BCR
Breakpoint cluster region protein (EC 2.7.11.1) (Renal carcinoma antigen NY-REN-26) [BCR1] [D22S11]
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The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
MeSH Terms
- Aniline Compounds
- Antineoplastic Agents
- Clinical Decision-Making
- Consensus Development Conferences as Topic
- Dasatinib
- Disease Management
- Fusion Proteins, bcr-abl
- Gene Expression
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Life Expectancy
- Monitoring, Physiologic
- Nitriles
- Protein Kinase Inhibitors
- Pyrimidines
- Quality of Life
- Quinolines
- Survival Analysis
Aging is known to induce immunosenescence, resulting in alterations in both the innate and adaptive immune system. Here we evaluated the effects of aging on B cell subsets in peripheral blood of 155 immunologically healthy individuals in four age categories (range 20-95y) via multi-parameter flow cytometry. Furthermore, we studied the naive and antigen-experienced B cell receptor (BCR) repertoire of different age groups and compared it to the clonal BCR repertoire of chronic lymphocytic leukemia (CLL), a disease typically presenting in elderly individuals. Total numbers and relative frequencies of B cells were found to decline upon aging, with reductions in transitional B cells, memory cell types, and plasma blasts in the 70 y group. The BCR repertoire of naive mature B cells and antigen-experienced B cells did not clearly alter until age 70y. Clear changes in IGHV gene usage were observed in naive mature B cells of 70 y individuals, with a transitional pattern in the 50-70y group. IGHV gene usage of naive mature B cells of the 50-70y, but not the 70 y, age group resembled that of both younger (50-70y) and older (70 y) CLL patients. Additionally, CLL-associated stereotypic BCR were found as part of the healthy control BCR repertoire, with an age-associated increase in frequency of several stereotypic BCR (particularly subsets #2 and #5). Composition of the peripheral B cell compartment changes with ageing, with clear reductions in non-switched and CD27 IgG switched memory B cells and plasma blasts in especially the 70 y group. The BCR repertoire is relatively stable until 70y, whereafter differences in IGHV gene usage are seen. Upon ageing, an increasing trend in the occurrence of particular CLL-associated stereotypic BCR is observed.
Keywords
- Aging
- B-lymphocyte
- BCR repertoire
- CLL
- Stereotypic BCR
The Lin28b Let7 axis in fetal/neonatal development plays a role in promoting CD5 B1a cell generation as a B-1 B cell developmental outcome. Here we identify the Let7 target, Arid3a, as a crucial molecular effector of the B-1 cell developmental program. Arid3a expression is increased at pro-B cell stage and markedly increased at pre-B and immature B cell stages in the fetal/neonatal liver B-1 development relative to that in the Lin28b Let7 adult bone marrow (BM) B-2 cell development. Analysis of B-lineage restricted Lin28b transgenic (Tg) mice, Arid3a knockout and Arid3a Tg mice, confirmed that increased Arid3a allows B cell generation without requiring surrogate light chain (SLC) associated pre-BCR stage, and prevents MHC class II cell expression at the pre-B and newly generated immature B cell stages, distinct from pre-BCR dependent B development with MHC class II in adult BM. Moreover, Arid3a plays a crucial role in supporting B1a cell generation. The increased Arid3a leads higher Myc and Bhlhe41, and lower Siglec-G and CD72 at the pre-B and immature B cell stages than normal adult BM, to allow BCR signaling induced B1a cell generation. Arid3a-deficiency selectively blocks the development of B1a cells, while having no detectable effect on CD5 B1b, MZ B, and FO B cell generation resembling B-2 development outcome. Conversely, enforced expression of Arid3a by transgene is sufficient to promote the development of B1a cells from adult BM. Under the environment change between birth to adult, altered BCR repertoire in increased B1a cells occurred generated from adult BM. However, crossed with B1a-restricted V /D/J IgH knock-in mice allowed to confirm that SLC-unassociated B1a cell increase and CLL/lymphoma generation can occur in aged from Arid3a increased adult BM. These results confirmed that in fetal/neonatal normal mice, increased Arid3a at the pre-B cell and immature B cell stages is crucial for generating B1a cells together with the environment for self-ligand reactive BCR selection, B1a cell maintenance, and potential for development of CLL/Lymphoma in aged mice.
MeSH Terms
- Aging
- Animals
- B-Lymphocyte Subsets
- DNA-Binding Proteins
- Gene Expression Regulation, Leukemic
- Histocompatibility Antigens Class II
- Leukemia, Lymphocytic, Chronic, B-Cell
- Mice
- Mice, Knockout
- Neoplasm Proteins
- Precursor Cells, B-Lymphoid
- Receptors, Antigen, B-Cell
- Transcription Factors
Keywords
- Arid3a
- B-1 development
- B1a
- CLL/lymphoma
- Lin28b
Natural killer (NK) cells are a very important component of the innate immune response involved in the lysis of virus infected and tumor cells. Aging has a profound impact in the frequency, phenotype and function of NK cells. Chronic Myeloid Leukemia (CML) is caused by the BCR-ABL gene formation encoding aberrant oncoprotein tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKIs) induces durable deep molecular response. The response to treatment and life expectancy is lower in older patients with chronic phase of CML than in younger patients. In this work we analyse NK cells from TKI-treated CML patients and healthy controls stratified according to age. We have analyzed the expression of NK receptors, activation markers, NK cell differentiation in CD56 and CD56 NK cell subsets and the expression of CD107a and IFN-γ in NK cells stimulated with K562. Whereas significant differences on the phenotype and function of NK cells were found between middle-aged (35-65 years old) and elderly (older than 65) healthy individuals, NK cells from TKI-treated CML patients do not show significant differences related with age in most parameters studied, indicating that age is not a limitation of the NK cell recovery after treatment with TKI. Our results also revealed differences in the expression of NK receptors, activation markers and functional assays in NK cells from TKI-treated CML patients compared with age-matched healthy controls. These results highlight the relevance of NK cells in TKI-treated patients and the need of an extensive analysis of the effect of aging on NK cell phenotype and function in these patients in order to define new NK-cell based strategies directed to control CML progression and achieve long-term disease remission after TKI cessation.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Antineoplastic Agents
- Cell Differentiation
- Female
- Genes, abl
- Humans
- K562 Cells
- Killer Cells, Natural
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Lymphocyte Activation
- Male
- Middle Aged
- Protein Kinase Inhibitors
- Treatment Outcome
Keywords
- CML
- NK cell subsets
- NK receptors
- activation markers
- aging
- cytokines
- differentiation markers
- tyrosine kinase inhibitors
Defective clearance of apoptotic cells in MFG-E8 deficient mice results in lupus-like disease in the mixed B6x129, but not pure B6 background. The lack of overt autoimmunity in MFG-E8-/- B6 mice suggests that accumulation of apoptotic cells is not sufficient to break central tolerance. However, the delayed clearance of apoptotic cells in the follicles of MFG-E8-/- B6 mice provides an excellent opportunity to investigate how B cells respond to excessive apoptotic cells in the periphery under relatively non-inflammatory conditions. In MFG-E8-/- B6 mice, we found increased IgG2c production against apoptotic cells and oxidized LDL. Apoptotic cell induced antibody responses depended on MyD88 signal and T cell help. In addition, MFG-E8-/- B6 mice had enlarged MZ B cell compartments as well as an enhanced antibody response to NP-Ficoll. Moreover, a significant percentage of MZ B cells in aged MFG-E8-/- B6 mice migrated into follicles. Injecting apoptotic cells or oxidized LDL into wild type mice as well as physiological accumulation of LDL in ApoE-/- mice recapitulated the translocation of MZ B cells. To determine how MFG-E8 deficiency affects the functions of autoreactive B cells specific for nucleic acids in the periphery under non-inflammatory conditions, we utilized BCR transgenic mice to bypass central selection and compared the differentiation of TLR9 dependent anti-dsDNA 56R B cells and TLR7 dependent anti-ssRNA H564 B cells in MFG-E8-/- mice. In MFG-E8-/- 56R mice, anti-dsDNA specific 56R/Vκ38c B cells differentiated into MZ B cells but not AFCs. On the contrary, in MFG-E8-/-H564 mice, anti-ssRNA specific H564 B cells further differentiated into GC B cells and AFCs. Adoptive transfer of activated autoreactive B cells confirmed that H564 B cells were more sensitive to apoptotic cell antigens than 56R B cells. Our observations provide new insights about the MZ B cell translocation in lupus patients as well as the dichotomy of TLR9 and TLR7 signals in the pathogenesis of lupus.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- Apoptosis
- B-Lymphocytes
- Cell Differentiation
- Cell Movement
- Cell Proliferation
- Cholesterol, LDL
- Disease Models, Animal
- Female
- Immunoglobulin G
- Kidney
- Lupus Erythematosus, Systemic
- Membrane Glycoproteins
- Mice, Transgenic
- Milk Proteins
- T-Lymphocytes
- Toll-Like Receptor 7
- Toll-Like Receptor 9
In mice, fetal/neonatal B-1 cell development generates murine CD5 B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a V 11/D/J knock-in mouse line (V 11t) that generates an autoreactive antiphosphatidylcholine BCR. Our study revealed that antiphosphatidylcholine B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN), and body cavity as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel, and blood. The body cavity-deposited B1a cells also remigrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an antithymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eμ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgM IgD CD5 CD23 CD43 cells, resembling aggressive human mantle cell lymphoma. Thus, our findings reveal that early generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and mantle cell lymphoma-like neoplasia in aged mice.
MeSH Terms
- Aging
- Animals
- Autoantigens
- B-Lymphocytes
- Carcinogenesis
- Cell Differentiation
- Cyclin D1
- Gene Knock-In Techniques
- Lymphoma, Mantle-Cell
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Phosphatidylcholines
- Receptors, Antigen, B-Cell
- STAT3 Transcription Factor
Predicting patient life expectancy is of great importance for clinicians in making treatment decisions. This prediction needs to be conducted in a dynamic manner, based on longitudinal biomarkers repeatedly measured during the patient's post-treatment follow-up period. The prediction is updated any time a new biomarker measurement is obtained. The heterogeneity across patients of biomarker trajectories over time requires flexible and powerful approaches to model noisy and irregularly measured longitudinal data. In this article, we use functional principal component analysis (FPCA) to extract the dominant features of the biomarker trajectory of each individual, and use these features as time-dependent predictors (covariates) in a transformed mean residual life (MRL) regression model to conduct dynamic prediction. Simulation studies demonstrate the improved performance of the transformed MRL model that includes longitudinal biomarker information in the prediction. We apply the proposed method to predict the remaining time expectancy until disease progression for patients with chronic myeloid leukemia, using the transcript levels of an oncogene, BCR-ABL.
MeSH Terms
- Biomarkers
- Biometry
- Computer Simulation
- Disease Progression
- Genes, abl
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Life Expectancy
- Longitudinal Studies
- Principal Component Analysis
- RNA, Messenger
- Time Factors
Keywords
- Life expectancy
- Longitudinal data
- Stochastic process
- Supermodel
- Survival analysis
Although B cell development requires expression of the B cell antigen receptor (BCR), it remains unclear whether engagement of self-antigen provides a positive impact for most B cells. Here, we show that BCR engagement by self-ligand during development in vivo results in up-regulation of the Nod-like receptor member Nod1, which recognizes the products of intestinal commensal bacteria. In anti-thymocyte/Thy-1 autoreactive BCR knock-in mice lacking self-Thy-1 ligand, immunoglobulin light chain editing occurred, generating B cells with up-regulated Nod1, including follicular and marginal zone B cells with natural autoreactivity. This BCR editing with increased Nod1 resulted in preferential survival. In normal adult mice, most mature B cells are enriched for Nod1 up-regulated cells, and signaling through Nod1 promotes competitive survival of mature B cells. These findings demonstrate a role for microbial products in promoting survival of mature B cells through up-regulated Nod1, providing a positive effect of BCR engagement on development of most B cells.
MeSH Terms
- Aging
- Animals
- B-Lymphocytes
- Gene Knock-In Techniques
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Transgenic
- NLR Proteins
- Nod1 Signaling Adaptor Protein
- Receptors, Antigen, B-Cell
- Signal Transduction
- Up-Regulation
The elderly have reduced humoral immunity, as manifested by increased susceptibility to infections and impaired vaccine responses. To investigate the effects of aging on B-cell receptor (BCR) repertoire evolution during an immunological challenge, we used a phylogenetic distance metric to analyze Ig heavy-chain transcript sequences in both young and elderly individuals before and after influenza vaccination. We determined that BCR repertoires become increasingly specialized over a span of decades, but less plastic. In 50% of the elderly individuals, a large space in the repertoire was occupied by a small number of recall lineages that did not decline during vaccine response and contained hypermutated IgD B cells. Relative to their younger counterparts, older subjects demonstrated a contracted naive repertoire and diminished intralineage diversification, signifying a reduced substrate for mounting novel responses and decreased fine-tuning of BCR specificities by somatic hypermutation. Furthermore, a larger proportion of the repertoire exhibited premature stop codons in some elderly subjects, indicating that aging may negatively affect the ability of B cells to discriminate between functional and nonfunctional receptors. Finally, we observed a decreased incidence of radical mutations compared with conservative mutations in elderly subjects' vaccine responses, which suggests that accumulating original antigenic sin may be limiting the accessible space for paratope evolution. Our findings shed light on the complex interplay of environmental and gerontological factors affecting immune senescence, and provide direct molecular characterization of the effects of senescence on the immune repertoire.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antibodies, Viral
- B-Lymphocytes
- Cell Lineage
- Chronic Disease
- Codon, Nonsense
- Cytomegalovirus
- Cytomegalovirus Infections
- Gene Rearrangement, B-Lymphocyte, Heavy Chain
- Genes, Immunoglobulin
- Humans
- Immunoglobulin D
- Immunoglobulin Heavy Chains
- Influenza A virus
- Influenza B virus
- Influenza Vaccines
- Male
- Middle Aged
- Mutation
- Receptors, Antigen, B-Cell
- Vaccination
- Young Adult
Keywords
- CMV
- UniFrac
- aging
- antibody repertoire
- influenza vaccine
The goal of annual influenza vaccination is to reduce mortality and morbidity associated with this disease through the generation of protective immune responses. The objective of the current study was to examine markers of immunosenescence and identify immunosenescence-related differences in gene expression, gene regulation, cytokine secretion, and immunologic changes in an older study population receiving seasonal influenza A/H1N1 vaccination. Surprisingly, prior studies in this cohort revealed weak correlations between immunosenescence markers and humoral immune response to vaccination. In this report, we further examined the relationship of each immunosenescence marker (age, T cell receptor excision circle frequency, telomerase expression, percentage of CD28 CD4 T cells, percentage of CD28 CD8 T cells, and the CD4/CD8 T cell ratio) with additional markers of immune response (serum cytokine and chemokine expression) and measures of gene expression and/or regulation. Many of the immunosenescence markers indeed correlated with distinct sets of individual DNA methylation sites, miRNA expression levels, mRNA expression levels, serum cytokines, and leukocyte subsets. However, when the individual immunosenescence markers were grouped by pathways or functional terms, several shared biological functions were identified: antigen processing and presentation pathways, MAPK, mTOR, TCR, BCR, and calcium signaling pathways, as well as key cellular metabolic, proliferation and survival activities. Furthermore, the percent of CD4 and/or CD8 T cells lacking CD28 expression also correlated with miRNAs regulating clusters of genes known to be involved in viral infection. Integrated (DNA methylation, mRNA, miRNA, and protein levels) network biology analysis of immunosenescence-related pathways and genesets identified both known pathways (e.g., chemokine signaling, CTL, and NK cell activity), as well as a gene expression module not previously annotated with a known function. These results may improve our ability to predict immune responses to influenza and aid in new vaccine development, and highlight the need for additional studies to better define and characterize immunosenescence.
Keywords
- DNA methylation
- aging
- gene expression profiling
- immunity
- influenza A/H1N1 virus
- influenza vaccines
- miRNA
Chronic myeloid leukemia (CML) is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome which encodes a constitutively activated tyrosine kinase (BCR-ABL). The first line treatment for CML consists on BCR-ABL inhibitors such as Imatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, it is of great value to find molecules that enhance the anti-proliferative effect of first-line drugs. Hyaluronan is the main glycosaminglican of the extracellular matrix which is involved in tumor progression and multidrug resistance. We have previously demonstrated that the inhibition of hyaluronan synthesis by 4-methylumbelliferone (4MU) induces senescence and can revert Vincristine resistance in CML cell lines. However, the effect of 4MU on Imatinib therapy remains unknown. The aim of this work was to determine whether the combination of 4MU with Imatinib is able to modulate the proliferation as well as apoptosis and senescence induction in human CML cell lines. For this purpose the ATCC cell line K562, and its multidrug resistant derivate, Kv562 were used. Cells were exposed to 4MU, Imatinib or a combination of both. We demonstrated that 4MU and Imatinib co-treatment abrogated the proliferation of both cell lines. However, such co-treatment did not increase the levels of apoptosis when compared with the treatment with Imatinib alone. For both cell lines the mechanisms of tumor suppression involved was senescence, since the combination of 4MU and Imatinib arrested the cell cycle and increased senescence associated β-galactosidase activity and senescence associated heterochromatin foci presence when compared to each drug alone. Moreover, 4MU, Imatinib and 4MU Imatinib decreased pAkt/Akt ratio in both cell lines and reduced the pERK/ERK ratio only in K562 cells. These findings highlight the potential use of 4MU together with Imatinib for CML therapy.
MeSH Terms
- Antineoplastic Agents
- Apoptosis
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Extracellular Signal-Regulated MAP Kinases
- Humans
- Hymecromone
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Phosphorylation
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-akt
Keywords
- 4-methylumbelliferone
- Chronic myeloid leukemia
- Imatinib
- Senescence
Chronic myeloid leukemia is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome (Ph), generated by a reciprocal translocation occurring between chromosomes 9 and 22 [t(9;22)(q34;q11)]. As a consequence, a fusion gene (bcr-abl) encoding a constitutively active kinase is generated. The first-line treatment consists on BCR-ABL inhibitors such as Imatinib, Nilotinib and Dasatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, finding molecules that enhance the anti-proliferative effect of first-line drugs is of value. Hyaluronan oligomers (oHA) are known to be able to sensitize several tumor cells to chemotherapy. We have previously demonstrated that oHA can revert Vincristine resistance in mouse lymphoma and human leukemia cell lines. However, little is known about the role of oHA in hematological malignancies. The aim of this work was to determine whether oHA are able to modulate the anti-proliferative effect of Imatinib in chronic myeloid leukemia (CML) cell lines. The effect on apoptosis and senescence as well as the involvement of signaling pathways were also evaluated. For this purpose, the human CML cell lines K562 and Kv562 (resistant) were used. We demonstrated that oHA sensitized both cell lines to the anti-proliferative effect of Imatinib increasing apoptosis and senescence. Moreover, this effect would be accomplished through the down-regulation of the PI3K signaling pathway. These findings highlight the potential of oHA when used as a co-adjuvant therapy for chronic myeloid leukemia.
MeSH Terms
- Animals
- Apoptosis
- Cell Line, Tumor
- Cellular Senescence
- Cytoprotection
- Drug Resistance, Neoplasm
- Fusion Proteins, bcr-abl
- Gene Expression Regulation, Leukemic
- Humans
- Hyaluronic Acid
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Mice
Keywords
- Imatinib
- apoptosis
- chronic myeloid leukemia
- hyaluronan oligomers
- senescence
The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRAS(V12), or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRAS(V12)-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation--a common feature of aging--has the potential to limit aging-associated oncogenesis.
MeSH Terms
- Aging
- Animals
- Bone Marrow
- Cell Transformation, Neoplastic
- Fusion Proteins, bcr-abl
- Inflammation
- Mice
- Mice, Inbred BALB C
- Mice, Transgenic
- Precursor Cells, B-Lymphoid
- Proto-Oncogene Proteins c-myc
- Stem Cell Niche
B cells undergo a number of different developmental stages, from initial formation of their B cell receptor (BCR) genes to differentiation into antibody-secreting plasma cells. Because the BCR is vital in these differentiation steps, autoreactive and exogenous antigen binding to the BCR exert critical selection pressures to shape the B cell repertoire. Older people are more prone to infectious disease, less able to respond well to vaccination and more likely to have autoreactive antibodies. Here we review evidence of changes in B cell repertoires in older people, which may be a reflection of age-related changes in B cell selection processes.
MeSH Terms
- Aging
- Animals
- Antibody Diversity
- Autoantibodies
- B-Lymphocytes
- Cell Differentiation
- Clonal Selection, Antigen-Mediated
- Humans
- Immunity, Humoral
- Receptors, Antigen, B-Cell
Keywords
- B cell
- ageing
- antibodies
- repertoire
- selection
Our goal was to evaluate the perioperative, functional and intermediate term oncological outcomes of robot assisted radical prostatectomy (RARP) in patients ≥ 70 years. The study population (N = 3241) consisted of consecutive patients who underwent RARP for localized prostate cancer by a single surgeon (VP) from January 2008 through February 2012. A query of our Institutional Review Board approved registry identified 400 men ≥ 70 years of age, with good functional status (Charlson co-morbidity index < 3). These patients were propensity score matched to younger patients. Perioperative and postoperative functional and oncologic outcomes for the two groups were compared. Full nerve sparing as well as the ease of nerve sparing were similar in 2 groups. Intra-operative complications were comparable. Postoperative complication occurrence rates were similar. At mean follow up of 34.1 months and 37.2 months respectively in younger and older patients, the continence rate was comparable in 2 groups (91.3% and 87.3%).Average time to continence and potency were similar in 2 groups. A greater proportion of younger patients became potent than elderly (52.3% vs 33.5%,p < 0.001).The biochemical recurrence (BCR) rate was comparable in 2 groups (7.8% vs 8.3%; p = 0.79). The mean time to BCR was also comparable in 2 groups (16 months vs 22.6 months; p = 0.07). In appropriately selected patients (minimal comorbidities with CCI ≤ 2, life expectancy >10 years, localized prostate cancer) RARP is a reasonable option in patients ≥ 7 0 years and provides comparable perioperative, functional and intermediate term oncologic outcomes as compared to younger patients.
MeSH Terms
- Aged
- Erectile Dysfunction
- Follow-Up Studies
- Humans
- Life Expectancy
- Male
- Middle Aged
- Neoplasm Staging
- Perioperative Period
- Propensity Score
- Prostatectomy
- Prostatic Neoplasms
- Recovery of Function
- Robotics
- Treatment Outcome
- Urinary Incontinence
Keywords
- Age stratified analysis
- Oncological outcomes
- Potency
- Prostatectomy
- Robot assisted radical prostatectomy
- Urinary incontinence
Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD(-)CD27(-) (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate-severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Antigens, Surface
- B-Lymphocyte Subsets
- Cellular Senescence
- Humans
- Immunologic Memory
- Immunophenotyping
- Lymphocyte Activation
- Middle Aged
- Phenotype
- Receptors, Antigen, B-Cell
- Severity of Illness Index
- Telomerase
- Young Adult
Keywords
- Aging
- Alzheimer
- B lymphocytes
- Centenarian offspring
- Inflammation
- Telomerase
We examined whether age alters the emergence of high-affinity germinal center B (GCB) cells and switched memory B cells (swBmem) during a primary immune response to a thymus-dependent antigen, using a novel flow cytometric assay to distinguish relative BCR affinity. In young mice, high-affinity B cells predominate in the GCB pool and comprise a smaller proportion of the nascent swBmem pool two weeks after immunization. In aged mice, we observe significant reductions of high-affinity clones among GCB cells, but not nascent swBmem cells. The defect in GC affinity maturation was not overcome by providing excess carrier-specific T cells from young mice, as these cells still displayed compromised effector TFH differentiation in the aged animals. Our results suggest that B cells in aged animals have a reduced ability to prompt effector TFH differentiation, leading to a compromised GC response that results in reduced generation of high-affinity GCB and plasma cells; despite normal production of early swBmem cells.
MeSH Terms
- Aging
- Animals
- B-Lymphocytes
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Germinal Center
- Immunologic Memory
- Mice, Inbred C57BL
- T-Lymphocytes, Helper-Inducer
Keywords
- Antibody affinity
- Germinal center
- Immune senescence
- Memory B cell
- T follicular helper
Elderly humans show decreased humoral immunity to pathogens and vaccines, yet the effects of aging on B cells are not fully known. Chronic viral infection by CMV is implicated as a driver of clonal T cell proliferations in some aging humans, but whether CMV or EBV infection contributes to alterations in the B cell repertoire with age is unclear. We have used high-throughput DNA sequencing of IGH gene rearrangements to study the BCR repertoires over two successive years in 27 individuals ranging in age from 20 to 89 y. Some features of the B cell repertoire remain stable with age, but elderly subjects show increased numbers of B cells with long CDR3 regions, a trend toward accumulation of more highly mutated IgM and IgG Ig genes, and persistent clonal B cell populations in the blood. Seropositivity for CMV or EBV infection alters B cell repertoires, regardless of the individual's age: EBV infection correlates with the presence of persistent clonal B cell expansions, whereas CMV infection correlates with the proportion of highly mutated Ab genes. These findings isolate effects of aging from those of chronic viral infection on B cell repertoires and provide a baseline for understanding human B cell responses to vaccination or infectious stimuli.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antibodies, Viral
- B-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytomegalovirus
- Cytomegalovirus Infections
- Epstein-Barr Virus Infections
- Genes, Immunoglobulin
- Herpesvirus 4, Human
- Humans
- Middle Aged
- Mutation
- Young Adult
Our laboratory has contributed to the areas of B cell receptor (BCR) and pre-BCR gene identification and transcription and has focused on the problem of the aged immune system in mice and humans for the last 15 years. We have found biomarkers for the decrease in B cell function in aged mice and humans. These include decreases in immunoglobulin (Ig) class switch (e.g., IgM to IgG), decreases in the enzyme AID (activation-induced cytidine deaminase) and decreases in the transcription factor E47. The E47 mRNA stability is decreased in old B cells due to decreased phospho-MAPKinase and phospho-TTP (tristetraprolin). Inflammation, e.g., TNF-α, which increases with age, impacts B cells directly by increasing their TNF-α and NF-κB and leads to the above decreased pathway. Both class switch and affinity maturation are decreased in elderly responses to the influenza vaccine and biomarkers we have found (numbers and percentages of switched memory B cells and AID in stimulated B cells in culture) can predict a beneficial or decreased immune response to the vaccine. Current and future avenues to improve the humoral immune response in the elderly are discussed.
MeSH Terms
- Age Factors
- Aging
- Animals
- B-Lymphocytes
- Humans
- Immunity, Humoral
- Immunoglobulin Class Switching
- Mice
Bosutinib is a third-generation dual tyrosine kinase inhibitor (TKI) inhibiting Abl and Src kinases. It was developed to act on up-regulated tyrosine kinases (TKs) like BCR-ABL in Philadelphia chromosome positive (Ph ) chronic myeloid leukemia (CML) when resistance to first- and second-generation TKIs developed. However, first- and second-generation TKIs show off-target effects on bone metabolism, whereas studies on skeletal adverse effects of bosutinib are still lacking. Therefore, it was the aim of this study to continuously expose juvenile rats to bosutinib and to analyze its influence on the growing bone. Starting after weaning, 4-week-old Wistar rats were chronically exposed over a 28-day period to varying concentrations of bosutinib, which were continuously administered subcutaneously via implanted Alzet® micro-osmotic pumps. After necropsy, the length of the femora and tibiae were analyzed. Continuous administration of bosutinib by micro-osmotic pumps led to serum drug levels in the lower therapeutic range, was well tolerated, and exhibited only minor adverse effects on the growing skeleton. Micro-osmotic pumps represent a convenient system for continuous TKI release in young growing rats. Compared to first- and second-generation TKIs, bosutinib seems to exert fewer adverse effects on the growing bone.
MeSH Terms
- Aging
- Aniline Compounds
- Animals
- Bone Development
- Drug Delivery Systems
- Femur
- Infusion Pumps, Implantable
- Male
- Nitriles
- Osmosis
- Protein Kinase Inhibitors
- Quinolines
- Rats
- Rats, Wistar
- Tibia
- Weight Gain