ABSTRACT
The development of safe, long-term, effective vaccines is still a challenge for many infectious diseases. Thus, the search of new vaccine strategies and production platforms that allow rapidly and effectively responding against emerging or reemerging pathogens has become a priority in the last years. Targeting the antigens directly to dendritic cells (DCs) has emerged as a new approach to enhance the immune response after vaccination. This strategy is based on the fusion of the antigens of choice to monoclonal antibodies directed against specific DC surface receptors such as CD40. Since time is essential, in silico approaches are of high interest to select the most immunogenic and conserved epitopes to improve the T- and B-cells responses. The purpose of this review is to present the advances in DC vaccination, with special focus on DC targeting vaccines and epitope mapping strategies and provide a new framework for improving vaccine responses against infectious diseases.
Subject(s)
Communicable Diseases, Emerging , Vaccines , Antigens , CD40 Antigens , Communicable Diseases, Emerging/prevention & control , Dendritic Cells , Humans , VaccinationABSTRACT
The 3' regulatory region (3'RR) located downstream from the Cα gene is the conductor of transcription, accessibility, and remodeling of the IgH locus at mature B-cell stages. Convincing demonstrations of the essential contributions of the 3'RR in B-cell lymphomagenesis have been provided by mouse models which bring the oncogene c-Myc under the 3'RR transcriptional control. In this study, we developed a mouse model of CD138+ plasma B-cell lymphomas. If the KI of c-myc directly into Cα just 5' to the 3'RR in iMycCα mice produced B-cell lymphomas with low kinetics, we enforced c-myc production in iMycCα mice by the generation of homozygous c-myc transgenic mice. Our results show that homozygous iMycCα mice lead to a mouse model of plasma CD138+ B-cell lymphomas with interesting and wide transcriptomic similarities to human multiple myeloma and appropriated emergence kinetics that can be used to test new experimental therapeutic approaches.
Subject(s)
Immunoglobulin Heavy Chains , Lymphoma, B-Cell , Animals , B-Lymphocytes/pathology , Disease Models, Animal , Humans , Immunoglobulin Heavy Chains/genetics , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Mice , Mice, Transgenic , Regulatory Sequences, Nucleic AcidABSTRACT
Chromosomal translocations linking various oncogenes to transcriptional enhancers of the immunoglobulin heavy chain (IgH) locus are often implicated as the cause of B-cell malignancies. Two major IgH transcriptional enhancers have been reported so far. The Eµ enhancer located upstream of the Cµ gene controls early events in B-cell maturation such as VDJ recombination. The 3' regulatory region (3'RR) located downstream from the Cα gene controls late events in B-cell maturation such as IgH transcription, somatic hypermutation, and class switch recombination. Convincing demonstrations of the essential contributions of both Eµ and 3'RR in B-cell lymphomagenesis have been provided by transgenic and knock-in animal models which bring the oncogene c-myc under Eµ/3'RR transcriptional control. This short review summarizes the different mouse models so far available and their interests/limitations for progress in our understanding of human c-myc-induced B-cell lymphomagenesis.
Subject(s)
Disease Models, Animal , Gene Expression Regulation, Neoplastic , Genes, myc/genetics , Immunoglobulin Heavy Chains/genetics , Lymphoma, B-Cell/genetics , Animals , Enhancer Elements, Genetic , Humans , Lymphoma, B-Cell/pathology , Mice , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Translocation, GeneticABSTRACT
Numerous B-cell lymphomas feature translocations linking oncogenes to different locations in the immunoglobulin heavy chain (IgH) locus. During Burkitt lymphoma (BL), IgH breakpoints for c-myc translocation stand either close to JH segments or within switch regions. Transcription, accessibility, and remodeling of the IgH locus are under the control of the 2 potent cis-acting enhancer elements: Eµ and the 3' regulatory region (3'RR). To ensure their respective contributions to oncogene deregulation in the context of the endogenous IgH locus, we studied transgenic mice harboring a knock-in of c-myc in various positions of the IgH locus (3' to JH segments, 5' to Cµ with Eµ deletion and Cα). The observed spectrum of tumors, kinetics of emergence, and transcriptome analysis provide strong evidence that both Eµ and 3'RR deregulate c-myc and cooperate together to promote B-cell lymphomagenesis. Transgenics mimicking endemic BL (with c-myc placed 3' to JH segments) exhibited the highest rate of B-cell lymphoma emergence, the highest Ki67 index of proliferation, and the highest transcriptomic similarities to human BL. The 3'RR enhancer alone deregulated c-myc and initiated the development of BL-like lymphomas, suggesting that its targeting would be of therapeutic interest to reduce c-myc oncogenicity in vivo.
Subject(s)
Dromaiidae , Lymphoma, B-Cell , Animals , Immunoglobulin Heavy Chains/genetics , Lymphoma, B-Cell/genetics , Mice , Mice, Transgenic , Regulatory Sequences, Nucleic AcidSubject(s)
B-Lymphocytes/physiology , Cell Differentiation , Immunoglobulin Heavy Chains/genetics , Regulatory Sequences, Nucleic Acid/physiology , Animals , B-Lymphocyte Subsets/physiology , Cell Differentiation/genetics , Cell Differentiation/immunology , Genetic Loci , Humans , Regulatory Sequences, Nucleic Acid/geneticsSubject(s)
B-Lymphocytes/immunology , Cytidine Deaminase/genetics , Enhancer Elements, Genetic/genetics , Immunoglobulin Heavy Chains/genetics , Receptors, Antigen, B-Cell/genetics , Animals , Cell Differentiation , Computational Biology , DNA End-Joining Repair , DNA Repair , High-Throughput Screening Assays , Immunoglobulin Class Switching , Lymphocyte Activation , Mice , Mice, Knockout , Receptors, Antigen, B-Cell/metabolismSubject(s)
B-Lymphocytes/physiology , Enhancer Elements, Genetic/genetics , Immunoglobulin Heavy Chains/genetics , Immunoglobulin kappa-Chains/genetics , Precursor Cells, B-Lymphoid/physiology , Regulatory Sequences, Nucleic Acid/genetics , V(D)J Recombination/genetics , Animals , Cell Differentiation , Gene Silencing , Genes, RAG-1/genetics , Immunoglobulin Class Switching , Mice , Mice, Knockout , Transcriptional ActivationSubject(s)
3' Flanking Region/genetics , 5' Flanking Region/genetics , B-Lymphocytes/immunology , Enhancer Elements, Genetic , Immunoglobulin Heavy Chains/genetics , Locus Control Region/genetics , Regulatory Sequences, Nucleic Acid/genetics , Animals , Cells, Cultured , Female , Homeodomain Proteins/physiology , Immunoglobulin Class Switching/genetics , Male , Mice , Mice, Knockout , Sequence Deletion , Somatic Hypermutation, Immunoglobulin , Transcription, GeneticABSTRACT
The immunoglobulin heavy chain (IgH) 3' regulatory region (3'RR) superenhancer controls B2 B-cell IgH transcription and cell fate at the mature stage but not early repertoire diversity. B1 B cells represent a small percentage of total B cells differing from B2 B cells by several points such as precursors, development, functions, and regulation. B1 B cells act at the steady state to maintain homeostasis in the organism and during the earliest phases of an immune response, setting them at the interface between innate and acquired immunity. We investigated the role of the 3'RR superenhancer on B1 B-cell fate. Similar to B2 B cells, the 3'RR controls µ transcription and cell fate in B1 B cells. In contrast to B2 B cells, 3'RR deletion affects B1 B-cell late repertoire diversity. Thus, differences exist for B1 and B2 B-cell 3'RR control during B-cell maturation. For the first time, these results highlight the contribution of the 3'RR superenhancer at this interface between innate and acquired immunity.
Subject(s)
B-Lymphocytes/immunology , Immunoglobulin Heavy Chains/genetics , Regulatory Sequences, Nucleic Acid/physiology , Adaptive Immunity , Animals , B-Lymphocytes/cytology , Cell Line , Genes, Immunoglobulin Heavy Chain/genetics , Immunity, Innate , Mice , Sequence Analysis, DNA , Transcription, Genetic , V(D)J RecombinationSubject(s)
3' Flanking Region/genetics , B-Lymphocyte Subsets/physiology , Enhancer Elements, Genetic/genetics , Immunoglobulin A/metabolism , Immunoglobulin Heavy Chains/genetics , Peritoneum/immunology , Pleura/immunology , Animals , Cell Differentiation , Cell Lineage , Gene Expression Regulation , Immunoglobulin A/genetics , Immunoglobulin Class Switching , Mice , Mice, 129 Strain , Mice, KnockoutABSTRACT
The four transcriptional enhancers located in the 3' regulatory region (3'RR) of the IgH locus control the late phases of B-cell maturation, namely IgH locus transcription, somatic hypermutation and class switch recombination. Doctor Jekyll by nature, the 3'RR acts as Mister Hyde in case of oncogenic translocation at the IgH locus taking under its transcriptional control the translocated oncogene. The aim of this review is to show this duality on the basis of the latest scientific advances in the structure and function of the 3'RR and to hIghlight the targeting of the 3'RR as a potential therapeutic approach in mature B-cell lymphomas.
