identified and proposed to originate CLL [26, 27]. This small subset of B-cells constitutively produces antibodies and has been connected to autoimmune disorders.…”