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Several allergic and immunologic diseases including asthma, food allergy (FA), chronic spontaneous urticaria (CSU), atopic dermatitis (AD), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), and Behçet’s disease (BD) are characterized by the involvement of Th2 immunity. Several mediators lead to immunoglobulin (Ig)E production, thus including key cytokines such as interleukin (IL)-4, IL-5, and IL-13. Among them, IL-31 and IL-33 have been recently studied as novel biomarkers and future therapeutic targets for allergic and immunological disorders. IL-31 is a proinflammatory cytokine—it regulates cell proliferation and is involved in tissue remodeling. IL-33, acting through its receptor suppression of tumorigenity (ST2L), is an alarmin cytokine from the IL-1 family, whose expression is mediated by tissue damage. The latter has a pleiotropic effect, as it may modulate specific and innate immune cells functions. To date, several researchers have investigated the involvement of IL-31 and IL-33 in several allergic and immune-mediated diseases. Further studies are needed to understand the future applications of these molecules as novel therapeutic agents. This paper aims to give the readers a complete and updated review of IL-31 and IL-33 involvement among the most common autoimmune and allergic disorders.

HLA-G is a HLA class Ib antigen that possesses immunomodulatory properties. HLA-G-expressing CD4+ and CD8+ T lymphocytes, NK cells, monocytes, and dendritic cells with immunoregulatory functions are present in small percentages of patients with physiologic conditions. Quantitative and qualitative derangements of HLA-G+ immune cells have been detected in several conditions in which the immune system plays an important role, such as infectious, neoplastic, and autoimmune diseases as well as in complications from transplants and pregnancy. These observations strongly support the hypothesis that HLA-G+ immune cells may be implicated in the complex mechanisms underlying the pathogenesis of these disorders.

The world is now experiencing its third major epidemic of coronavirus (CoV) infections began in Wuhan, Hubei, China, in late 2019 and named COVID-19. After an initial explosive outbreak of pneumonia of unknown etiology in China, the disease spread first to neighboring Asian countries and then worldwide. Patients with COVID-19 presented with a constellation of symptoms such as fever, dry cough, dyspnea, sore throat, and nasal congestion and radiological findings showed bilateral lung glassy opacities. Vitamin D has many mechanisms by which it reduces the risk of microbial infection and death, including physical barrier, cellular natural immunity, and adaptive immunity. Vitamin D supplementation has shown favorable effects in viral infections including influenza and HIV. The effects of vitamin D supplementation during covid 19 infection remain controversial. Looking ahead, clinical studies are needed to define better cut offs for vitamin D levels and, finally, which dosage is the best.

Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3 rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.

Antiphospholipid antibody syndrome (APS) is an autoimmune acquired thrombophilia characterized by recurrent thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). APS can be primary, if it occurs in the absence of any underlying disease, or secondary, if it is associated with another autoimmune disorder, most commonly systemic lupus erythematosus. The exact pathogenetic mechanism of APS is unknown, but different, not mutually exclusive, models have been proposed to explain how anti-PL autoantibodies might lead to thrombosis and pregnancy morbidity. Diagnosis of APS requires that a patient has both a clinical manifestation (arterial or venous thrombosis and/or pregnancy morbidity) and persistently positive aPL, but the clinical spectrum of the disease encompasses additional manifestations which may affect every organ and cannot be explained exclusively by a prothrombotic state. Treatment for aPL-positive patients is based on the patient’s clinical status, presence of an underlying autoimmune disease, and history of thrombotic events. In case of aPL positivity without previous thrombotic events, the treatment is mainly focused on reduction of additional vascular risk factors, while treatment of patients with definite APS is based on long-term anticoagulation. Pregnancy complications are usually managed with low-dose aspirin in association with low molecular weight heparin. Refractory forms of APS could benefit from adding hydroxychloroquine and/or intravenous immunoglobulin to anticoagulation therapy. Promising novel treatments include anti-B cell monoclonal antibodies, new-generation anticoagulants, and complement cascade inhibitors. The objective of this review paper is to summarize the recent literature on APS from pathogenesis to current therapeutic options.

Systemic lupus erythematosus (SLE) patients have an increased risk of cardiovascular disease and thrombotic events, and the presence of antiphospholipid antibodies further raises the risk of these complications. Here we report a case of a patient with SLE and triple positivity for antiphospholipid antibodies who developed a popliteal artery thrombosis in the context of a severe hyperhomocysteinemia after the introduction of methotrexate (MTX) treatment. MTX is one of the most prescribed medications for a wide spectrum of autoimmune diseases, including SLE. On the other hand, by interfering with folate metabolism, it may induce hyperhomocysteinemia, which, in turn, may increase the risk of vascular complications. Current recommendations suggest screening and, when possible, treating classical and disease-related cardiovascular risk factors in all lupus patients. Based on what observed in our case, we suggest a follow-up of homocysteine levels after the introduction of drugs capable of inducing hyperhomocysteinemia, such as MTX, in SLE patients at high cardiovascular risk.

Soluble interleukin (IL)-15 exists under two forms: as monomer (sIL-15) or as heterodimeric complex in association with sIL-15Rα (sIL-15/IL-15Rα). Both forms have been successfully tested in experimental tumor murine models and are currently undergoing investigation in phase I/II clinical trials. Despite more than 20 years research on IL-15, some controversial issues remain to be addressed. A first point concerns the detection of the sIL-15/IL-15Rα in plasma of healthy donors or patients with cancer and its biological significance. The second and third unsolved question regards the protumorigenic role of the IL-15/IL-15Rα complex in human cancer and the detrimental immunological consequences associated to prolonged exposure of natural killer (NK) cells to both forms of soluble IL-15, respectively. Data suggest that in vivo prolonged or repeated exposure to monomeric sIL-15 or the soluble complex may lead to NK hypo-responsiveness through the expansion of the CD8+/CD44+ T cell subset that would suppress NK cell functions. In vitro experiments indicate that soluble complex and monomeric IL-15 may cause NK hyporesponsiveness through a direct effect caused by their prolonged stimulation, suggesting that this mechanism could also be effective in vivo. Therefore, a better knowledge of IL-15 and a more appropriate use of both its soluble forms, in terms of concentrations and time of exposure, are essential in order to improve their therapeutic use. In cancer, the overproduction of sIL-15/IL-15Rα could represent a novel mechanism of immune escape. The soluble complex may act as a decoy cytokine unable to efficiently foster NK cells, or could induce NK hyporesponsiveness through an excessive and prolonged stimulation depending on the type of IL-15Rα isoforms associated. All these unsolved questions are not merely limited to the knowledge of IL-15 pathophysiology, but are crucial also for the therapeutic use of this cytokine. Therefore, in this review, we will discuss key unanswered issues on the heterogeneity and biological significance of IL-15 isoforms, analyzing both their cancer-related biological functions and their therapeutic implications.

Hypereosinophilic Syndrome (HES) is a rare disorder with a heterogeneous clinical presentation. If not recognized, it can lead to diagnostic delay and worse prognosis. Our study aimed to describe the real-world scenario of patients presenting with hypereosinophilia (HE), diagnosed with HES in an Italian Immunology Excellence University Centre. In addition, we also assessed the feasibility of a two-tailed approach for HES diagnosis, which consists of proceeding from the beginning with the differential diagnosis and systematic evaluation of organ damage. A retrospective observational single-center study was conducted. All patients underwent blood and instrumental tests to simultaneously identify HES etiology and any organ damage, through a process we called the \"two-tailed approach\". Two hundred forty-seven patients with HE referred to our center underwent the two-tailed approach. Due to either the presence of a straightforward underlying disease associated with HE, or the lack of sustained hypereosinophilia, 168 patients (68.0%) were excluded from the study. Seventy-nine patients (31 females, 39.2%) with a mean age of 54.9 years were finally diagnosed with HES. 19 (24.1%) patients were diagnosed with reactive HES, 15 (19.0%) with overlap HES, 1 (1.3%) with myeloid-HES, 10 (12.7%) with lymphocytic HES, and 8 (10.1%) with idiopathic HES. Sixty-three patients showed involvement of at least two organs: the lung (32/63, 50.7%), the skin (24/63, 38.1%), the bowel (23/63, 36.5%), and the peripheral nervous system (25.4%). Eight patients (8/63, 12.7%) showed heart involvement. The diagnosis was achieved in 4 ± 1.8 months, and no deaths were observed. HE is a common reason for consultations with allergists and clinical immunologists, and the two-tailed approach, which tests simultaneously for diagnosis and organ damage, should be implemented from the initial evaluation of patients with HE. The lower rate of idiopathic HES diagnosis and the higher frequency of heart involvement we found confirm the usefulness of the tool in reducing the risk of mistakes in classifying HES subtypes and the diagnostic delay, thus allowing prompt and tailored treatment and better outcomes.

Background Amebiasis is a rare condition in developed countries but epidemiologically growing. Clinical manifestation may range from asymptomatic to invasive disease, amoebic liver abscess being the most common manifestation. We report a peculiar case of left hepatic amoebic liver abscess in a patient without a well-known source of infection and presenting with left portal vein thrombosis. Case presentation Patient, working as longshoreman, presented with complaints of remittent-intermittent fever lasting from 2 weeks. Physical examination was normal. Blood tests showed mild anemia, neutrophilic leukocytosis and elevated inflammation markers. Chest x-rays was normal. Abdominal ultrasound showed multiple hypoechoic liver masses. CT-scan of abdomen showed enlarged left liver lobe due to the presence of large abscess cavity along with thrombosis of left portal vein. The indirect hemagglutination test for the detection of antibodies to Entamoeba histolytica (Eh) was positive. Ultrasound-guided percutaneous drainage revealed “anchovy sauce” pus. Metronidazole and a follow up imaging at 3 months showed resolution of abscess cavity. Conclusion This case shows that amoebic liver abscess is possible even in first world country patients without travel history. Left sided abscess and portal vein thrombosis are rare and hence reported.

Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders characterised by persistent hypereosinophilia associated with organ damage. Due to its rarity and heterogeneity in its clinical presentation, HES remains underdiagnosed or misdiagnosed, often leading to delayed diagnosis and irreversible organ damage. The complexity of HES diagnosis is even more complicated due to the absence of standardised criteria. Moreover, the lack of structured referral pathways among specialists, including allergists, clinical immunologists, haematologists, and rheumatologists, further hinders optimal patient care. To address these challenges, the Italian National Hypereosinophilic Syndrome (INHES) Network aimed to enhance the diagnosis, management, and research of HES. INHES objectives also include connecting specialised centres, facilitating data collection on HES and eosinophilic-associated conditions, and improving healthcare standards through consensus guidelines. To do this, INHES has created a web-based platform called “Phleos” to develop a comprehensive referral map, ensuring timely and appropriate patient access to expert care. Phleos is a web-based datasheet, per GDPR regulations, to systematically collect anonymised clinical data, including absolute eosinophil counts, organ involvement, laboratory parameters, instrumental assessments, and treatments. A structured classification system enables differentiation among idiopathic, lymphocytic, myeloid, familial, reactive, and overlap forms of HES. Moreover, the platform integrates standardised diagnostic pathways and treatment protocols to harmonise patient care across participating centres. The INHES Network aims to mitigate diagnostic delays, optimise therapeutic decision-making, and advance research in eosinophilic disorders by fostering interdisciplinary collaboration and establishing a unified framework. This initiative represents a crucial step toward a cohesive national strategy, ultimately improving clinical outcomes for HES patients in Italy.