1,720,987 research outputs found
Gamma-chain provides a spontaneous and GH-dependent signal for cell cycle progression related to its cellular amount
No full textUnraveling the link between ectodermal disorders and primary immunodeficiencies
No full textPrimary immunodeficiencies (PIDs) include a heterogeneous group of mostly monogenic diseases characterized by functional/developmental alterations of the immune system. Skin and skin annexa abnormalities may be a warning sign of immunodeficiency, since both epidermal and thymic epithelium have ectodermal origin. In this review, we will focus on the most common immune disorders associated with ectodermal alterations. Elevated IgE levels represent the immunological hallmark of hyper-IgE syndrome, characterized by severe eczema and susceptibility to infections. Ectodermal dysplasia (ED) is a group of rare disorders that affect tissues of ectodermal origin. Hypoidrotic ED (HED), the most common form, is inherited as autosomal dominant, autosomal recessive or X-linked trait (XLHED). HED and XLHED are caused by mutations in NEMO and EDA-1 genes, respectively, and show similarities in the cutaneous involvement but differences in the susceptibility to infections and immunological phenotype. Alterations in the transcription factor FOXN1 gene, expressed in the mature thymic and skin epithelia, are responsible for human and murine athymia and prevent the development of the T-cell compartment associated to ectodermal abnormalities such as alopecia and nail dystrophy. The association between developmental abnormalities of the skin and immunodeficiencies suggest a role of the skin as a primary lymphoid organ. Recently, it has been demonstrated that a co-culture of human skin-derived keratinocytes and fibroblasts, in the absence of thymic components, can support the survival of human haematopoietic stem cells and their differentiation into T-lineage committed cells
Altered signaling through IL-12 receptor in children with very high serum IgE levels
Full text linkAn alteration of Th1/Th2 homeostasis may lead to diseases in humans. In this study, we investigated
whether an impaired IL-12R signaling occurred in children with elevated serum IgE levels divided on
the basis of the IgE levels (group A: >2000 kU/l; group B: <2000 kU/l). We evaluated the integrity of
the IL-12R signaling through the analysis of phosphorylation/activation of STAT4, and mRNA expression
and membrane assembly of the receptor chains. At a functional level, a proliferative defect of lymphocytes
from group A patients was observed. In these patients, an abnormal IL-12R signaling was documented,
and this finding was associated with abnormal expression of the IL-12Rb2 chain. Our data
indicate that in patients with very high IgE levels the generation of Th1 response is impaired, and that
this abnormality associates with abnormal IL-12R signaling
Gamma chain expression level influences spontaneous cell proliferation in different malignant hematopoietic cell lines
No full textAberrant autophagic vesicles in the lymphocytes from patients affected with Ataxia-Telangiectasia
No full textINTRODUCTION: Ataxia-Telangiectasia (AT) is a rare disorder mostly characterized by cerebellar neurodegeneration and immunodeficiency. AT is caused by mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene encoding a kinase, mostly localized in the nucleus and involved in cell-cycle control and DNA repair. ATM also displays a cytoplasmic localization, where its role is still poorly defined.
OBJECTIVE: To evaluate potential abnormalities in the autophagic vesicle formation, which could be responsible for an inappropriate cell-clearance.
METHODS: The ultrastructure of autophagic structures, such as autophagosomes (AP) and autolysosomes (AL), was analyzed by transmission electron microscopy (TEM) in lymphocytes obtained from AT patients and healthy controls and cultured at basal conditions or in a serum-starved medium. A quantitative analysis was also performed.
RESULTS: In the patients at basal conditions, we found that the number of APs was 7 times higher than in the controls (14.00 vs 2.00 average number/100μm2), while the number of ALs was more than two times lower compared to the healthy subjects (2.00 vs 4.80 average number/100μm2). Under basal conditions, APs/ALs ratio was much higher in the patients than in the controls (7 vs 0.5). Under starved conditions, in the patients the number of APs did not further increase, resulting in an APs/ALs ratio comparable to the controls.
CONCLUSIONS: Our data suggest an aberrant pattern of autophagic structures in lymphocytes from AT patients, characterized by an imbalance between autolysosomes and autophagosomes, suggesting an impairment in the cell clearance network
Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation
No full textNoonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity. Since only a few cases of NS/LAH associated to SHOC2 mutations have been so far described, the complex phenotype of the syndrome and the exact mechanism impairing GH/IGFI axis still remain to be elucidated and studies on larger cohort of subjects are needed to better delineate this syndrome
Role of the common γ chain in cell cycle progression of human malignant cell lines
No full textThe γ-chain (γc) is a transducing element shared between several cytokine receptors whose alteration causes X-linked severe combined immunodeficiency. Recently, a direct involvement of γc in self-sufficient growth in a concentration-dependent manner was described, implying a direct relationship between the amount of the molecule and its role in cell cycle progression. In this study, we evaluate whether γc expression could interfere in cell cycle progression also in malignant hematopoietic cells. Here, we first report that in the absence of γc expression, lymphoblastoid B-cell lines (BCLs) die at a higher extent than control cells. This phenomenon is caspase-3 independent and is associated to a decreased expression of the antiapoptotic Bcl-2 family members. By contrast, increased expression of γc protein directly correlates with spontaneous cell growth in several malignant hematopoietic cell lines. We, also, find that the knockdown of γc protein through short interfering RNA is able to decrease the cell proliferation rate in these malignancies. Furthermore, an increased expression of all D-type cyclins is found in proliferating neoplastic cells. In addition, a direct correlation between the amount of γc and cyclins A2 and B1 expression is found. Hence, our data demonstrate that the amount of the γc is able to influence the transcription of genes involved in cell cycle progression, thus being directly involved in the regulatory control of cell proliferation of malignant hematopoietic cells
Genetic basis of altered central tolerance and autoimmune diseases: a lesson from AIRE mutations
No full textThe thymus is a specialized organ that provides an inductive environment for the development of T cells from multi-potent hematopoietic progenitors. Self non-self discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Tolerance represents a state of immunologic non-responsiveness in the presence of a particular antigen. Immune system becomes tolerant to self-antigens through the two main processes, central and peripheral tolerance. The central tolerance takes place within the thymus and represents the mechanism by which T cells binding with high avidity self-antigens, that are potentially autoreactive, are eliminated through the so called negative selection. This process is mostly mediated by medullary thymic epithelia cells (mTECs) and medullary dendritic cells (DCs). A remarkable event in the process is the expression of tissue specific antigens (TSA) by mTECs driven by the transcription factor autoimmune regulator (AIRE). Mutations in this gene result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a rare autosomal recessive disease (OMIM 240300). Thus far, this syndrome is the paradigm of a genetically determined failure of central tolerance and autoimmunty. Patients with APECED have a variable pattern of autoimmune reactions, involving different endocrine and nonendocrine organs. However, although APECED is a monogenic disorder, it is characterized by a wide variability of the clinical expression, thus implying a further role for disease-modifying genes and environmental factors in the pathogenesis. Studies on this polyreactive autoimmune syndrome gave an enormous contribution to unraveling several issues of the molecular basis of autoimmunity. This review will focus on the developmental, functional and molecular events governing central tolerance and on the clinical implication of its failure
Altered regulatory mechanisms governing cell survival in children affected with clustering of autoimmune disorders
No full textClustering of Autoimmune Diseases (CAD) is now emerging as a novel clinical entity within monogenic immune defects with a high familial occurrence. Aim of this study is to evaluate the regulatory mechanisms governing cell survival, paying a particular attention to Fas-induced apoptosis, in a cohort of 23 children affected with CAD. In 14 patients, Fas stimulation failed to induce cell apoptosis and in 1 case it was associated with Fas gene mutation. Our study highlights the importance to evaluate cell apoptosis in the group of children with CAD, which, with this regard, represents a distinct clinical entity
- …
