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Nowadays functional ingredients have a significant potential for improving current low fish meal (FM) aquafeed formulation in sustaining growth and enhancing animal robustness for Mediterranean aquaculture. Among them, nucleotides (NT) and nucleic acids (NA) drew attention for their application in the last two decades. NT are organic molecules involved in many life-supporting pathways, and are the building blocks of NA, which stand as genetic repositories. NT are naturally present in organic ingredients, and among them FM is known to be one of the highest NT sources. When this NT source is seriously limited, fish might be under the minimum NT requirements, especially in fast growing life stages of carnivorous species. Hence, a trial on European sea bass juveniles was carried out, testing two dietary FM levels (FM10, FM20 as 10% and 20% FM, respectively) supplemented with 500 mg kg-1 yeast-originate NT or NA dose over 80 days. Thereafter, fish were exposed to one week of sub-optimal thermal and dissolved oxygen condition (30°C and 4.0 mg/L O2) to further explore the effect of NT and NA inclusion on immune response and gut microbiome alteration. At the end of the growth period NT increased feed intake at both FM dietary levels. FM20 combined with NA and NT further improved growth performance, enhancing lipid efficiency and increased anti-inflammatory TGF-β. After sub-optimal environmental conditions both NT and NA exerted prebiotic functions on gut microbiome by promoting beneficial lactic acid bacteria such as Weissella and Leuconostoc. At the same time NT in 10% FM diet increased the abundance of Bacillus taxon. In conclusion, the combination of NT/NA included at 500 mg kg-1 was able to promote growth when included in 20% FM level, assuming higher nutritional NT requirement when combined with 10% FM. On the other hand, NT/NA added in 10% FM upregulate proinflammatory IL-1β and favor beneficial gut bacterial taxa.

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.

Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.

STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.

Understanding the mechanisms of immune tolerance is currently one of the most important challenges of scientific research. Pregnancy affects the immune system balance, leading the host to tolerate embryo alloantigens. Previous reports demonstrated that β-adrenergic receptor (β-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of β2-ARs, but recently we have demonstrated that also β3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that β3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that β3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of β3-AR, promotes the biological shift toward a tolerant immunophenotype and that this is the same trick that embryo and cancer use to create an aura of immune-tolerance in a competent immune environment. This study confirms the analogies between fetal development and tumor progression and suggests that the expression of β3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.

Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes.Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes.Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of “Primary Immune Deficiency (PID—related) genes.”Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified.Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.