Limits...
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.

Show MeSH

Related in: MedlinePlus

Hypothetical immunologic mechanisms implicated in the mutated CLL subset. The mutated CLL subset might derive from any B cells that acquire “de novo self-reactivity” while undergoing the somatic hypermutation process. Following this “de novo auto-reactivity” development, a normal CD5- B cell can theoretically be transformed into a “de novo auto-reactive” memory B cell that expresses CD5 (increasing the threshold for BCR activation), undergoes receptor revision (changing light chain to evade autoimmunity), down-regulates surface Ig (to avoid activation), and remains under check by germinal center exclusion (to diminish the chance to progress in the maturation and become plasma cell). Finally, all these tolerance mechanisms converts the CD5- B cell into an “anergic-edited, CD5+CD27+ memory B cell” excluded from germinal centres
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368117&req=5

Fig2: Hypothetical immunologic mechanisms implicated in the mutated CLL subset. The mutated CLL subset might derive from any B cells that acquire “de novo self-reactivity” while undergoing the somatic hypermutation process. Following this “de novo auto-reactivity” development, a normal CD5- B cell can theoretically be transformed into a “de novo auto-reactive” memory B cell that expresses CD5 (increasing the threshold for BCR activation), undergoes receptor revision (changing light chain to evade autoimmunity), down-regulates surface Ig (to avoid activation), and remains under check by germinal center exclusion (to diminish the chance to progress in the maturation and become plasma cell). Finally, all these tolerance mechanisms converts the CD5- B cell into an “anergic-edited, CD5+CD27+ memory B cell” excluded from germinal centres

Mentions: We propose an alternative theory in that an “original autoreactive B cell” (unmutated) or a “de novo autoreactive B cell” (mutated) undergo the same tolerance mechanisms either in the bone marrow (central) or in the periphery (lymph nodes), leading to homogenous gene expression. On the one hand, in this theory, original autoreactive B cells (unmutated) undergo receptor editing, anergy, and CD5 expression without success, leading to unmutated CLL cells with autoreactivity, retention of signaling through BCRs and poor prognosis (Fig. 1). On the other hand, a normal B cell that acquires autoreactivity during a somatic hypermutation process successfully undergoes receptor revision, anergy, CD5 expression and possible germinal center exclusion, leading to mutated CLL cells without autoreactivity or anergy, and only with self-renewing, low/absent BCR signaling and good prognosis (Fig. 2). Variations of this theory have been proposed to explain other CD5+ B cell lymphomas [109].Fig. 1


Immunological aspects in chronic lymphocytic leukemia (CLL) development.

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

Hypothetical immunologic mechanisms implicated in the mutated CLL subset. The mutated CLL subset might derive from any B cells that acquire “de novo self-reactivity” while undergoing the somatic hypermutation process. Following this “de novo auto-reactivity” development, a normal CD5- B cell can theoretically be transformed into a “de novo auto-reactive” memory B cell that expresses CD5 (increasing the threshold for BCR activation), undergoes receptor revision (changing light chain to evade autoimmunity), down-regulates surface Ig (to avoid activation), and remains under check by germinal center exclusion (to diminish the chance to progress in the maturation and become plasma cell). Finally, all these tolerance mechanisms converts the CD5- B cell into an “anergic-edited, CD5+CD27+ memory B cell” excluded from germinal centres
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: Hypothetical immunologic mechanisms implicated in the mutated CLL subset. The mutated CLL subset might derive from any B cells that acquire “de novo self-reactivity” while undergoing the somatic hypermutation process. Following this “de novo auto-reactivity” development, a normal CD5- B cell can theoretically be transformed into a “de novo auto-reactive” memory B cell that expresses CD5 (increasing the threshold for BCR activation), undergoes receptor revision (changing light chain to evade autoimmunity), down-regulates surface Ig (to avoid activation), and remains under check by germinal center exclusion (to diminish the chance to progress in the maturation and become plasma cell). Finally, all these tolerance mechanisms converts the CD5- B cell into an “anergic-edited, CD5+CD27+ memory B cell” excluded from germinal centres
Mentions: We propose an alternative theory in that an “original autoreactive B cell” (unmutated) or a “de novo autoreactive B cell” (mutated) undergo the same tolerance mechanisms either in the bone marrow (central) or in the periphery (lymph nodes), leading to homogenous gene expression. On the one hand, in this theory, original autoreactive B cells (unmutated) undergo receptor editing, anergy, and CD5 expression without success, leading to unmutated CLL cells with autoreactivity, retention of signaling through BCRs and poor prognosis (Fig. 1). On the other hand, a normal B cell that acquires autoreactivity during a somatic hypermutation process successfully undergoes receptor revision, anergy, CD5 expression and possible germinal center exclusion, leading to mutated CLL cells without autoreactivity or anergy, and only with self-renewing, low/absent BCR signaling and good prognosis (Fig. 2). Variations of this theory have been proposed to explain other CD5+ B cell lymphomas [109].Fig. 1

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