Atherosclerosis antigens as targets for immunotherapy.

Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction and stroke, underlying the first cause of mortality worldwide. Adaptive immunity plays critical roles in atherosclerosis, and numerous studies have ascribed both atheroprotective and atherogenic functions to specific subsets of T and B cells. However, less is known on how antigen specificity determines the protective or adverse outcome of such adaptive responses.

miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton's tyrosine kinase inhibitor ibrutinib.

Activation-induced deaminase expression defines mature B cell lymphoma in the mouse.

Germinal centers (GCs) are the sites of secondary antibody diversification and underlie the mechanism of action of many vaccination strategies. Activation-induced deaminase (AID) triggers secondary antibody diversification through the introduction of somatic changes in immunoglobulin genes which lead to the generation of antibodies of higher affinity and more specialized effector functions. However, AID can also target other genomic regions, giving rise to mutations and chromosome translocations with oncogenic potential.

MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, enhancing the viral infection of Burkitt lymphoma cells.

MYC is an oncogenic transcription factor dysregulated in about half of total human tumors. While transcriptomic studies reveal more than 1000 genes regulated by MYC, a much smaller fraction of genes is directly transactivated by MYC. Virtually all Burkitt lymphoma (BL) carry chromosomal translocations involving MYC oncogene.

Assessing the impact of an antigen-specific antibody response on atherosclerosis development in mice.

The antibody immune response plays a critical role in atherosclerosis. Here, we present a protocol for assessing the impact of an antigen-specific germinal center antibody response on atherosclerosis development, using a pro-atherogenic mouse model deficient for the production of germinal-center-derived antibodies. We describe steps for bone marrow transfer from donor mice into irradiated recipient mice.

MDA-LDL vaccination induces athero-protective germinal-center-derived antibody responses.

Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction, and stroke and is the leading cause of mortality worldwide. Immunization of pro-atherogenic mice with malondialdehyde-modified low-density lipoprotein (MDA-LDL) neo-antigen is athero-protective. However, the immune response to MDA-LDL and the mechanisms responsible for this athero-protection are not completely understood.

Single cell clonal analysis identifies an AID-dependent pathway of plasma cell differentiation.

Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody-secreting plasma cells. Here, we have addressed the role of activation-induced deaminase (AID), which initiates somatic hypermutation and class switch recombination, in the terminal differentiation of GC B cells. By combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells, we have identified a novel subset of late-prePB cells (L-prePB), which shares the strongest clonal relationships with plasmablasts (PBs).

Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming.

Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear.

Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.

Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG).

ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies.

Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area.

A new role for circulating T follicular helper cells in humoral response to anti-PD-1 therapy.

Background: Lung cancer is one of the most frequent malignancies in humans and is a major cause of death. A number of therapies aimed at reinforcing antitumor immune response, including antiprogrammed cell death protein 1 (anti-PD-1) antibodies, are successfully used to treat several neoplasias as non-small cell lung cancer (NSCLC). However, host immune mechanisms that participate in response to anti-PD-1 therapy are not completely understood.

miRNA-Based Therapies in B Cell Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a diverse class of hematological cancers, many of which arise from germinal center (GC)-experienced B cells. Thus GCs, the sites of antibody affinity maturation triggered during immune responses, also provide an environment that facilitates B cell oncogenic transformation. miRNAs provide attractive and mechanistically different strategies to treat these malignancies based on their potential for simultaneous modulation of multiple targets.

Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction.

Objective: microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. Approach and Results: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis.

Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL.

Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex are frequently found in different human cancers. While the tumor suppressor function of this complex is widely established in solid tumors, its role in hematologic malignancies is largely unknown. Recurrent point mutations in BCL7A gene, encoding a subunit of the SWI/SNF complex, have been reported in diffuse large B-cell lymphoma (DLBCL), but their functional impact remains to be elucidated.

Bptf determines oncogenic addiction in aggressive B-cell lymphomas.

Chromatin remodeling factors contribute to establish aberrant gene expression programs in cancer cells and therefore represent valuable targets for therapeutic intervention. BPTF (Bromodomain PhD Transcription Factor), a core subunit of the nucleosome remodeling factor (NURF), modulates c-MYC oncogenic activity in pancreatic cancer. Here, we analyze the role of BPTF in c-MYC-driven B-cell lymphomagenesis using the Eμ-Myc transgenic mouse model of aggressive B-cell lymphoma.

Transfer of extracellular vesicle-microRNA controls germinal center reaction and antibody production.

Intercellular communication orchestrates effective immune responses against disease-causing agents. Extracellular vesicles (EVs) are potent mediators of cell-cell communication. EVs carry bioactive molecules, including microRNAs, which modulate gene expression and function in the recipient cell.

From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation.

B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center B cells, plasma cells and memory B cells.

Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID.

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies.

Association between Chagas disease and changes in the optic nerve and retinal nerve fiber layer.

Purpose: To test the hypothesis that Chagas disease predisposes to optic nerve and retinal nerve fiber layer alterations.

Methods: We conducted a cross-sectional study including 41 patients diagnosed with Chagas disease and 41 controls, paired by sex and age. The patients underwent ophthalmologic examinations, including intraocular pressure measurements, optic nerve and retinal nerve fiber layer screening with retinography, optical coherence tomography, and standard automated perimetry.