Exploring Epigenetic Drugs in the Regulation of Inflammatory Autoimmune Diseases

During recent years, numerous studies have shown that epigenetics, heritable changes that do not involve alterations in the DNA sequence, play an important role in the development, function, and regulation of the immune system as well as in the onset and progress of autoimmune diseases. For that reason, in the following chapter, we will review some of the most important concepts about epigenetics and how they modulate the development and function of immune cells, specifically macrophages, dendritic cells, and T cells. Moreover, we will review the role of epigenetics on autoimmune diseases, as well as the use of pharmacological modulation of the epigenetic machinery, as an innovative way to approach a potential new treatment or improve the current treatments of autoimmune diseases

A Spontaneous Mouse Model of Lupus: Physiology and Therapy

Spontaneous models of lupus were recognized four decades ago beginning in the early 1960s with the NZB/NZW F1 (NZB/W F1) mouse, an F1 hybrid between the New Zealand Black (NZB) and New Zealand White (NZW) mice. Although the parental strains display limited autoimmunity, the NZB/W F1 develops severe lupus-like features similar to that of human lupus patients. Here, we will address the genetic characteristics of the model and discuss its main characteristics such as the presence of serum antinuclear autoantibodies (ANA) including anti-dsDNA, mild vasculitis, and the development of immune complex-mediated glomerulonephritis. Similar to human lupus, the disease develops primarily in female mice after six months of age, with a lesser percentage and severity in male mice. The relation of this phenomenon will be examined in the context of estrogen levels. The participation of both innate and adaptive immunity will be addressed as well as the contribution of both T and B cells in the development of the clinical aspects of the disease. We will focus on the use of the model as a valuable tool for elucidating the pathogenic mechanisms of the disease, as well as its use as preclinical testing of therapeutic for human use

Human and rodent humoral immune responses to Andes virus structural proteins

AbstractIn the present work we identified B-cell epitopes recognized by sera of humans and rodents naturally infected with Andes virus, a hantavirus present in Chile and Argentina. Analysis of patient and rodent sera with overlapping peptides revealed 21 human and rodent epitopes on the three structural proteins. Whereas in the nucleoprotein the region comprising aa 248–260 was shown to be the key determinant of human sera, the major antigenic site of rodent antibody reactivity is located at aa 326–338. In G1, the main epitope recognized by human sera was mapped to aa 14–26, while rodent antibodies bound predominantly to aa 599–611. In contrast, humans and mice had strong responses to three regions in G2 (aa 691–703, aa 918–930, aa 955–967), of which the last two are associated with neutralization of Hantaan virus. This insight affords important information for the development of immunotherapies for the acute phase of hantavirus cardiopulmonary syndrome

All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation

We demonstrate that all-trans retinoic acid (RA) induces FoxP3+ adaptive T regulatory cells (A-Tregs) to acquire a gut-homing phenotype (α4β7+ CC chemokine receptor 9+) and the capacity to home to the lamina propria of the small intestine. Under conditions that favor the differentiation of A-Tregs (transforming growth factor–β1 and interleukin 2) in vitro, the inclusion of RA induces nearly all activated CD4+ T cells to express FoxP3 and greatly increases the accumulation of these cells. In the absence of RA, A-Treg differentiation is abruptly impaired by proficient antigen presenting cells or through direct co-stimulation. In the presence of RA, A-Treg generation occurs even in the presence of high levels of co-stimulation, with RA attenuating co-stimulation from interfering from FoxP3 induction. The recognition that RA induces gut imprinting, together with our finding that it enhances A-Treg conversion, differentiation, and expansion, indicates that RA production in vivo may drive both the imprinting and A-Treg development in the face of overt inflammation

Complete sequence of the genome of the human isolate of Andes virus CHI-7913: comparative sequence and protein structure analysis

Indexación: ScieloWe report here the complete genomic sequence of the Chilean human isolate of Andes virus CHI-7913. The S, M, and L genome segment sequences of this isolate are 1,802, 3,641 and 6,466 bases in length, with an overall GC content of 38.7%. These genome segments code for a nucleocapsid protein of 428 amino acids, a glycoprotein precursor protein of 1,138 amino acids and a RNA-dependent RNA polymerase of 2,152 amino acids. In addition, the genome also has other ORFs coding for putative proteins of 34 to 103 amino acids. The encoded proteins have greater than 98% overall similarity with the proteins of Andes virus isolates AH-1 and Chile R123. Among other sequenced Hantavirus, CHI-7913 is more closely related to Sin Nombre virus, with an overall protein similarity of 92%. The characteristics of the encoded proteins of this isolate, such as hydrophobic domains, glycosylation sites, and conserved amino acid motifs shared with other Hantavirus and other members of the Bunyaviridae family, are identified and discussed

Cyclosporin A-treated Dendritic Cells may affect the outcome of organ transplantation by decreasing CD4+CD25+ regulatory T cell proliferation

http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602010000300010&lng=es&nrm=isoOne of the mechanisms for generation of tolerance involves immature dendritic cells (DCs) and a subpopulation of regulatory CD4+ CD25+ T lymphocytes (TREG). The purpose of this work was to analyze how Cyclosporine A (CsA), a widely used immunosuppressive drug, may affect TREG proliferation. Purified and activated murine DCs obtained from bone marrow precursors differentiated with rGMCSF were co-cultured with purified CFSE-labeled TREG from OTII mice, and their phenotype and proliferation analyzed by flow cytometry. Our data indicate that DCs differentiated in the presence of CsA show an altered phenotype, with a lower expression of MHC-II and a lower activating capacity. Additionally, these CsA-treated DCs show decreased production of IL-2 and IL-12 and increased IL-10 secretion when stimulated with LPS, indicating an effect on the polarization of the immune response. Interestingly, CsA-treated DCs show an anti-tolerogenic effect since they reduce the proliferation of TREG cells from 72 to 47%. Further inhibition to a 24% of TREG proliferation was obtained as a direct effect of CsA on TREG. In conclusion, the anti-tolerogenic effect of CsA should be considered in the planning of immunosuppression in the context of clinical transplantation

Analysis of Protease Activity in Live Antigen-presenting Cells Shows Regulation of the Phagosomal Proteolytic Contents During Dendritic Cell Activation

Here, we describe a new approach designed to monitor the proteolytic activity of maturing phagosomes in live antigen-presenting cells. We find that an ingested particle sequentially encounters distinct protease activities during phagosomal maturation. Incorporation of active proteases into the phagosome of the macrophage cell line J774 indicates that phagosome maturation involves progressive fusion with early and late endocytic compartments. In contrast, phagosome biogenesis in bone marrow–derived dendritic cells (DCs) and macrophages preferentially involves endocytic compartments enriched in cathepsin S. Kinetics of phagosomal maturation is faster in macrophages than in DCs. Furthermore, the delivery of active proteases to the phagosome is significantly reduced after the activation of DCs with lipopolysaccharide. This observation is in agreement with the notion that DCs prevent the premature destruction of antigenic determinants to optimize T cell activation. Phagosomal maturation is therefore a tightly regulated process that varies according to the type and differentiation stage of the phagocyte