Thymic stromal alterations and genetic disorders of immune system

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FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches

Since the discovery of FOXN1 deficiency, the human counterpart of the nude mouse, a growing body of evidence investigating the role of FOXN1 in thymus and skin, has been published. FOXN1 has emerged as fundamental for thymus development, function, and homeostasis, representing the master regulator of thymic epithelial and T cell development. In the skin, it also plays a pivotal role in keratinocytes and hair follicle cell differentiation, although the underlying molecular mechanisms still remain to be fully elucidated. The nude severe combined immunodeficiency phenotype is indeed characterized by the clinical hallmarks of athymia with severe T cell immunodeficiency, congenital alopecia, and nail dystrophy. In this review, we summarize recent discoveries in the field and give interesting perspective about new and promising therapeutic approaches for disorders of immune system with athymia

Assessment of chest high-field magnetic resonance imaging in children and young adults with noncystic fibrosis chronic lung disease: comparison to high-resolution computed tomography and correlation with pulmonary function.

Magnetic resonance imaging (MRI) has been proposed as a radiation-free alternative to high resolution computed tomography (HRCT) for the assessment and follow-up of chest disorders. Thus far, no study has compared the efficacy of high-field MRI and HRCT in children and adults with noncystic fibrosis (CF) chronic lung disease. The aims of our study were: (1) to assess whether chest high-field MRI is as effective as chest HRCT in identifying pulmonary abnormalities; and (2) to investigate the relationships between the severity and extent of lung disease, and functional data in patients with non-CF chronic lung disease. Forty-one subjects (median age, 13.8 years; range, 5.9-29.3 years; 30 children/11 adults) with primary ciliary dyskinesia (n = 14), primary immunodeficiency (n = 14), or recurrent pneumonia (n = 13) underwent pulmonary function tests, chest HRCT (120 kV, dose-modulated mAs) and high-field 3.0-T MRI (HASTE; transversal orientation; repetition time/echo time/flip angle/acquisition time, infinite/92 milliseconds/150 degrees/approximately 90 seconds). HRCT and MRI images were scored in consensus by 2 raters using a modified version of the Helbich scoring system. The maximal score was 25. HRCT and high-field MRI total scores were 11 (range: 1-20) and 11 (range: 1-17), respectively. There was good agreement between the 2 techniques for all scores (r > 0.8). HRCT and MRI total scores, and extent of bronchiectasis scores were significantly related to pulmonary function tests (r = -0.4, P < 0.05). The MRI mucous plugging score was significantly related to pulmonary function tests (r = -0.4, P < 0.05). Chest high-field 3.0-T MRI appears to be as effective as HRCT in assessing the extent and severity of lung abnormalities in non-CF chronic lung diseases, and might be a reliable radiation-free option to HRCT

Altered signaling through IL-12 receptor in children with very high serum IgE levels

An 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

From Murine to Human Nude/SCID: The Thymus, T-Cell Development and the Missing Link

Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia

Epigenetic Alterations in Inborn Errors of Immunity

The epigenome bridges environmental factors and the genome, fine-tuning the process of gene transcription. Physiological programs, including the development, maturation and maintenance of cellular identity and function, are modulated by intricate epigenetic changes that encompass DNA methylation, chromatin remodeling, histone modifications and RNA processing. The collection of genome-wide DNA methylation data has recently shed new light into the potential contribution of epigenetics in pathophysiology, particularly in the field of immune system and host defense. The study of patients carrying mutations in genes encoding for molecules involved in the epigenetic machinery has allowed the identification and better characterization of environment-genome interactions via epigenetics as well as paving the way for the development of new potential therapeutic options. In this review, we summarize current knowledge of the role of epigenetic modifications in the immune system and outline their potential involvement in the pathogenesis of inborn errors of immunity

Otolarylogical features in a cohort of patients affected with 22q11.2 deletion syndrome: a monocentric survey

Otorhinolaryngologic manifestations are common in 22q11.2 deletion syndrome (22q11.2DS), but poorly described. This study aimed to better define the ear-nose-throat (ENT) phenotype of 22q11.2DS patients, in the attempt to best detect subjects requiring subspecialist intervention. We enrolled 25 patients affected with 22q11.2DS. Anatomic and functional ENT findings were investigated using clinical, laboratory and instrumental data. Immunophenotype and frequency of infections were evaluated. Univariate and multivariate analyses were performed. ENT anomalies were found in 88% of patients, and in 20% congenital palate defects required surgery. Adenoids hypertrophy or palatine tonsils hypertrophy were noted in 80 and 48%. Fourty-eight percent of subjects had rhinolalia/phonia, severe in half of these. We also found nasal regurgitation or laryngeal penetration/aspiration in 20 and 16%, respectively. Instrumental exams revealed a mild conductive hypoacusia in 32% (bilateral in most cases), tympanometric anomalies in 28%, and swallowing abnormalities in 16%. Statistical univariate analysis showed a direct association between rhinolalia/phonia and episodes of laryngeal aspiration (P=0.016) and between tympanometric anomalies and increased adenoid volume (P=0.044). No association between episodes of food aspiration and palatal anomalies was found. Moreover, no statistically significant association was observed between the number of airway infections and the ENT findings. This study contributes to better define the ENT phenotype in patients with 22q11.2DS, helpful to prevent potential complications. Furthermore, the identification of a subcategory of patients may allow the early adoption of specific speech therapy programs to improve the clinical outcome of 22q11.2DS patients

Severe combined immunodeficiency-an update

Severe combined immunodeficiencies (SCIDs) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life-threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken. Conventionally, SCIDs are classified according either to the main pathway affected by the molecular defect or on the basis of the specific immunologic phenotype that reflects the stage where the blockage occurs during the differentiation process. However, during the last few years many new causative gene alterations have been associated with unusual clinical and immunological phenotypes. Many of these novel forms of SCID also show extra-hematopoietic alterations, leading to complex phenotypes characterized by a functional impairment of several organs, which may lead to a considerable delay in the diagnosis. Here we review the biological and clinical features of SCIDs paying particular attention to the most recently identified forms and to their unusual or extra-immunological clinical features