Letteratura scientifica selezionata sul tema "Immuneregulation"

Abstract Humans vary considerably both in their baseline and activated immune phenotypes. We developed a user-friendly open-access web portal, ImmuneRegulation, that enables users to interactively explore immune regulatory elements that drive cell-type or cohort-specific gene expression levels. ImmuneRegulation currently provides the largest centrally integrated resource on human transcriptome regulation across whole blood and blood cell types, including (i) ∼43,000 genotyped individuals with associated gene expression data from ∼51,000 experiments, yielding genetic variant-gene expression associations on ∼220 million eQTLs; (ii) 14 million transcription factor (TF)-binding region hits extracted from 1945 ChIP-seq studies; and (iii) the latest GWAS catalog with 67,230 published variant-trait associations. Users can interactively explore associations between queried gene(s) and their regulators (cis-eQTLs, trans-eQTLs or TFs) across multiple cohorts and studies. These regulators may explain genotype-dependent gene expression variations and be critical in selecting the ideal cohorts or cell types for follow-up studies or in developing predictive models. Overall, ImmuneRegulation significantly lowers the barriers between complex immune regulation data and researchers who want rapid, intuitive and high-quality access to the effects of regulatory elements on gene expression in multiple studies to empower investigators in translating these rich data into biological insights and clinical applications, and is freely available at https://immuneregulation.mssm.edu.

Abstract C-type lectins are multifunctional sugar-binders on dendritic cells (DCs) and macrophages that internalize antigens for processing and presentation. MGL recognizes galactose and N-acetylgalactosamine and it is expressed on immature DCs and alternatively activated macrophages (AAM). Helminth parasites contain large number of glycosilated components which appears to play a role in the immuneregulation induced by such infections. To address whether MGL may influence the immune response and resistance to T. crassiceps we infected i.p. MGL deficient (MGL-/-, C57BL/6 background) and wildtype mice (MGL+/+) with 15 non-budding T. crassiceps metacestodes. Parasite burden, cellular and humoral responses were measured during 8 wks of infection. mMGL-/- DCs displayed lower ability to bind T. crassiceps antigens. Compared with wild-type mice, mMGL-/- mice failed to produce significant levels of inflammatory cytokines during the first two weeks of Taenia infection. MGL-/- mice developed a Th2-dominant whereas wild-type mice developed a Th1-dominant immune response after Taenia infection. Associated with the insufficient production of early inflammatory cytokines, mMGL-/- mice harbored significantly higher numbers of parasites whereas WT mice were resistant. Finally, FACS analysis showed overexpression of IL-4Rα, PDL1 and PDL2 on macrophage surface in MGL-/- group unrevealing AAM phenotypes. Thus, MGL may be involved in T. crassiceps recognition and subsequent innate immune activation.

Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs. Therefore, chronic diseases can activate self-reactive lymphocytes, inducing tissue-restricted autoimmunity. During organ transplantation, donor lymphocytes are tested against recipient serum (i.e., cross-matching) to detect antibodies (Abs) against donor human leukocyte antigens, which has been shown to reduce Ab-mediated hyperacute rejection. However, primary allograft dysfunction and rejection still occur frequently. Because donor lymphocytes do not express tissue-restricted SAgs, preexisting Abs against SAgs are undetectable during conventional cross-matching. Preexisting and de novo immune responses to tissue-restricted SAgs (i.e., autoimmunity) play a major role in rejection. In this review, we discuss the evidence that supports autoimmunity as a contributor to rejection. Testing for preexisting and de novo immune responses to tissue-restricted SAgs and treatment based on immune responses after organ transplantation may improve short- and long-term outcomes after transplantation.

Abstract Most experimental models of allograft tolerance depend on manipulation of immune responses at the time of transplant. In such systems, the graft itself probably plays an important role in the induction of unresponsiveness but as a consequence may suffer immune mediated damage. Ideally, recipients would be made specifically unresponsive before transplant such that the graft is protected from the outset. In this report, we demonstrate that CBA mice pretreated with donor-specific transfusion plus anti-CD4 Ab 28 days before transplant accept cardiac allografts indefinitely without further intervention. Adoptive transfer of spleen cells from mice with long term surviving grafts results in donor-specific graft acceptance in naive secondary recipients, indicating that tolerance in this system involves immuneregulation. Regulation develops as a result of the pretreatment protocol alone, since transfer of cells from pretreated but untransplanted mice to naive recipients also leads to prolonged allograft survival without additional therapy. Neutralizing IL-4 at the time of tolerance induction had no effect on graft outcome in primary recipients. However, removal of IL-4 from the adoptive transfer donors at the time of tolerance induction prevented long term engraftment in the majority of secondary recipients. Our data demonstrate that pretreatment of transplant recipients can establish immune regulation powerful enough to override the responses of an intact immune repertoire and that under stringent conditions at least, development of this regulatory population may in part be dependent on IL-4.

Abstract Type 1 Diabetes (T1D) is caused by T cell-mediated destruction of insulin-producing beta cells of the pancreas. The “fertile field” hypothesis of T1D proposes that in a genetically predisposed individual, an inflamed environment prompts the organ towards autoimmunity. In this study, we tested whether chronic and localized accumulation of type I interferons (TI-IFNs) creates a “fertile field” that releases diabetogenic T cells from immuneregulation. In vitro incubation of mouse T cells with IFN-beta renders memory and regulatory T cells with a dramatic defect in the production of phospho-STAT3 in response to the regulatory cytokine IL-10 (but not to IL-6). This resulted in prevention of upregulation of IL-10 induced genes. Altered signaling was NOT caused by reduction of IL-10 receptor expression, nor induction of Suppressor of Cytokine Signaling (SOCS) 1 or 3. Instead, microarray analysis suggested a novel role for the transcription factor STAT1 in dampening IL-10 signaling. IFNbeta induces STAT1 expression causing a reversal of the intracellular STAT1/STAT3 protein ratio that favors a competitive role of STAT1. In agreement, STAT1-KO T cells exposed to IFN-beta did not show any defect in IL-10 signaling. In diabetes-prone NOD mice we discovered a persistent reduction of IL-10 signaling in Tmem and Treg restricted to pancreatic and mesenteric lymph nodes (correlating with the reported local accumulation of TI-IFNs). Treatment of these mice with an IFNRA blocking antibody (that delays the onset and reduces the incidence of T1D) showed a clear restoration of IL-10 signaling. Overall, these data reveal a novel immune defect that, if properly targeted could enhance the efficacy of immunomodulatory strategies to control T1D.

Les syndromes de surcroissance liés à PIK3CA (PROS) sont un groupe de maladies génétiques rares caractérisées par une croissance anormale des tissus et des organes, typiquement causée par des mutations de novo en mosaïque post-zygotique de gain de fonction dans le gène PIK3CA. Ces mutations, qui surviennent au cours du développement embryonnaire, peuvent affecter divers organes et donner lieu à des manifestations cliniques distinctes. Chez l'homme, le tissu adipeux est particulièrement sensible à ces mutations. Récemment, nous avons développé un modèle de souris portant la mutation activatrice PIK3CA spécifiquement dans le tissu adipeux (souris Adipo-CreER). Ces souris présentent une hypoglycémie sévère et un dérèglement endocrinien et métabolique important. Nos résultats montrent que les cellules primaires dérivées de ce modèle de souris dépendent davantage de la glycolyse aérobie, ce qui peut être attribué à l'expression élevée de facteurs de transcription tels que c-Myc et HIF-1. En outre, la suractivation de PIK3CA dans le tissu adipeux crée un microenvironnement particulier caractérisé par une altération du métabolisme, un remodelage de la matrice extracellulaire, une augmentation de la prolifération cellulaire, des cassures de l'ADN et une augmentation de l'infiltration des macrophages. L'analyse unicellulaire et la cytométrie de flux de l'infiltration des cellules immunitaires révèlent que les macrophages présentent un phénotype immunomodulateur semblable à ceux que l'on trouve dans les microenvironnements tumoraux, ce qui pourrait favoriser la croissance des malformations et l'altération de la clairance. Pour valider nos observations, nous examinerons des échantillons humains de PROS, en nous concentrant sur l'infiltration des cellules immunitaires. Nous avons notamment observé une plus forte expression de PD1, qui semble être en corrélation avec la suractivation de PIK3CA et qui pourrait servir de nouvelle cible thérapeutique pour les patients atteints de PROS qui ne répondent que faiblement ou pas du tout aux traitements actuels
PIK3CA-related overgrowth syndromes (PROS) are a group of rare genetic disorders characterized by abnormal tissue and organ overgrowth, typically caused by de novo mosaic post-zygotic gain-of-function mutations in the PIK3CA gene. These mutations, occurring during embryonic development, can affect various organs and result in distinct clinical manifestations. In humans, adipose tissue is particularly susceptible to these mutations. Recently, we developed a mouse model carrying the PIK3CA activating mutation specifically in adipose tissue (Adipo-CreER mice). These mice exhibit severe hypoglycemia and experience significant endocrine and metabolic dysregulation. Our findings show that primary cells derived from this mouse model have an increased reliance on aerobic glycolysis, which can be attributed to elevated expression of transcription factors such as c-Myc and HIF-1. Furthermore, the overactivation of PIK3CA in adipose tissue creates a distinctive microenvironment characterized by altered metabolism, extracellular matrix remodeling, increased cell proliferation, DNA breaks, and enhanced macrophage infiltration. Single-cell analysis and flow cytometry of immune cell infiltration reveal that macrophages display an immunomodulatory phenotype akin to those found in tumor microenvironments, potentially promoting malformation growth and impaired clearance. To validate our observations, we will examine human PROS samples, focusing on immune cell infiltration. Notably, we observed higher expression of PD1, which appears to correlate with PIK3CA overactivation and may serve as a novel therapeutic target for PROS patients who exhibit low or no response to current treatments

Testicular immune imbalance plays a considerable role in the origin of unexplained male infertility. The protection of spermatogenic cells from systemic immune reactions is crucial for maintaining standard spermatozoa generation. Since early postnatal development, the immune system is attuned to the auto-components of the host, yet sperm maturation first occurs during puberty. The variation in timing leads to the identification of spermatogenic proteins as foreign or antigenic. The creation of antibodies targeting these antigens triggers autoimmune responses, which can negatively affect sperm movement, functionality, and reproductive capability. Therefore, it is imperative for the testes to create a specialized immunoprivileged microhabitat that safeguards the allogenic germ cells. Protection of the testicles is achieved through a synchronized effort that includes different cells within the testes and native immune cells. The defense mechanism for the testicles entails isolating cells that could provoke an immune response by employing the blood-testis barrier alongside a combination of hormonal, local cellular signaling, immune-dampening, and immuneregulating processes. These complex processes require a combined theoretical understanding to clarify the physiological background and address immunogenic infertility caused by a dysregulated immune response in the testes. This chapter aims to (a) explain testicular immune privilege components, (b) describe how testicular somatic and immune cells interact to maintain the immune environment, and (c) show how various mechanisms work together to preserve this immune privilege.