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Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified. Moreover, mutations in FAS often show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern. FAS mutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants in FAS and increased TCR αβ double-negative T cells (DNTs, a hallmark of ALPS) have been identified in multifactorial autoimmune diseases, while FAS itself could play a potential role in carcinogenesis. These findings suggest that alterations of FAS-mediated apoptosis could trespass the universe of inborn errors of immunity and that somatic mutations leading to ALPS could only be the tip of the iceberg of acquired immunodeficiencies.

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS , FASLG , and FADD , all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute’s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

Lymphoproliferation can represent the first or leading disease sign in different inborn errors of immunity (IEI), which include autoimmune lymphoproliferative syndrome (ALPS), common variable immunodeficiency (CVID), combined immunodeficiencies, activated phosphoinositide 3-kinase δ syndrome (APDS), Epstein-Barr (EBV)-related disorders, and others. The genetic and molecular background and the clinical implications of IEI presenting with lymphoproliferation are partly unexplored. Therefore, the diagnosis and clinical management of this category of patients is particularly challenging. As treatments targeting the specific genetic defect are available for some of the IEIs associated with lymphoproliferation, identifying the molecular diagnosis is of great clinical relevance and could significantly improve the patient’s long-term outcome. To this purpose, a first-level immunological assessment is strongly recommended in patients with persistent or recurrent unexplained lymphoproliferation, and specific second-level analysis can orient towards the correct clinical suspicion. The mechanisms responsible for polyclonal, benign lymphoproliferation in IEI also cause an increased susceptibility to clonal, malignant lymphoproliferation. Therefore, a careful follow-up is recommended in all the patients with IEI and polyclonal lymphoproliferation, to promptly identify the development of clonality. Moreover, as malignant lymphoproliferation can be the first disease sign of some IEI, there is increasing interest in the possibility of recognizing IEIs in patients presenting with lymphoid malignancies. This work, by describing some relevant case studies, reviews the role of lymphoproliferative features in three of the most paradigmatic conditions, particularly ALPS, CVID, and APDS, and provides an updated discussion on the diagnosis, treatment, and follow-up of patients with IEI and lymphoproliferative features.

GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency. Patients were recruited contacting all the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers, the Hematology Department in their institution and Italian societies involved in the field of vascular anomalies, otorhinolaryngology, dermatology, infectious and respiratory diseases. Median age at the time of first manifestation, molecular diagnosis and last follow-up visit was 12.5 (age-range, 2–52 years), 18 (age-range, 7–64 years) and 22 years (age-range, 3–64), respectively. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were the most frequent symptoms at the onset of the disease. The majority of patients (55%) underwent hematopoietic stem cell transplantation. During the follow-up rarer manifestations emerged. The clinical penetrance was highly variable, with the coexistence of severely affected pediatric patients and asymptomatic adults in the same pedigree. Two individuals remained asymptomatic at the last follow-up visit. Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and show that lymphedema may be associated with null/regulatory mutations. Countrywide studies providing long prospective follow-up are essential to unveil the exact burden of rarer manifestations and the natural history in GATA2 deficiency.

Durum wheat ( Triticum turgidum spp. durum ) is a major cereal adopted since antiquity to feed humans. Due to its use, dating back several millennia, this species features a wide genetic diversity and landraces are considered important repositories of gene pools which constitute invaluable tools for breeders. The aim of this work is to provide a first characterization of a wheat landrace, referred to as ‘TB2018’, that was collected in the Apulia region (Southern Italy). ‘TB2018’ revealed, through visual inspection, characters reminiscent of the traditional variety ‘Senatore Cappelli’, while exhibiting a distinctive trait, i.e., reduced stature. Indeed, the comparison with a set of Italian durum wheat cultivars conducted in this study, in which 24 CPVO plant descriptors were adopted, placed the ‘TB2018’ landrace in proximity to the ‘Senatore Cappelli’ cultivar. In addition, the close similarity between the two genotypes was confirmed by the analysis of the seed protein pattern. A relative reduction was detected for ‘TB2018’ root elongation in the early stages of plant growth. The ‘TB2018’ genome sequence, obtained through low-coverage resequencing and comparison to the reference ‘Svevo’ cultivar is also reported in this study, followed by a genome-wide comparison against 259 durum wheat accessions that placed ‘TB2018’ close to the ‘Cappelli’ reference. Hundreds of genes putatively affected by variants that possess Gene Ontology descriptors were detected, among which some were shown to be putatively linked to the morphological traits that distinguish ’TB2018’ from ’Senatore Cappelli’, Overall, this study poses the basis for a possible exploitation of ’TB2018’ per se in cultivation or as a source of alternative alleles in the breeding of traditional cultivars. This work also presents a genomic methodology that exploits the information contained in a low-depth, whole-genome sequence to derive genotypic data useful for cross-platform (chip data) comparisons.

Durum wheat (Triticum turgidum spp. durum) is a major cereal adopted since antiquity to feed humans. Due to its use, dating back several millennia, this species features a wide genetic diversity and landraces are considered important repositories of gene pools which constitute invaluable tools for breeders. The aim of this work is to provide a first characterization of a wheat landrace, referred to as 'TB2018', that was collected in the Apulia region (Southern Italy). 'TB2018' revealed, through visual inspection, characters reminiscent of the traditional variety 'Senatore Cappelli', while exhibiting a distinctive trait, i.e., reduced stature. Indeed, the comparison with a set of Italian durum wheat cultivars conducted in this study, in which 24 CPVO plant descriptors were adopted, placed the 'TB2018' landrace in proximity to the 'Senatore Cappelli' cultivar. In addition, the close similarity between the two genotypes was confirmed by the analysis of the seed protein pattern. A relative reduction was detected for 'TB2018' root elongation in the early stages of plant growth. The 'TB2018' genome sequence, obtained through low-coverage resequencing and comparison to the reference 'Svevo' cultivar is also reported in this study, followed by a genome-wide comparison against 259 durum wheat accessions that placed 'TB2018' close to the 'Cappelli' reference. Hundreds of genes putatively affected by variants that possess Gene Ontology descriptors were detected, among which some were shown to be putatively linked to the morphological traits that distinguish 'TB2018' from 'Senatore Cappelli', Overall, this study poses the basis for a possible exploitation of 'TB2018' per se in cultivation or as a source of alternative alleles in the breeding of traditional cultivars. This work also presents a genomic methodology that exploits the information contained in a low-depth, whole-genome sequence to derive genotypic data useful for cross-platform (chip data) comparisons.

Background Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as “activation”, is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels. In this work, we investigated how activation affects the competence of astrocytes to handle iron overload and the ensuing oxidative stress. Methods Cultures of pure cortical astrocytes were preincubated with proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) or conditioned medium from lipopolysaccharide-activated microglia to promote activation and then exposed to a protocol of iron overload. Results We demonstrate that activated astrocytes display an efficient protection against iron-mediated oxidative stress and cell death. Based on this evidence, we performed a comprehensive biochemical and molecular analysis, including a transcriptomic approach, to identify the molecular basis of this resistance. Conclusions We propose the protective phenotype acquired after activation not to involve the most common astrocytic antioxidant pathway, based on the Nrf2 transcription factor, but to result from a complex change in the expression and activity of several genes involved in the control of cellular redox state.