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Immunological aspects in chronic lymphocytic leukemia (CLL) development.

García-Muñoz R, Galiacho VR, Llorente L - Ann. Hematol. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Hematology Department, Hospital San Pedro, c/Piqueras 98, Logroño, La Rioja, 26006, Spain. rgmunoz@riojasalud.es

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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Infectious tolerance induced by CLL-B cells
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Fig5: Infectious tolerance induced by CLL-B cells

Mentions: IL-10 is a potent inducer of B lymphocyte differentiation as well as an inhibitor of T cell lymphocytes and antigen-presenting cells [129]. Autocrine IL-10 is produced by autoreactive (systemic lupus erythematosus SLE) [130, 131] and immature CD5+ B cells [132]. Significantly, IL-10 could protect from apoptosis and induce the expression of BCL-2 in B cells [129]. Notably, CD5 provides viability signals and leads to IL-10 production, which acts as an autocrine growth factor for leukemic B cells [72]. However, CD5 does not properly inhibit BCR-mediated signaling in CLL B cells [71]. It is possible that autoantigen stimulation through BCR in an autoreactive B cell guide the expression of CD5+ by increasing the threshold for BCR activation to avoid the process leading to antibody production. Moreover, it could also induce the autocrine production of IL-10 to down-regulate costimulatory molecules like CD80, thus promoting an immunosuppressive microenvironment that blocks the activation of T and antigen-presenting cells to avoid autoimmunity. In CLL, this mechanism might induce a process known as infectious tolerance [133] in cell–cell contact, mediated by autocrine IL-10, in a similar manner to regulatory T [134] or B cells [135, 136]. If these autoreactive B cells persist and proliferate by autoantigenic stimulus, presumably a persistent T cell inhibition could be maintained in a straight line with the load of autoreactive CD5+ and IL-10+ B cells. This hypothesis could explain the existence of defective synapses in CLL (Fig. 5).Fig. 5


Immunological aspects in chronic lymphocytic leukemia (CLL) development.

García-Muñoz R, Galiacho VR, Llorente L - Ann. Hematol. (2012)

Infectious tolerance induced by CLL-B cells
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368117&req=5

Fig5: Infectious tolerance induced by CLL-B cells
Mentions: IL-10 is a potent inducer of B lymphocyte differentiation as well as an inhibitor of T cell lymphocytes and antigen-presenting cells [129]. Autocrine IL-10 is produced by autoreactive (systemic lupus erythematosus SLE) [130, 131] and immature CD5+ B cells [132]. Significantly, IL-10 could protect from apoptosis and induce the expression of BCL-2 in B cells [129]. Notably, CD5 provides viability signals and leads to IL-10 production, which acts as an autocrine growth factor for leukemic B cells [72]. However, CD5 does not properly inhibit BCR-mediated signaling in CLL B cells [71]. It is possible that autoantigen stimulation through BCR in an autoreactive B cell guide the expression of CD5+ by increasing the threshold for BCR activation to avoid the process leading to antibody production. Moreover, it could also induce the autocrine production of IL-10 to down-regulate costimulatory molecules like CD80, thus promoting an immunosuppressive microenvironment that blocks the activation of T and antigen-presenting cells to avoid autoimmunity. In CLL, this mechanism might induce a process known as infectious tolerance [133] in cell–cell contact, mediated by autocrine IL-10, in a similar manner to regulatory T [134] or B cells [135, 136]. If these autoreactive B cells persist and proliferate by autoantigenic stimulus, presumably a persistent T cell inhibition could be maintained in a straight line with the load of autoreactive CD5+ and IL-10+ B cells. This hypothesis could explain the existence of defective synapses in CLL (Fig. 5).Fig. 5

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Hematology Department, Hospital San Pedro, c/Piqueras 98, Logroño, La Rioja, 26006, Spain. rgmunoz@riojasalud.es

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.

Show MeSH
Related in: MedlinePlus