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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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Complement deficiencies and low levels of immunoglobulins observed in CLL could contribute to autoimmunity
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Fig4: Complement deficiencies and low levels of immunoglobulins observed in CLL could contribute to autoimmunity

Mentions: Moreover, complement binding to immune complexes or to autoantigens could protect from autoimmunity by enhancing the presentation of antigens to self-reactive B cells at the immature stage or in the T1–T2 transitional stages [127] (Fig. 3). Complement deficiencies and low levels of immunoglobulins observed in CLL could contribute to impaired retention of self-antigens bound to complement and/or antibodies (immune complexes) in the bone marrow and spleen, having a negative impact on central tolerance mechanisms and contributing to the selection of autoreactive clones that are related or unrelated to CLL (Fig. 4).Fig. 4


Immunological aspects in chronic lymphocytic leukemia (CLL) development.

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

Complement deficiencies and low levels of immunoglobulins observed in CLL could contribute to autoimmunity
© Copyright Policy
Related In: Results  -  Collection

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

Fig4: Complement deficiencies and low levels of immunoglobulins observed in CLL could contribute to autoimmunity
Mentions: Moreover, complement binding to immune complexes or to autoantigens could protect from autoimmunity by enhancing the presentation of antigens to self-reactive B cells at the immature stage or in the T1–T2 transitional stages [127] (Fig. 3). Complement deficiencies and low levels of immunoglobulins observed in CLL could contribute to impaired retention of self-antigens bound to complement and/or antibodies (immune complexes) in the bone marrow and spleen, having a negative impact on central tolerance mechanisms and contributing to the selection of autoreactive clones that are related or unrelated to CLL (Fig. 4).Fig. 4

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