RESUMEN
Age-associated B cells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21-/low ). The Ig repertoire expressed by ABCs in aged mice is diverse and exhibits signs of somatic hypermutation (SHM). A CD21-/low B-cell population is expanded in autoimmune diseases, e.g. systemic lupus erythematosus, as well as in lupus-prone NZB/W mice and in mice lacking a pre-B cell receptor (SLC-/- ). However, the nature of the CD21-/low B cells (hereafter ABCs) in autoimmunity is not well understood. Here we show that in young SLC-/- mice, the vast majority of the ABCs express memory B-cell (MBC) markers in contrast to wild-type controls. A similar population is present in lupus-prone MRL mice before and at disease onset. In SLC-/- mice, a majority of the ABCs are IgM+ , their VH genes have undergone SHM, show clonal diversification and clonal restriction at the H-CDR3 level. ABC hybridomas, established from SLC-/- mice, secrete typical lupus autoantibodies, e.g. anti-Smith antigen, and some of those that bind to DNA comprise a H-CDR3 that is identical to previously described IgM anti-DNA antibodies from lupus-prone mice. Together, these results reveal that ABCs in autoimmune mice are comprised of autoreactive MBCs expressing highly restricted H-CDR3 repertoires.
Asunto(s)
Envejecimiento/inmunología , Autoinmunidad , Subgrupos de Linfocitos B/inmunología , Envejecimiento/genética , Secuencia de Aminoácidos , Animales , Células Presentadoras de Antígenos/inmunología , Autoanticuerpos/biosíntesis , Autoanticuerpos/genética , Autoinmunidad/genética , Regiones Determinantes de Complementariedad/genética , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Hibridomas/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoglobulina M/genética , Inmunoglobulina M/metabolismo , Memoria Inmunológica/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos MRL lpr , Ratones Endogámicos NZB , Ratones Noqueados , Receptores de Células Precursoras de Linfocitos B/deficiencia , Receptores de Células Precursoras de Linfocitos B/genética , Receptores de Células Precursoras de Linfocitos B/inmunología , Receptores de Complemento 3d/metabolismo , Homología de Secuencia de Aminoácido , Hipermutación Somática de InmunoglobulinaRESUMEN
B lymphopoiesis in aged mice is characterized by reduced B cell precursors and an altered Ab repertoire. This likely results, in part, from reduced surrogate L chains in senescent B cell precursors and compromised pre-BCR checkpoints. Herein, we show that aged mice maintain an ordinarily minor pool of early c-kit(+) pre-B cells, indicative of poor pre-BCR expression, even as pre-BCR competent early pre-B cells are significantly reduced. Therefore, in aged mice, B2 B lymphopoiesis shifts from dependency on pre-BCR expansion and selection to more pre-BCR-deficient pathways. B2 c-kit(+) B cell precursors, from either young or aged mice, generate new B cells in vitro that are biased to larger size, higher levels of CD43, and decreased kappa L chain expression. Notably, immature B cells in aged bone marrow exhibit a similar phenotype in vivo. We hypothesize that reduced surrogate L chain expression contributes to decreased pre-B cells in aged mice. The B2 pathway is partially blocked with limited B cell development and reduced pre-BCR expression and signaling. In old age, B2 pathways have limited surrogate L chain and increasingly generate new B cells with altered phenotype and L chain expression.
Asunto(s)
Envejecimiento/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Diferenciación Celular/inmunología , Inmunoglobulina de Cadenas Ligeras Subrogadas/biosíntesis , Inmunoglobulina de Cadenas Ligeras Subrogadas/genética , Envejecimiento/genética , Animales , Subgrupos de Linfocitos B/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Diferenciación Celular/genética , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Células Cultivadas , Inmunoglobulina de Cadenas Ligeras Subrogadas/metabolismo , Inmunofenotipificación , Linfopenia/genética , Linfopenia/inmunología , Linfopenia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Células Precursoras de Linfocitos B/deficiencia , Receptores de Células Precursoras de Linfocitos B/metabolismo , Receptores de Células Precursoras de Linfocitos B/fisiología , Células Precursoras de Linfocitos B/inmunología , Células Precursoras de Linfocitos B/metabolismo , Células Precursoras de Linfocitos B/patología , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Early B-cell development is an ordered and highly regulated process with alternating phases of cell proliferation and differentiation leading to B cells with the ability to recognize an extraordinarily large repertoire of different antigens. Here, we discuss what is currently known about the receptors in B-cell progenitors and how their signaling pathways influence immunoglobulin (Ig) gene rearrangement and the transcriptional program of early B cells. In particular, we address the interplay of the interleukin-7 receptor and the pre-B-cell receptor (preBCR) in shaping the survival, proliferation, and differentiation of early B cells. Each receptor addresses a unique set of signaling components but they also share signaling pathways, most prominently the MAPK/Erk and phosphoinositide-3 kinase pathways. The latter pathway regulates transcription factors of the FoxO family that play a central role in the proliferation to differentiation switch of pre-B cells. Interestingly, these two alternative cellular programs (proliferation and differentiation) are both controlled by the preBCR. Finally, we discuss how mutations or alterations of these pathways result in deregulated pre-B-cell expansion and leukemia.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Diferenciación Celular/inmunología , Células Precursoras de Linfocitos B/inmunología , Transducción de Señal/inmunología , Animales , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/patología , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/inmunología , Diferenciación Celular/genética , Humanos , Receptores de Células Precursoras de Linfocitos B/deficiencia , Receptores de Células Precursoras de Linfocitos B/genética , Receptores de Células Precursoras de Linfocitos B/fisiología , Células Precursoras de Linfocitos B/citología , Células Precursoras de Linfocitos B/patología , Transducción de Señal/genética , Activación Transcripcional/inmunologíaRESUMEN
B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.