Thymic Stromal Lymphopoietin (TSLP) Is Cleaved by Human Mast Cell Tryptase and Chymase.

Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play key roles in asthma. We evaluated the early proteolytic effects of tryptase and chymase released by HLMCs on TSLP by mass spectrometry. We also investigated whether TSLP and its fragments generated by these enzymes induce angiogenic factor release from HLMs. Mass spectrometry (MS) allowed the identification of TSLP cleavage sites caused by tryptase and chymase. Recombinant human TSLP treated with recombinant tryptase showed the production of 1-97 and 98-132 fragments. Recombinant chymase treatment of TSLP generated two peptides, 1-36 and 37-132. lfTSLP induced the release of VEGF-A, the most potent angiogenic factor, from HLMs. By contrast, the four TSLP fragments generated by tryptase and chymase failed to activate HLMs. Long-term TSLP incubation with furin generated two peptides devoid of activating property on HLMs. These results unveil an intricate interplay between mast cell-derived proteases and TSLP. These findings have potential relevance in understanding novel aspects of asthma pathobiology.

High Prevalence of Long COVID in Common Variable Immunodeficiency: An Italian Multicentric Study.

The long-term effects of SARS-CoV-2 infection represent a relevant global health problem. Long COVID (LC) is defined as a complex of signs and symptoms developed during or after SARS-CoV-2 infection and lasting > 12 weeks. In common variable immunodeficiency (CVID) patients, we previously reported higher risk of hospitalization and death during SARS-CoV-2 infection, as well as prolonged swab positivity and frequent reinfections. The aim of the present study was to assess the risk of LC in an Italian cohort of CVID patients. We used a translated version of the survey proposed by Centers for Disease Control and Prevention (CDC) to collect data on LC. In the enrolled cohort of 175 CVID patients, we found a high prevalence of LC (65.7%). The most frequent LC symptoms were fatigue (75.7%), arthralgia/myalgia (48.7%), and dyspnea (41.7%). The majority of patients (60%) experienced prolonged symptoms, for at least 6 months after infection. In a multivariate analysis, the presence of complicated phenotype (OR 2.44, 95% CI 1.88-5.03; p = 0.015), obesity (OR 11.17, 95% CI 1.37-90.95; p = 0.024), and female sex (OR 2.06, 95% CI 1.09-3.89; p = 0.024) significantly correlated with the development of LC. In conclusion, in this multicenter observational cohort study, we demonstrated that CVID patients present an increased prevalence of LC when compared to the general population. Improved awareness on the risk of LC in CVID patients could optimize management of this new and alarming complication of SARS-CoV-2 infection.

Exhaled Nitric Oxide as Biomarker of Type 2 Diseases.

Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders.

Real-world characteristics of "super-responders" to mepolizumab and benralizumab in severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis.

Background: The current definition of severe eosinophilic asthma (SEA) super-responders to biologic treatment does not include patients with other eosinophil-based comorbidities. Although eosinophilic granulomatosis with polyangiitis (EGPA) is frequently associated with SEA, we lack data on a possible super-response to biologic treatments in patients suffering from these two diseases. We aim to assess super-responder features in real-life patients with SEA and EGPA treated with mepolizumab and benralizumab. Methods: We enrolled 39 patients with SEA and EGPA eligible for treatment with mepolizumab or benralizumab. Super-responder assessment was performed considering oral corticosteroid (OCS) cessation, lack of exacerbations, forced expiratory volume in 1 s and Asthma Control Test (ACT) improvement. Results: Super-responders showed worse clinical baseline characteristics than non-super-responder patients, with a greater improvement in severe asthma exacerbations, OCS dose reduction and ACT score increase. Definition of super-responders was consistent only considering a 12-month course of monoclonal antibody, lacking sensitivity in earlier evaluations. Conclusion: Mepolizumab and benralizumab are safe and effective in patients with EGPA and SEA, since a consistent proportion of patients show a super-response after 12 months of treatment. Further studies will address specific criteria for super-responder assessment in these patients.

Early Ear, Nose and Throat Manifestations in Eosinophilic Granulomatosis with Poliangioitis: Results from Our Cohort Group and Literature Review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, systemic necrotizing vasculitis affecting small-to-medium-sized vessels. EGPA's clinical manifestations are heterogeneous, affecting different organs and systems, and the upper respiratory tract can be affected by ear, nose and throat (ENT) involvement. The aim of our study was to assess type manifestations at the time of diagnosis in a cohort of EGPA patients and correlate findings with baseline variables (sex, age, antineutrophil cytoplasmic antibodies-ANCA-status) and literature reports. The main ENT manifestations in our patients at the time of diagnosis were: chronic rhinosinusitis with nasal polyposis (CRSwNP) (52%), turbinate hypertrophy (48%), nasal swelling (40%), rhinorrhea (40%), chronic rhinosinusitis without nasal polyposis (CRSsNP) (32%), nasal bone deformities (32%), nasal crusts (20%), nasal mucosal ulcers (12%), corditis (12%), hoarseness/dysphonia (12%), hearing loss (12%), mucoceles (4%) and eosinophilic rhinitis (4%). No correlations were found between sex, age, ANCA status and ENT clinical manifestations. A polymorphic ENT involvement is often observed in the early stages of EGPA. The presence of nasal, sinus, ear and/or laryngeal manifestations in patients with asthma and hypereosinophilia, independently of sex, age or ANCA status, should raise an alert for further investigation and differential diagnosis for EGPA. ENT specialists should be aware of their leading position in this diagnostic race.

Cytokine dysregulation despite immunoglobulin replacement therapy in common variable immunodeficiency (CVID).

Introduction: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) can prevent severe infections but not underlying immune dysregulation. Methods: In this study, we evaluated the serum concentrations of proinflammatory (TNF-α, IL-1ß, IL-6) and immunoregulatory cytokines (IL-10), as well as lipopolysaccharide (LPS) and soluble CD14 (sCD14) in CVID individuals with infectious only (INF-CVID), and those with additional systemic autoimmune and inflammatory disorders (NIC-CVID), and healthy donors (HD). Results: Our results showed increased serum concentrations of TNF-α, IL-1ß, IL-6, and IL-10 in both INF-CVID and NIC-CVID subjects compared to HD. However, elevations of TNF-α, IL-1ß, IL-6, and IL-10 were significantly more marked in NIC-CVID than INF-CVID. Additionally, LPS concentrations were increased only in NIC-CVID but not in INF-CVID compared to HD. Circulating levels of sCD14 were significantly increased in NIC-CVID compared to both INF-CVID and HD. Discussion: These findings indicate persistent cytokine dysregulation despite IgRT in individuals with CVID. Moreover, the circulating cytokine profile reveals the heterogeneity of immune dysregulation in different subgroups of CVID subjects.

Decline of gastric cancer mortality in common variable immunodeficiency in the years 2018-2022.

Introduction: In patients with Common Variable Immunodeficiency, malignancy has been reported as the leading cause of death in adults, with a high risk of B-cell lymphomas and gastric cancer. Methods: We conducted a five-year prospective study aiming to update the incidence and mortality of gastric cancer and the incidence of gastric precancerous lesions in 512 CVID patients who underwent a total of 400 upper gastrointestinal endoscopies. Results: In the pre-pandemic period, 0.58 endoscopies were performed per patient/year and in the COVID-19 period, 0.39 endoscopies were performed per patient/year. Histology revealed areas with precancerous lesions in about a third of patients. Patients who had more than one gastroscopy during the study period were more likely to have precancerous lesions. Two patients received a diagnosis of gastric cancer in the absence of Helicobacter pylori infection. The overall prevalence of Helicobacter pylori infection in biopsy specimens was 19.8% and related only to active gastritis. Among patients who had repeated gastroscopies, about 20% progressed to precancerous lesions, mostly independent of Helicobacter pylori. Discussion: While gastric cancer accounted for one in five deaths from CVID in our previous survey, no gastric cancer deaths were recorded in the past five years, likely consistent with the decline in stomach cancer mortality observed in the general population. However, during the COVID-19 pandemic, cancer screening has been delayed. Whether such a delay or true decline could be the reason for the lack of gastric cancer detection seen in CVID may become clear in the coming years. Due to the high incidence of precancerous lesions, we cannot rely on observed and predicted trends in gastric cancer mortality and strongly recommend tailored surveillance programs.

Could it be hereditary angioedema?-Perspectives from different medical specialties.

Hereditary angioedema (HAE) is a rare autosomal dominant disease, with patients often suffering with associated symptoms for many years before receiving a correct diagnosis. The symptoms greatly impact a patient's quality of life (QoL) and include excruciating abdominal pain and angioedema of the skin and submucosa. Angioedema of the larynx represents a significant mortality risk in undiagnosed patients, and a large proportion of patients with HAE receive incorrect diagnoses and undergo unnecessary surgery. HAE-specific treatments can control and prevent acute life-threatening episodes, in addition to improving QoL, emphasizing the value of early diagnosis for patients. Diagnostic delay may be due to a lack of HAE awareness by healthcare professionals and the similarity of HAE symptoms with those of more common conditions, complicating differential diagnosis. The multifaceted nature of the condition may result in visits to one of many different medical settings, for example: the Emergency Room, pediatrics, general practice, otolaryngology, gastroenterology, and dermatology. Therefore, it is crucial that physicians in multiple healthcare specialties are aware of the disease to ensure that patients with HAE receive a timely diagnosis. Using patient cases from various medical specialties, this review highlights the necessity for cross-specialty awareness of HAE and outlines the essential information for the various healthcare professionals that may encounter a patient with HAE symptoms, in order to effectively treat and/or diagnose HAE.

BNT162b2 Elicited an Efficient Cell-Mediated Response against SARS-CoV-2 in Kidney Transplant Recipients and Common Variable Immunodeficiency Patients.

SARS-CoV-2 vaccination is the standard of care for the prevention of COVID-19 disease. Although vaccination triggers both humoral and cellular immune response, COVID-19 vaccination efficacy is currently evaluated by measuring antibodies only, whereas adaptative cellular immunity is unexplored. Our aim is to test humoral and cell-mediated response after three doses of BNT162b vaccine in two cohorts of fragile patients: Common Variable Immunodeficiency (CVID) patients and Kidney Transplant Recipients (KTR) patients compared to healthy donors. We enrolled 10 healthy controls (HCs), 19 CVID patients and 17 KTR patients. HC BNT162b third dose had successfully mounted humoral immune response. A positive correlation between Anti-Spike Trimeric IgG concentration and neutralizing antibody titer was also observed. CVID and KTR groups showed a lower humoral immune response compared to HCs. IFN-γ release induced by epitopes of the Spike protein in stimulated CD4+ and CD8+ T cells was similar among vaccinated HC, CVID and KTR. Patients vaccinated and infected showed a more efficient humoral and cell-mediated response compared to only vaccinated patients. In conclusion, CVID and KTR patients had an efficient cell-mediated but not humoral response to SARS-CoV-2 vaccine, suggesting that the evaluation of T cell responses could be a more sensitive marker of immunization in these subjects.

Neurologic and Psychiatric Manifestations of Bradykinin-Mediated Angioedema: Old and New Challenges.

Neurologic manifestations have been occasionally described in patients with bradykinin-mediated angioedema. The existing literature is currently limited to case series and case reports mainly described in the hereditary forms (HAE) concerning central nervous system (CNS) involvement. On the contrary, very little is known about peripheral and autonomic nervous system manifestations. CNS involvement in HAE may present with symptoms including severe headaches, visual disturbance, seizures, and various focal and generalized deficits. In addition, a stroke-like clinical picture may present in HAE patients. In turn, some drugs used in patients with cardiovascular and neurologic disorders, such as recombinant tissue plasminogen activator (r-tPA) and angiotensin-converting enzyme inhibitors (ACEI), may produce medication-induced angioedema, resulting in a diagnostic challenge. Finally, most patients with HAE have higher levels of psychological distress, anxiety, and depression. With this review, we aimed to provide an organized and detailed analysis of the existing literature on neurologic and psychiatric manifestations of HAE to shed light on these potentially invalidating symptoms and lay the foundation for further personalized diagnostic pathways for patients affected by this protean disease.

Effectiveness and safety of anti-IL-5/Rα biologics in eosinophilic granulomatosis with polyangiitis: a two-year multicenter observational study.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis characterized by asthma, systemic manifestations, and blood and tissue eosinophilia. Objective: To assess the effectiveness and safety of mepolizumab (anti-IL-5) and benralizumab (anti-IL-5Rα) in EGPA for 24 months. Methods: We conducted a multicenter observational study, including patients with EGPA treated with anti-IL-5/Rα biologics in 9 Italian specialized facilities. Systemic disease activity, remission and relapse rate were evaluated from 3 to 24 months after treatment initiation. Respiratory outcomes, hematological parameters, corticosteroid (OCS) and immunosuppressants consumption were also assessed. Results: 49 patients with relapsing-refractory EGPA were included [26 (53.1%) benralizumab 30mg, 20 (40.8%) mepolizumab 100mg, 3 (6.1%) mepolizumab 300mg]. Overall, 38.8% and 57.1% achieved remission after 12 and 24 months, respectively (69.2% benralizumab and 43.5% mepolizumab). Lower OCS intake and higher blood eosinophil count at baseline were associated with remission at 24 months. Both biologics exerted beneficial effects on severe asthma outcomes. Indeed, 61.2% (61.5% benralizumab and 60.8% mepolizumab) remained exacerbation-free during treatment. Lung function parameters showed improvements in the overall cohort (all p<0.05), but began to decline from month 12, especially with mepolizumab. Marked reduction in blood eosinophils was registered with mepolizumab (p<0.0001), while benralizumab depleted both eosinophils (p<0.0001) and basophils (p<0.0001). In general, 69.6% (76% benralizumab and 61.9% mepolizumab) of OCS-dependent patients lowered their daily dose by 75%, while 28.3% discontinued these drugs. Immunosuppressants were suspended in 88.2% of cases. Adverse events were reported in 8.2% of patients. Conclusions: These real-world data suggest that anti-IL-5/Rα biologics are effective and safe in the long-term as add-on treatments for patients with EGPA.

A Multidisciplinary Approach for Type 2 Allergic Diseases: What Do Biologics Teach Us?

Patients with atopic/allergic disorders, including atopic dermatitis (AD), allergic rhino-conjunctivitis (AR), chronic rhinosinusitis with/without nasal polyps (CRSwNP/CRSsNP), bronchial asthma, food allergy, and eosinophilic esophagitis (EoE), often share a common genetic background, a type Th2 polarized immune response, and several environmental factors [...].

Predictors of trainees' proficiency during the learning curve of robot-assisted radical prostatectomy at high- -volume institutions: results from a multicentric series.

Introduction: The aim of this series was to evaluate predictors of Proficiency score (PS) achievement on a multicentric series of robot-assisted radical prostatectomies (RARP) performed by trainee surgeons with two different surgical techniques at four tertiary-care centers. Material and methods: Four institutional datasets were merged and queried for RARPs performed by surgeons during their learning curve (LC) between 2010 and 2020 using two different approaches (Group A, Retzius-sparing RARP, n = 164; Group B, standard anterograde RARP, n = 79). Logistic regression analysis was performed to identify predictors of PS achievement for the overall trainee cohort. For all analyses, a two-sided p <0.05 was considered significant. Results: Group B showed significantly increased median operative time, positive surgical margins (PSM) status, increased number of nerve-sparing procedures, shorter LC time (each p <0.04). PS, continence status, potency, biochemical recurrence and 1-year trifecta rates were comparable between groups (each p >0.3). On multivariable analysis, time from LC starting ≥12 months (OR = 2.79; 95%IC [1.15-6.76]; p = 0.02) and a nerve-sparing intent (OR = 3.18; 95%IC [1.15-8.77]; p = 0.02) were independent predictors of PS score achievement (Table 3). Conclusions: Higher PS rates for RARP trainees may be expected after 12 months from LC beginning. Short-term training courses are unlikely to confer proper surgical training, while long-term structured training programs seem to be beneficial on perioperative outcomes.

Multicentric Observational Study on Safety and Tolerability of COVID-19 Vaccines in Patients with Angioedema with C1 Inhibitor Deficiency: Data from Italian Network on Hereditary and Acquired Angioedema (ITACA).

Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH. Adult patients with AE-C1-INH, followed by Reference Centers belonging to the Italian Network for Hereditary and Acquired Angioedema (ITACA), were enrolled in this study. Patients received nucleoside-modified mRNA vaccines and vaccines with adenovirus vectors. Data on acute attacks developed in the 72 h following COVID-19 vaccinations were collected. The frequency of attacks in the 6 months after the COVID-19 vaccination was compared with the rate of attacks registered in the 6 months before the first vaccination. Between December 2020 and June 2022, 208 patients (118 females) with AE-C1-INH received COVID-19 vaccines. A total of 529 doses of the COVID-19 vaccine were administered, and the majority of patients received mRNA vaccines. Forty-eight attacks of angioedema (9%) occurred within 72 h following COVID-19 vaccinations. About half of the attacks were abdominal. Attacks were successfully treated with on-demand therapy. No hospitalizations were registered. There was no increase in the monthly attack rate following the vaccination. The most common adverse reactions were pain at the site of injection and fever. Our results show that adult patients with angioedema due to C1 inhibitor deficiency can be safely vaccinated against SARS-CoV-2 in a controlled medical setting and should always have available on-demand therapies.

A beacon in the dark: COVID-19 course in CVID patients from two European countries: Different approaches, similar outcomes.

Background: CVID patients present an increased risk of prolonged SARS-CoV-2 infection and re-infection and a higher COVID-19-related morbidity and mortality compared to the general population. Since 2021, different therapeutic and prophylactic strategies have been employed in vulnerable groups (vaccination, SARS-CoV-2 monoclonal antibodies and antivirals). The impact of treatments over the last 2 years has not been explored in international studies considering the emergence of viral variants and different management between countries. Methods: A multicenter retrospective/prospective real-life study comparing the prevalence and outcomes of SARS-CoV-2 infection between a CVID cohort from four Italian Centers (IT-C) and one cohort from the Netherlands (NL-C), recruiting 773 patients. Results: 329 of 773 CVID patients were found positive for SARS-CoV-2 infection between March 1st, 2020 and September 1st 2022. The proportion of CVID patients infected was comparable in both national sub-cohorts. During all waves, chronic lung disease, "complicated" phenotype, chronic immunosuppressive treatment and cardiovascular comorbidities impacted on hospitalization, whereas risk factors for mortality were older age, chronic lung disease, and bacterial superinfections. IT-C patients were significantly more often treated, both with antivirals and mAbs, than NL-C patients. Outpatient treatment, available only in Italy, started from the Delta wave. Despite this, no significant difference was found for COVID-19 severity between the two cohorts. However, pooling together specific SARS-CoV-2 outpatient treatments (mAbs and antivirals), we found a significant effect on the risk of hospitalization starting from Delta wave. Vaccination with ≥ 3 doses shortened RT-PCR positivity, with an additional effect only in patients receiving antivirals. Conclusions: The two sub-cohorts had similar COVID-19 outcomes despite different treatment approaches. This points out that specific treatment should now be reserved for selected subgroups of CVID patients, based on pre-existing conditions.

Is there a role for microbiome-based approach in common variable immunodeficiency?

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and increased susceptibility to infections, autoimmune disorders and cancer. CVID embraces a plethora of heterogeneous manifestations linked to complex immune dysregulation. While CVID is thought to be due to genetic defects, the exact cause of this immune disorder is unknown in the large majority of cases. Compelling evidences support a linkage between the gut microbiome and the CVID pathogenesis, therefore a potential for microbiome-based treatments to be a therapeutic pathway for this disorder. Here we discuss the potential of treating CVID patients by developing a gut microbiome-based personalized approach, including diet, prebiotics, probiotics, postbiotics and fecal microbiota transplantation. We also highlight the need for a better understanding of microbiota-host interactions in CVID patients to prime the development of improved preventive strategies and specific therapeutic targets.

Interplay between C1-inhibitor and group IIA secreted phospholipase A2 impairs their respective function.

High levels of human group IIA secreted phospholipase A2 (hGIIA) have been associated with various inflammatory disease conditions. We have recently shown that hGIIA activity and concentration are increased in the plasma of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) and negatively correlate with C1-INH plasma activity. In this study, we analyzed whether the presence of both hGIIA and C1-INH impairs their respective function on immune cells. hGIIA, but not recombinant and plasma-derived C1-INH, stimulates the production of IL-6, CXCL8, and TNF-α from peripheral blood mononuclear cells (PBMCs). PBMC activation mediated by hGIIA is blocked by RO032107A, a specific hGIIA inhibitor. Interestingly, C1-INH inhibits the hGIIA-induced production of IL-6, TNF-α, and CXCL8, while it does not affect hGIIA enzymatic activity. On the other hand, hGIIA reduces the capacity of C1-INH at inhibiting C1-esterase activity. Spectroscopic and molecular docking studies suggest a possible interaction between hGIIA and C1-INH but further experiments are needed to confirm this hypothesis. Together, these results provide evidence for a new interplay between hGIIA and C1-INH, which may be important in the pathophysiology of hereditary angioedema.

Safety of mRNA COVID-19 Vaccines in Patients with Inborn Errors of Immunity: an Italian Multicentric Study.

PURPOSE: Little is known about vaccine safety in inborn errors of immunity (IEI) patients during the current vaccination campaign for COVID-19. To better investigate the reactogenicity and adverse event profile after two, three, and four doses of mRNA vaccines, we conducted an observational, multicentric study on 342 PID patients from four Italian Referral Centres. METHODS: We conducted a survey on self-reported adverse reactions in IEI patients who received mRNA vaccine by administering a questionnaire after each dose. RESULTS: Over the whole study period, none of the patients needed hospitalization or had hypersensitivity reactions, including anaphylaxis and delayed injection site reaction. After two vaccination doses, 35.4% of patients showed only local reactogenicity-related symptoms (RrS), 44.4% reported both systemic and local RrS, and 5% reported only systemic RrS. In more than 60% of cases, local or systemic RrS were mild. After the first and second booster doses, patients showed fewer adverse events (AEs) than after the first vaccination course. Patients aged 50 years and older reported adverse events and RrS less frequently. Among AEs requiring treatment, one common variable immune deficiency patient affected by T cell large granular lymphocytic leukemia developed neutropenia and one patient had Bell's paralysis perhaps during herpes zoster reactivation. CONCLUSION: Although our follow-up period is relatively short, the safety data we reported are reassuring. This data would help to contrast the vaccine hesitancy often manifested by patients with IEI and to better inform their healthcare providers.

Gender dimorphism in IgA subclasses in T2-high asthma.

Immunoglobulin A (Chan in J Allergy Clin Immunol 134:1394-14014e4, 2014), the second most abundant immunoglobulin in serum, plays an important role in mucosal homeostasis. In human serum, there are two subclasses of IgA, IgA1 (≅ 90%) and IgA2 (≅ 10%), transcribed from two distinct heavy chain constant regions. This study evaluated the serum concentrations of total IgA, IgA1, and IgA2, and total IgG, IgG1, IgG2, IgG3, and IgG4 in T2-high asthmatics compared to healthy controls and the presence of gender-related variations of immunoglobulins. Total IgA levels were increased in asthmatics compared to controls. Even more marked was the increase in total IgA in male asthmatics compared to healthy male donors. IgA1 were increased only in male, but not in female asthmatics, compared to controls. Concentrations of IgG2, but not IgG1, IgG3, and IgG4, were reduced in asthmatics compared to controls. IgG4 levels were reduced in female compared to male asthmatics. In female asthmatics, IgA and IgA1 levels were increased in postmenopause compared to premenopause. IgA concentrations were augmented in mild, but not severe asthmatics. A positive correlation was found between IgA levels and the age of patients and an inverse correlation between serum concentrations of IgA2 and IgE in asthmatics. A positive correlation between total IgA or IgA2 and IgG2 was found in asthmatics. These results highlight a gender dimorphism in IgA subclasses in male and female T2-high asthmatics. More adequate consideration of immunological gender disparity in asthma may open new opportunities in personalized medicine by optimizing diagnosis and targeted therapy.