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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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The role of complement in apoptotic cell recognition and prevention of autoimmunity. Complement binding to immune complexes or to auto-antigens protects from autoimmunity by enhancing presentation of antigens to self-reactive B cells at an immature stage. Phagocytosis of apoptotic cells generally induces the release of anti-inflammatory cytokines
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Fig3: The role of complement in apoptotic cell recognition and prevention of autoimmunity. Complement binding to immune complexes or to auto-antigens protects from autoimmunity by enhancing presentation of antigens to self-reactive B cells at an immature stage. Phagocytosis of apoptotic cells generally induces the release of anti-inflammatory cytokines

Mentions: Apoptotic cells are recognized by multiple receptors, including complement C3 and C1q fractions, as well as natural autoantibodies (IgM) [124–126]. Natural IgM autoantibodies bind to phospholipids exposed on apoptotic cells and also activate the classical pathway, generating C1q, C4b, C3b, and iC3b ligands for complement receptors. Phagocytosis of apoptotic cells generally induces anti-inflammatory cytokines such as transforming growth factor B and IL-10 [124, 125] (Fig. 3). The association between complement or immunoglobulin deficiencies and CLL could be attributed to a failure of complement-dependent opsonization, resulting in an accumulation of apoptotic cells and a release of autoantigens that constitute a continuous stimulus for CLL clone proliferation (Fig. 3).Fig. 3


Immunological aspects in chronic lymphocytic leukemia (CLL) development.

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

The role of complement in apoptotic cell recognition and prevention of autoimmunity. Complement binding to immune complexes or to auto-antigens protects from autoimmunity by enhancing presentation of antigens to self-reactive B cells at an immature stage. Phagocytosis of apoptotic cells generally induces the release of anti-inflammatory cytokines
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: The role of complement in apoptotic cell recognition and prevention of autoimmunity. Complement binding to immune complexes or to auto-antigens protects from autoimmunity by enhancing presentation of antigens to self-reactive B cells at an immature stage. Phagocytosis of apoptotic cells generally induces the release of anti-inflammatory cytokines
Mentions: Apoptotic cells are recognized by multiple receptors, including complement C3 and C1q fractions, as well as natural autoantibodies (IgM) [124–126]. Natural IgM autoantibodies bind to phospholipids exposed on apoptotic cells and also activate the classical pathway, generating C1q, C4b, C3b, and iC3b ligands for complement receptors. Phagocytosis of apoptotic cells generally induces anti-inflammatory cytokines such as transforming growth factor B and IL-10 [124, 125] (Fig. 3). The association between complement or immunoglobulin deficiencies and CLL could be attributed to a failure of complement-dependent opsonization, resulting in an accumulation of apoptotic cells and a release of autoantigens that constitute a continuous stimulus for CLL clone proliferation (Fig. 3).Fig. 3

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