A novel homozygous mutation of the AIRE gene in an APECED patient from Pakistan: case report and review of the literature

Autoimmune-poly-endocrinopathy-candidiasis-ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison's disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto's thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G > C (p. Arg132Ser; p. R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin a molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to a importins, we show that p. R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

Regulatory T (Treg) cells represent a subpopulation of suppressor CD4+ T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity

Detection of GAD65 Autoreactive T-Cells by HLA Class I Tetramers in Type 1 Diabetic Patients

Type 1 diabetes (T1D) is an autoimmune disease, in which pancreatic β cells are destroyed in genetically predisposed individuals. While the direct contribution of autoantibodies to the disease pathogenesis is controversial, it is generally recognised that the mechanism of β cell destruction is mediated by autoreactive T cells that had escaped the thymic selection. We aimed to design a method to detect circulating CD8+ T cells autoreactive against an epitope of the glutamic acid decarboxylase autoantigen, isoform 65 (GAD65) ex vivo in T1D patients by using HLA class I tetramers. Low frequencies of GAD65 peptide-specific CD8+ cytotoxic T lymphocytes were detected in peripheral blood lymphocytes (PBMC) of normal controls after GAD65 peptide-specific stimulation. Conversely, their frequencies were significantly higher than in controls in PBMC of T1D patients after GAD65 peptide stimulation. These preliminary data are encouraging in order to develop a reliable assay to be employed in large-scale screening studies

Immunoregulatory Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles on T Lymphocytes.

The immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. We have recently shown that the immunosuppressive effects of MSCs on B lymphocytes in peripheral blood mononuclear cell (PBMC) culture can be reproduced by extracellular vesicles (EVs) isolated from MSC culture supernatants. Here we investigated the effect of bone marrow-derived MSC-EVs on T cells on PBMC cultures stimulated with anti-CD3/CD28 beads. Stimulation increased the number of proliferating CD3+ cells as well as of regulatory T cells (Tregs). Coculture with MSCs inhibited the proliferation of CD3+ cells, with no significant changes in apoptosis. Addition of MSC-EVs to PBMCs did not affect proliferation of CD3+ cells, but induced the apoptosis of CD3+ cells and of the CD4+ subpopulation and increased the proliferation and the apoptosis of Tregs. Moreover, MSC-EV treatment increased the Treg/Teff ratio and the immunosuppressive cytokine IL-10 concentration in culture medium. The activity of indoleamine 2,3-dioxygenase (IDO), an established mediator of MSC immunosuppressive effects, was increased in supernatants of PBMCs cocultured with MSCs, but was not affected by the presence of MSC-EVs. MSC-EVs demonstrate immunomodulatory effects on T cells in vitro. However, these effects and the underlying mechanisms appear to be different from those exhibited by their cells of origin

Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies

AbstractThe pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals

p53 Activation Effect in the Balance of T Regulatory and Effector Cell Subsets in Patients With Thyroid Cancer and Autoimmunity

Carcinomas evade the host immune system by negatively modulating CD4+ and CD8+ T effector lymphocytes through forkhead box protein 3 (FOXP3) positive T regulatory cells' increased activity. Furthermore, interaction of the programmed cell death 1 (PD1) molecule and its ligand programmed cell death ligand 1 (PDL1) inhibits the antitumor activity of PD1+ T lymphocytes. Immunotherapy has become a powerful strategy for tailored cancer patients' treatment both in adult and pediatric patients aiming to generate potent antitumor responses. Nevertheless, immunotherapies can generate autoimmune responses. This study aimed to investigate the potential effect of the transformation-related protein 53 (p53) reactivation by a peptide-based inhibitor of the MDM2/MDM4 heterodimer (Pep3) on the immune response in a solid cancer, i.e., thyroid carcinoma frequently presenting with thyroid autoimmunity. In peripheral blood mononuclear cell of thyroid cancer patients, Pep3 treatment alters percentages of CD8+ and CD4+ T regulatory and CD8+ and CD4+ T effector cells and favors an anticancer immune response. Of note that reduced frequencies of activated CD8+ and CD4+ T effector cells do not support autoimmunity progression. In evaluating PD1 expression under p53 activation, a significant decrease of activated CD4+PD1+ cells was detected in thyroid cancer patients, suggesting a defective regulation in the initial activation stage, therefore generating a protective condition toward autoimmune progression

Integration of Traditional and Western Medicine in Vietnamese Populations: A Review of Health Perceptions and Therapies.

In Vietnam, two types of traditional medicine (TM) are practiced: thuoc nam, medicine of the South, and thuoc bac, medicine of the North, both of which are largely based on herbal drugs used by different Vietnamese ethnic groups. This review presents recently published information from various databases regarding TM, especially herbal drugs, and its integration with Western medical practices outside and inside Vietnam. We first discuss the integration of traditional and modern health concepts by Vietnamese immigrants living outside Vietnam. Next, we describe native and emigrated health education and practices of pharmacy students, health professionals, and citizens living in Vietnam. Finally, we report the recent biological validation of medicinal plants and non-herbal therapies emerging from Vietnamese TM and their current and potential medical uses as identified by Western approaches. The main example described here involves utilization of the tree Artocarpus tonkinensis by the ethnic minority of Black Hmong in northern Vietnam, who use a decoction of its leaves to treat arthritis and backache without apparent adverse effects. Our comprehensive review emphasizes that, although Vietnam has a very rich collection of TM practices (particularly the use of herbal drugs), these therapies should be biologically and clinically validated with modern Western methods for optimal integration of Western and traditional medicine in global populations

Functional and Taxonomic Traits of the Gut Microbiota in Type 1 Diabetes Children at the Onset: A Metaproteomic Study

Type 1 diabetes (T1D) is a chronic autoimmune metabolic disorder with onset in pediatric/adolescent age, characterized by insufficient insulin production, due to a progressive destruction of pancreatic beta-cells. Evidence on the correlation between the human gut microbiota (GM) composition and T1D insurgence has been recently reported. In particular, 16S rRNA-based metagenomics has been intensively employed in the last decade in a number of investigations focused on GM representation in relation to a pre-disease state or to a response to clinical treatments. On the other hand, few works have been published using alternative functional omics, which is more suitable to provide a different interpretation of such a relationship. In this work, we pursued a comprehensive metaproteomic investigation on T1D children compared with a group of siblings (SIBL) and a reference control group (CTRL) composed of aged matched healthy subjects, with the aim of finding features in the T1D patients' GM to be related with the onset of the disease. Modulated metaproteins were found either by comparing T1D with CTRL and SIBL or by stratifying T1D by insulin need (IN), as a proxy of beta-cells damage, showing some functional and taxonomic traits of the GM, possibly related to the disease onset at different stages of severity

環境管理計画への市民参加とその規定因としてのエンパワーメント

<p>DMPC/2/siRNA treatment of Jurkat T cells, 48 hours from the beginning of transfection.</p