Publications by authors named "Antonio Pecoraro"

37 Publications

Differently expressed microRNA in response to the first Ig replacement therapy in common variable immunodeficiency patients.

Sci Rep 2020 12 8;10(1):21482. Epub 2020 Dec 8.

Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DISTABIF), Università della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100, Caserta, Italy.

Common variable immunodeficiency (CVID) is a complex primary immunodeficiency disorder characterized by a high clinical and genetic heterogeneity. The molecular underlying causes of CVID are not still now clear and the delays in diagnosis and treatment worsen the prognosis of the patients. MicroRNAs are non-coding, endogenous small RNAs often deregulated in human diseases, such as autoimmune and other immune-based disorders. In the present study, we aimed to evaluate miRNAs associated with the CVID and, in particular, with the response to the first Ig replacement therapy. To this aim, we compared miRNA profile obtained by serum samples of treatment-naïve CVID patients before and 24 h after the first Ig replacement therapy. For the first time, using a microarray assay followed by an integrated bioinformatics/biostatistics analysis, we identified five microRNAs (hsa-miR-6742, hsa-miR-1825, hsa-miR-4769-3p, hsa-miR-1228-3p, hsa-miR-1972) differently modulated in CVID patients by Ig infusion. All of them were down-regulated, excepted miR-6742 which was up-regulated. The latter may be of particular interest, since its functions are related to pathways involving Class I MHC mediated antigen processing and adaptive as well as innate Immune System. In conclusion, this study shows for the first time the modulation of miRNAs involved in CVID patients after the first Ig replacement therapy. Further studies are needed to assess whether such miRNAs could represent novel potential biomarkers in management and therapy of CVID patients.
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http://dx.doi.org/10.1038/s41598-020-77100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722869PMC
December 2020

Immunoglobulins G modulate endothelial function and affect insulin sensitivity in humans.

Nutr Metab Cardiovasc Dis 2020 10 10;30(11):2085-2092. Epub 2020 Jul 10.

Department of Translational Medical Sciences, Federico II University School of Medicine, Naples, Italy.

Background And Aims: Data from animals suggest that immunoglobulins G (IgG) play a mechanistic role in atherosclerosis and diabetes through endothelial dysfunction and insulin resistance. Patients with common variable immunodeficiency (CVID), who have low circulating levels of IgG and are treated with intravenous polyclonal IgG (IVIgG), may provide an ideal model to clarify whether circulating IgG modulate endothelial function and affect insulin sensitivity in humans.

Methods And Results: We studied 24 patients with CVID and 17 matched healthy controls (HC). Endothelial function was evaluated as flow mediated dilation (FMD) of the brachial artery at baseline and 1, 7, 14, and 21 days after IVIgG infusion in the CVID patients. We measured also plasma glucose, insulin, and calculated the HOMA-IR index. We also investigated the role of human IgG on the production of Nitric Oxide (NO) in vitro in Human Coronary Artery Endothelial Cells (HCAEC). Compared to HC, FMD of CVID patients was significantly impaired at baseline (9.4 ± 0.9 and 7.6 ± 0.6% respectively, p < 0.05) but rose above normal levels 1 and 7 days after IVIgG infusion to return at baseline at 14 and 21 days. Serum insulin concentration and HOMA-IR index dropped by 50% in CVID patients after IVIgG (p < 0.002 vs. baseline). In vitro IgG stimulated NO production in HCAEC.

Conclusions: Reduced IgG levels are associated with endothelial dysfunction and IVIgG stimulates endothelial function directly while improving insulin sensitivity. The current findings may suggest an anti-atherogenic role of human IgG.
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http://dx.doi.org/10.1016/j.numecd.2020.07.001DOI Listing
October 2020

HIV gp120 Induces the Release of Proinflammatory, Angiogenic, and Lymphangiogenic Factors from Human Lung Mast Cells.

Vaccines (Basel) 2020 May 3;8(2). Epub 2020 May 3.

Department of Translational Medical Sciences, University of Naples Federico II, 80138 Naples, Italy.

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are involved in chronic pulmonary diseases occurring at high frequency among HIV-infected individuals. Immunoglobulin superantigens bind to the variable regions of either the heavy or light chain of immunoglobulins (Igs). Glycoprotein 120 (gp120) of HIV-1 is a typical immunoglobulin superantigen interacting with the heavy chain, variable 3 (V3) region of human Igs. The present study investigated whether immunoglobulin superantigen gp120 caused the release of different classes of proinflammatory and immunoregulatory mediators from HLMCs. The results show that gp120 from different clades induced the rapid (30 min) release of preformed mediators (histamine and tryptase) from HLMCs. gp120 also caused the de novo synthesis of cysteinyl leukotriene C (LTC) and prostaglandin D (PGD) from HLMCs. Incubation (6 h) of HLMC with gp120 induced the release of angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The activating property of gp120 was mediated through the interaction with IgE V3 bound to FcεRI. Our data indicate that HIV gp120 is a viral superantigen, which induces the release of different proinflammatory, angiogenic, and lymphangiogenic factors from HLMCs. These observations could contribute to understanding, at least in part, the pathophysiology of chronic pulmonary diseases in HIV-infected individuals.
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http://dx.doi.org/10.3390/vaccines8020208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349869PMC
May 2020

The emerging role of T follicular helper (T) cells in aging: Influence on the immune frailty.

Ageing Res Rev 2020 08 25;61:101071. Epub 2020 Apr 25.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy; Istituti Clinici Scientifici Maugeri SpA Società Benefit (ICS Maugeri SpA SB), Telese Terme, BN, Italy.

The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (T) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of T cells have been identified in humans and mice and modifications in T cell phenotype and function progressively occur with age. Dysfunctional T cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (T) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to T cells in regulating immunity. Indeed, changes in T/T cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both T cells and T cells that occur in aging and recent findings suggesting that T cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.
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http://dx.doi.org/10.1016/j.arr.2020.101071DOI Listing
August 2020

A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.

J Allergy Clin Immunol 2020 07 22;146(1):211-213.e4. Epub 2020 Apr 22.

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; ASST-Spedali Civili di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.jaci.2020.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175894PMC
July 2020

Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype.

Front Immunol 2020 31;11:319. Epub 2020 Mar 31.

Department of Medicine-DIMED, University of Padova, Padova, Italy.

We report on an observational, multicenter study of 345 adult CVID patients, designed to assess the diagnostic value and the clinical association of serum free light chain (sFLC) pattern in Common Variable Immunodeficiency disorders (CVID). Sixty CVID patients were tested twice in order to assess intraindividual variability of sFLC. As control groups we included 138 patients affected by undefined primary antibody defects (UAD), lymphoproliferative diseases (LPDs), and secondary antibody deficiencies not related to hematological malignancies (SID). CVID patients presented lower κ and λ chain concentration compared to controls, showing low intraindividual sFLC variability. On the basis of the sFLC pattern, patients were classified into four groups: κ-λ+, κ+λ-, κ-λ-, κ+λ+. The most common pattern in CVID patients was κ-λ- (51%), followed by κ-λ+, (25%), κ+λ+ (22%), and κ+λ- (3%). In UAD, LPD, and SID groups κ+λ+ was the most common pattern observed. By analyzing the possible association between sFLC patterns and disease-related complications of CVID, we observed that patients belonging to the κ-λ- group presented more commonly unexplained enteropathy compared to the κ+λ+ group and showed higher frequency of bronchiectasis and splenomegaly compared to both the κ-λ+ and κ+λ+ patients. When compared to the other groups, κ-λ- had also lower serum IgG, IgA, and IgM concentrations at diagnosis, lower frequency of CD27+IgD-IgM- switched memory B cells, and higher frequency of CD21 B cells, receiving earlier CVID diagnosis. Thus, lower levels of sFLC might be an epiphenomenon of impairment in B cell differentiation, possibly leading κ-λ- patients to a higher risk for bacterial infections and chronic lung damage. Based on these results, we suggest adding sFLC assay to the diagnostic work-up of hypogammaglobulinemia and during follow-up. The assay may be useful to differentiate CVID from other causes of hypogammaglobulinemia and to early detect monoclonal lymphoproliferation occurring over years. Moreover, since the sFLC pattern seems to be related to disease phenotypes and clinical manifestations of CVID and after confirmation by further studies, sFLC assay might be considered a promising prognostic tool for identifying patients at higher risk of developing enteropathy and chronic lung damage or splenomegaly. This will allow designing a tailored follow-up for CVID patients.
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http://dx.doi.org/10.3389/fimmu.2020.00319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136404PMC
March 2021

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders.

Front Immunol 2020 28;11:338. Epub 2020 Feb 28.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency (PID) in adulthood and is characterized by severe reduction of immunoglobulin serum levels and impaired antibody production in response to vaccines and pathogens. Beyond the susceptibility to infections, CVID encompasses a wide spectrum of clinical manifestations related to a complex immune dysregulation that also affects liver. Although about 50% CVID patients present persistently deranged liver function, burden, and nature of liver involvement have not been systematically investigated in most cohort studies published in the last decades. Therefore, the prevalence of liver disease in CVID widely varies depending on the study design and the sampling criteria. This review seeks to summarize the evidence about the most relevant causes of liver involvement in CVID, including nodular regenerative hyperplasia (NRH), infections and malignancies. We also describe the clinical features of liver disease in some monogenic forms of PID included in the clinical spectrum of CVID as ICOS, NFKB1, NFKB2, CTLA-4, PI3Kδ pathway, ADA2, and IL21-R genetic defects. Finally, we discuss the clinical applications of the various diagnostic tools and the possible therapeutic approaches for the management of liver involvement in the context of CVID.
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http://dx.doi.org/10.3389/fimmu.2020.00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059194PMC
March 2021

Correlations Among Subcutaneous Immunoglobulin Dosage, Immunoglobulin G Serum Pre-infusional Levels and Body Mass Index in Primary Antibody Deficiency Patients: A Pooled Analysis from the SHIFT/IBIS Studies.

Clin Drug Investig 2020 Mar;40(3):279-286

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.

BACKGROUND AND OBJECTIVE: In recent years, two Italian non-interventional studies evaluated subcutaneous immunoglobulin (SCIG) treatment in patients affected by primary antibody deficiency (PAD). The SHIFT study considered patients who were treated with intravenous immunoglobulin (IVIG) or SCIG 16% (Vivaglobin) and then replaced this therapy with weekly treatments of SCIG 20% (Hizentra). The IBIS study evaluated patients previously taking a weekly SCIG 20% regimen, who instead began therapy with biweekly SCIG 20% to assess the correlation between the dose of immunoglobulin G (IgG) administered and the body mass index (BMI) of patients, determine if there is a need for dosage adjustments on a BMI basis, and identify the predictors of serum IgG trough levels in our cohort.

Methods: In this study, we analyzed the pooled data of 109 PAD patients enrolled in the SHIFT and IBIS studies. Only prospective phases were considered.

Results: The total monthly SCIG dose showed comparable trends among weight categories, except for underweight patients. When we considered the monthly SCIG dosage per kilogram of body weight, a significant decreasing trend according to BMI was observed. Data on IgG trough levels were available for 88 patients, with a mean IgG serum level of 8.4 ± 1.6 g/L. A stepwise regression model revealed that the mean monthly dosage of SCIG 20% (p = 0.04248) and the mean monthly dosage of IgG per kilogram of body weight were the only two independent predictors associated with IgG trough levels. No association was found between BMI and IgG trough levels.

Conclusions: These findings support the concept that the cumulative monthly dose of SCIG and the dose of SCIG per kilogram of body weight affect IgG trough levels in PAD patients, irrespective of BMI.
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http://dx.doi.org/10.1007/s40261-020-00885-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035227PMC
March 2020

The Intriguing Role of Interleukin 13 in the Pathophysiology of Asthma.

Front Pharmacol 2019 6;10:1387. Epub 2019 Dec 6.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.

Approximately 5-10% of asthmatic patients worldwide suffer from severe asthma. Experimental and clinical studies have demonstrated that IL-13 is an important cytokine in chronic airways inflammation. IL-13 is involved in Th2 inflammation and has been identified as a possible therapeutic target in the treatment of asthma. Two different human monoclonal antibodies (mAbs) anti-IL-13 (tralokinumab and lebrikizumab) block binding and signaling of IL-13 to its receptors, IL-13Rα1 and IL-13Rα2. Several randomized, double-blind, placebo-controlled multicenter studies have evaluated the safety and efficacy of tralokinumab and lebrikizumab in the treatment of adult patients with severe asthma, but all have failed to meet their primary endpoints. No serious adverse events related to the treatment with these anti-IL-13 mAbs have been reported in these studies. These negative clinical results contrast with positive findings from blocking IL-13 signaling in experimental models of asthma, raising doubts about the transferrable value of some models. Interestingly, dupilumab, a mAb which blocks both IL-4 and IL-13 signaling reduces exacerbation rates and improves lung function in severe asthmatics. These results suggest that IL-4 and IL-13 share some, but not all functional activities in airway inflammation. Tralokinumab might show efficacy in a highly selected cohort of asthmatics characterized by overexpression of IL-13.
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http://dx.doi.org/10.3389/fphar.2019.01387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908970PMC
December 2019

Adiponectin Receptors and Pro-inflammatory Cytokines Are Modulated in Common Variable Immunodeficiency Patients: Correlation With Ig Replacement Therapy.

Front Immunol 2019 27;10:2812. Epub 2019 Nov 27.

Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli," Caserta, Italy.

Adiponectin exerts beneficial pleiotropic effects through three receptors, AdipoR1, AdipoR2, and T-cadherin; it also exerts immunomodulatory effects. We previously demonstrated that adiponectin levels are altered in common variable immunodeficiency disease (CVID). The purpose of the present study was to investigate further the specific involvement of adiponectin in CVID by characterizing (i) the expression profile of adiponectin receptors on peripheral blood mononuclear cells; (ii) the levels of another relevant adipokine, namely leptin; (iii) the levels of five other cytokines (IL-2, IL-6, IL-10, TNFα, and IFNγ) in 24 patients on maintenance therapy, in 18 treatment-naïve patients (before and 24 h after the first Ig infusion) and in 28 healthy controls. We found that (i) adiponectin was down-expressed in patients on maintenance therapy and in treatment-naïve patients, and that it increased in treatment-naïve patients 24 h after the first Ig infusion; (ii) leptin expression did not differ between maintenance patients and controls either before or after the first Ig infusion; (iii) AdipoR1 expression was significantly higher on B lymphocytes, monocytes and NK cells of CVID patients than in controls; (iv) the expression of AdipoR1 and AdipoR2 on B lymphocytes, monocytes and NK cells was higher after the first Ig infusion than in treatment-naïve patients; (v) T-cadherin expression did not differ between treatment- naïve CVID patients and controls, and was not affected by Ig infusion; and (vi) IL-6, IL-8, IL-10, and TNFα levels were differently expressed in CVID patients on therapy maintenance and were not affected by the first Ig replacement therapy. This is the first study to demonstrate that the expression of AdipoRs in peripheral blood mononuclear cells from CVID patients differs from that of controls, and changes after the first Ig infusion. The specificity of adiponectin involvement in CVID is supported by the absence of changes in leptin levels and in the levels of the cytokines investigated. Taken together, these results suggest that the adiponectin system plays an important and specific role in CVID. A better understanding of adiponectin as a link in the cross-talk between the immune system and adipose tissue may provide additional benefits for the management of CVID patients.
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http://dx.doi.org/10.3389/fimmu.2019.02812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890605PMC
November 2020

Clozapine-associated secondary antibody deficiency.

Curr Opin Allergy Clin Immunol 2019 12;19(6):553-562

Immunodeficiency Centre for Wales, University Hospital of Wales.

Purpose Of Review: Clozapine has recently been described as a novel cause of secondary antibody deficiency (SAD), associated with long-term therapy. Here we critically review the evidence linking clozapine use to an increased infection risk, describe immunological alterations, and discuss potential mechanisms.

Recent Findings: Individuals with schizophrenia are at two to five times more likely to develop pneumonia than the general population, in particular, when receiving clozapine. Delayed-onset distinguishes clozapine-associated hypogammaglobulinaemia from agranulocytosis or neutropenia that occur at lesser frequency. Biomarker searches in treatment-resistant schizophrenia highlight an immune signature associated with long-term clozapine use. This includes reduction in class-switched memory B cells, echoing common variable immunodeficiency. Recent identification of a role for dopamine in T follicular helper-B cell interactions may inform future clinical studies.

Summary: The detrimental impact of the increased infection risk associated with clozapine necessitates a re-evaluation of the current monitoring strategies as well as further studies to better understand the underlying mechanisms of SAD in this setting. On the basis of available evidence, we suggest simple modifications to clozapine monitoring including integration of routine vaccination, smoking cessation, and assessment of humoral immunity. Further studies are required to understand the role of clozapine in neuroinflammation as well as other potentially autoantibody-mediated diseases.
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http://dx.doi.org/10.1097/ACI.0000000000000592DOI Listing
December 2019

Subcutaneous Immunoglobulin Twenty Percent Every Two Weeks in Pediatric Patients with Primary Immunodeficiencies: Subcohort Analysis of the IBIS Study.

Pediatr Allergy Immunol Pulmonol 2019 Jun 17;32(2):70-75. Epub 2019 Jun 17.

Department of Pediatric Immunology, Jeffrey Modell Center for Primary Immunodeficiency, Anna Meyer's Hospital, University of Florence, Florence, Italy.

Subcutaneous immunoglobulin G (SCIG) may be a better option than intravenous immunoglobulin G (IVIG) for patients with primary immunodeficiencies (PID) due to reduced systemic and serious adverse reactions and easier administration. The Infusione Bimensile di Immunoglobuline Sottocute (IBIS) study investigated the effects of Hizentra, a 20%-concentrated SCIG, administered biweekly in patients with PID. This subanalysis aimed to evaluate clinical and laboratory outcomes in the IBIS pediatric subcohort. Thirteen children with PID were observed for 12 months retrospectively (with previous IVIG/SCIG) and prospectively with biweekly Hizentra. Mean ± standard deviation serum IG levels during the retrospective (833.8 ± 175.7 mg/dL) and the prospective (842.0 ± 188.0 mg/dL) phases were comparable; there were also no differences in the number of infections. Biweekly Hizentra is a noninferior option with respect to previous IVIG/SCIG-based treatment.
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http://dx.doi.org/10.1089/ped.2018.0967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733055PMC
June 2019

Ultrasound-based transient elastography improves the detection of liver disease in common variable immunodeficiency.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2507-2508

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples, Naples, Italy.

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http://dx.doi.org/10.1016/j.jaip.2019.06.016DOI Listing
May 2020

Heterogeneity of Human Mast Cells With Respect to MRGPRX2 Receptor Expression and Function.

Front Cell Neurosci 2019 3;13:299. Epub 2019 Jul 3.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.

Mast cells and their mediators play a role in the control of homeostasis and in the pathogenesis of several disorders. The concept of rodent mast cell heterogeneity, initially established in the mid-1960s has been extended in humans. Human mast cells isolated and purified from different anatomic sites can be activated aggregation of cell surface high affinity IgE receptors (FcεRI) by antigens, superantigens, anti-IgE, and anti-FcεRI. MAS-related G protein-coupled receptor-X2 (MRGPRX2) is expressed at high level in human skin mast cells (MCs) (HSMCs), synovial MCs (HSyMCs), but not in lung MCs (HLMCs). MRGPX2 can be activated by neuropeptide substance P, several opioids, cationic drugs, and 48/80. Substance P (5 × 10 M - 5 × 10 M) induced histamine and tryptase release from HSMCs and to a lesser extent from HSyMCs, but not from HLMCs and human cardiac MCs (HHMCs). Morphine (10 M - 3 × 10 M) selectively induced histamine and tryptase release from HSMCs, but not from HLMCs and HHMCs. SP and morphine were incomplete secretagogues because they did not induce the synthesis of arachidonic acid metabolites from human mast cells. In the same experiments anti-IgE (3 μg/ml) induced the release of histamine and tryptase and the synthesis of prostaglandin D (PGD) from HLMCs, HHMCs, HSyMCs, and HSMCs. By contrast, anti-IgE induced the production of leukotriene C (LTC) from HLMCs, HHMCs, HSyMCs, but not from HSMCs. These results are compatible with the heterogeneous expression and function of MRGPRX2 receptor on primary human mast cells isolated from different anatomic sites.
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http://dx.doi.org/10.3389/fncel.2019.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616107PMC
July 2019

Liver stiffness assessment by transient elastography suggests high prevalence of liver involvement in common variable immunodeficiency.

Dig Liver Dis 2019 11 31;51(11):1599-1603. Epub 2019 May 31.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy. Electronic address:

Background: Up to 50% of patients with common variable immunodeficiency (CVID) present persistently increased serum levels of liver enzymes and/or mild hepatomegaly. Ultrasound-based transient elastography (TE) is largely used for early detection of the progression of chronic liver diseases, but has never been employed in CVID. We performed a cross-sectional study to evaluate TE values in a cohort of adult CVID-patients.

Methods: Full blood count, liver function test, liver and spleen sonogram and ultrasound-based TE were performed in 77 adult CVID patients. Demographic and clinical data were retrospectively collected from medical files.

Results: 33.8% (26/77) patients presented increased TE values ranging from moderate fibrosis to cirrhosis. TE values were positively correlated with ALP, γGT, spleen longitudinal diameter and peripheral blood counts (no significant correlation with BMI, AST, ALT, total proteins, albumin, bilirubin and hemoglobin). Moreover, liver stiffness was higher in patients with the clinical phenotypes polyclonal lymphoproliferation and enteropathy, and patients with both these complications had an increased risk (OR: 7.14) of presenting pathologic TE values compared with those without anyone of these.

Conclusions: Transient elastography is a useful tool to be used alongside clinical and laboratory data to assess liver involvement in CVID.
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http://dx.doi.org/10.1016/j.dld.2019.05.016DOI Listing
November 2019

Immunosuppressive therapy with rituximab in common variable immunodeficiency.

Clin Mol Allergy 2019 6;17. Epub 2019 May 6.

1Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), World Allergy Organization (WAO) Center of Excellence, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency in adulthood and is characterized by the marked reduction of IgG and IgA serum levels. Thanks to the successful use of polyvalent immunoglobulin replacement therapy to treat and prevent recurrent infections, non-infectious complications, including autoimmunity, polyclonal lymphoproliferation and malignancies, have progressively become the major cause of morbidity and mortality in CVID patients. The management of these complications is particularly challenging, often requiring multiple lines of immunosuppressive treatments. Over the last 5-10 years, the anti-CD20 monoclonal antibody (i.e., rituximab) has been increasingly used for the treatment of both autoimmune and non-malignant lymphoproliferative manifestations associated with CVID. This review illustrates the evidence on the use of rituximab in CVID. For this purpose, first we discuss the mechanisms proposed for the rituximab mediated B-cell depletion; then, we analyze the literature data regarding the CVID-related complications for which rituximab has been used, focusing on autoimmune cytopenias, granulomatous lymphocytic interstitial lung disease (GLILD) and non-malignant lymphoproliferative syndromes. The cumulative data suggest that in the vast majority of the studies, rituximab has proven to be an effective and relatively safe therapeutic option. However, there are currently no data on the long-term efficacy and side effects of rituximab and other second-line therapeutic options. Further randomized controlled trials are needed to optimize the management strategies of non-infectious complications of CVID.
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http://dx.doi.org/10.1186/s12948-019-0113-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501382PMC
May 2019

Superantigenic Activation of Human Cardiac Mast Cells.

Int J Mol Sci 2019 Apr 12;20(8). Epub 2019 Apr 12.

Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.

B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of , protein L of and gp120 of HIV are typical immunoglobulin superantigens. Mast cells are immune cells expressing the high-affinity receptor for IgE (FcεRI) and are strategically located in the human heart, where they play a role in several cardiometabolic diseases. Here, we investigated whether immunoglobulin superantigens induced the activation of human heart mast cells (HHMCs). Protein A induced the synthesis of cysteinyl leukotriene C (LTC) from HHMCs through the interaction with IgE V3 bound to FcεRI. Protein L stimulated the production of prostaglandin D (PGD) from HHMCs through the interaction with κ light chains of IgE. HIV glycoprotein gp120 induced the release of preformed (histamine) and synthesized mediators, such as cysteinyl leukotriene C (LTC), angiogenic (VEGF-A), and lymphangiogenic (VEGF-C) factors by interacting with the V3 region of IgE. Collectively, our data indicate that bacterial and viral immunoglobulin superantigens can interact with different regions of IgE bound to FcεRI to induce the release of proinflammatory, angiogenic, and lymphangiogenic factors from human cardiac mast cells.
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http://dx.doi.org/10.3390/ijms20081828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514993PMC
April 2019

Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies.

J Allergy Clin Immunol 2019 08 22;144(2):584-593.e7. Epub 2019 Mar 22.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Lacking protective antibodies, patients with primary antibody deficiencies (PADs) experience frequent respiratory tract infections, leading to chronic pulmonary damage. Macrolide prophylaxis has proved effective in patients with chronic respiratory diseases.

Objective: We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in patients with PADs.

Methods: We designed a 3-year, double-blind, placebo-controlled, randomized clinical trial to test whether oral azithromycin (250 mg administered once daily 3 times a week for 2 years) would reduce respiratory exacerbations in patients with PADs and chronic infection-related pulmonary diseases. The primary end point was the number of annual respiratory exacerbations. Secondary end points included time to first exacerbation, additional antibiotic courses, number of hospitalizations, and safety.

Results: Eighty-nine patients received azithromycin (n = 44) or placebo (n = 45). The number of exacerbations was 3.6 (95% CI, 2.5-4.7) per patient-year in the azithromycin arm and 5.2 (95% CI, 4.1-6.4) per patient-year in the placebo arm (P = .02). In the azithromycin group the hazard risk for having an acute exacerbation was 0.5 (95% CI, 0.3-0.9; P = .03), and the hazard risk for hospitalization was 0.5 (95% CI, 0.2-1.1; P = .04). The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (P = .004). Haemophilus influenzae and Streptococcus pneumoniae were the prevalent isolates, and they were not susceptible to macrolides in 25% of patients of both arms. Azithromycin's safety profile was comparable with that of placebo.

Conclusion: The study reached the main outcome centered on the reduction of exacerbation episodes per patient-year, with a consequent reduction in additional courses of antibiotics and risk of hospitalization.
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http://dx.doi.org/10.1016/j.jaci.2019.01.051DOI Listing
August 2019

Health-Related Quality of Life in Patients with CVID Under Different Schedules of Immunoglobulin Administration: Prospective Multicenter Study.

J Clin Immunol 2019 02 15;39(2):159-170. Epub 2019 Jan 15.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Objective: We assessed the health-related quality of life (HRQoL) in CVID adults receiving different schedules of immunoglobulin replacement therapy (IgRT) by intravenous (IVIG), subcutaneous (SCIG), and facilitated (fSCIG) preparations. For these patients, IgRT schedule was chosen after a period focused on identifying the most suitable individual option.

Methods: Three hundred twenty-seven participants were enrolled in a prospective, observational, 18-month study. Participants received IgRT for at least 2 years. The first 6 months were devoted to the educational process during which the choices related to IgRT were regularly re-assessed, and the shift to alternative regimen was permitted. During the following 12 months, clinical data were prospectively collected, and only patients who did not further modify their IgRT schedule were included in the analysis of HRQoL measured by CVID_QoL, a specific instrument, and by GHQ-12, a tool to assess minor psychiatric nonpsychotic disorders.

Results: Three hundred four patients were included in the analysis. CVID_QoL global score and its dimensions (emotional functioning, relational functioning, gastrointestinal symptoms) were similar in IVIG, SCIG, and fSCIG recipients. Patients receiving IgRT by different routes of administration reported similar capacity to make long-term plans, discomfort due to therapy, and concern to run out of medications. Multivariate analysis revealed the GHQ-12 status, but not the IgRT mode of administration, as the major factor impacting on treatment-related QoL items, and a significant impact of age on discomfort related to IgRT.

Conclusions: IgRT schedules do not impact the HRQoL in CVID if the treatment is established after an extensive educational period focused on individualizing the best therapeutic regimen.
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http://dx.doi.org/10.1007/s10875-019-0592-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445807PMC
February 2019

Prostaglandin D receptor antagonists in allergic disorders: safety, efficacy, and future perspectives.

Expert Opin Investig Drugs 2019 01 7;28(1):73-84. Epub 2018 Dec 7.

c Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) , University of Naples Federico II , Naples , Italy.

Introduction: Prostaglandin D (PGD) is a major cyclooxygenase mediator that is synthesized by activated human mast cells and other immune cells. The biological effects of PGD are mediated by D-prostanoid (DP), DP (CRTH2) and thromboxane prostanoid (TP) receptors that are expressed on several immune and non-immune cells involved in allergic inflammation. PGD exerts various proinflammatory effects relevant to the pathophysiology of allergic disorders. Several selective, orally active, DP receptor antagonists and a small number of DP receptor antagonists are being developed for the treatment of allergic disorders.

Areas Covered: The role of DP and DP receptor antagonists in the treatment of asthma and allergic rhinitis.

Expert Opinion: Head-to-head studies that compare DP antagonists with the standard treatment for allergic rhinitis are necessary to verify the role of these novel drugs as mono- or combination therapies. Further clinical trials are necessary to verify whether DP antagonists as monotherapies or, more likely, as add-on therapies, will be effective for the treatment of different phenotypes of adult and childhood asthma. Long-term studies are necessary to evaluate the safety of targeted anti-PGD treatments.
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http://dx.doi.org/10.1080/13543784.2019.1555237DOI Listing
January 2019

Gastric Cancer Is the Leading Cause of Death in Italian Adult Patients With Common Variable Immunodeficiency.

Front Immunol 2018 5;9:2546. Epub 2018 Nov 5.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

An increased prevalence of malignant lymphoma and of gastric cancer has been observed in large cohorts of patients with common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Surveillance strategies for cancers in CVID should be defined based on epidemiological data. Risks and mortality for cancers among 455 Italian patients with CVID were compared to cancer incidence data from the Italian Cancer Registry database. CVID patients showed an increased cancer incidence for all sites combined (Obs = 133, SIR = 2.4; 95%CI = 1.7-3.5), due to an excess of non-Hodgkin lymphoma (Obs = 33, SIR = 14.3; 95%CI = 8.4-22.6) and of gastric cancer (Obs = 25; SIR = 6.4; 95%CI = 3.2-12.5). CVID patients with gastric cancer and lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.8, 95%CI: 4.2-44.4 and HR: 4.2, 95%CI: 2.8-44.4). Similar to what observed in other series, CVID-associated lymphomas were more likely to be of B cell origin and often occurred at extra-nodal sites. We collected the largest case-series of gastric cancers in CVID subjects. In contrast to other reports, gastric cancer was the leading cause of death in CVID. Standardized mortality ratio indicated a 10.1-fold excess mortality among CVID patients with gastric cancer. CVID developed gastric cancer 15 years earlier than the normative population, but they had a similar overall survival. Only CVID diagnosed at early stage gastric cancer survived >24 months. Stomach histology from upper endoscopy performed before cancer onset showed areas of atrophic gastritis, intestinal metaplasia or dysplasia. CVID patients might progress rapidly to an advanced cancer stage as shown by patients developing a III-IV stage gastric cancer within 1 year from an endoscopy without signs of dysplasia. Based on high rate of mortality due to gastric cancer in Italian CVID patients, we hereby suggest a strategy aimed at early diagnosis, based on regular upper endoscopy and on infection treatment, recommending an implementation of national guidelines.
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http://dx.doi.org/10.3389/fimmu.2018.02546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230622PMC
September 2019

Gastroduodenal Disorders in Patients with CVID Undergoing Immunoglobulin Therapy.

Curr Pharm Biotechnol 2018 ;19(9):734-741

Department of Translational Medical Sciences (DISMET), Naples, Italy.

Background: Common variable immunodeficiency (CVID) encompasses a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infections, autoimmunity and malignancies. Gastrointestinal manifestations are frequently associated with CVID.

Objective: In this cross-sectional study, we evaluated gastric and duodenal involvement in a cohort of adult patients with CVID.

Methods: Upper gastrointestinal endoscopy was performed in 58 patients (26 males, mean age 47.8±15.6 years), diagnosed with CVID according to 2014 ESID criteria. Random biopsies were collected from gastric antrum and descending duodenum for the all enrolled subjects. Intraepithelial lymphocytosis in descending duodenum was defined as the presence of 25 lymphocytes per 100 enterocytes.

Results: The major histopathological findings that we found were: a) chronic active gastritis (44.8%), Helicobacter pylori-associated (8.6%), b) chronic duodenitis (39.6%) with intraepithelial lymphocytosis (31%) and absence of plasma cells (18.9%) and c) autoimmune atrophic gastritis (5.2%). Three patients (5.2%) presented Intestinal Metaplasia (IM) of the gastric antrum. This finding was associated with H. pylori infection and persisted after the eradication in one patient. IM was associated with autoimmune atrophic gastritis in two cases. Giardia lamblia infection was observed in the duodenum samples from three patients (5.2%). A diagnosis of Gastric adenocarcinoma was made in a 58-year- old woman diagnosed with gastric dysplasia one year earlier.

Conclusion: In our cohort of CVID patients, gastro-duodenal histopathological findings, including malignancies, are frequent and can affect long-term prognosis. A rigorous endoscopic follow-up is needed in CVID patients irrespective of the gastrointestinal symptoms.
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http://dx.doi.org/10.2174/1389201019666181010170630DOI Listing
February 2019

Validation of Calculated Globulin (CG) as a Screening Test for Antibody Deficiency in an Italian University Hospital.

Curr Pharm Biotechnol 2018 ;19(9):728-733

Department of Translational Medical Sciences, Division of Allergy and Clinical Immunology, Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy.

Background: Morbidity and mortality of primary and secondary antibody deficiencies (AD) are frequently associated with diagnostic delays. These could be avoided by a combination of factors including a widespread and effective development in screening tests.

Methods: Calculated globulin (CG), derived from the difference between serum total protein and albumin levels, reflects immunoglobulin serum levels and has shown to have a predictive value in the early diagnosis of antibody deficiencies. This study investigated the possibility to use low levels of CG to detect antibody deficiency in an Italian University Hospital.

Results: First, we conducted an analysis of anonymized adult samples collected at our biochemistry laboratory with a range of calculated globulin levels from 15 to 22 g/l. A CG cut-off of 19 g/l detected subjects with IgG lower than 600 mg/dl with a sensitivity of 70% and a specificity of 75%. To further verify the clinical usefulness of CG, we retrospectively evaluated the relationship between CG values and serum IgG levels in 38 patients diagnosed with CVID at our Institution. Using a CG cut-off of 19 g/l, we detected antibody deficiency in 97.3% (37/38) of the subjects present in our cohort.

Conclusion: Finally, we chose a CG value of 19 g/l as the cut-off for a prospective AD screening program. The results of this study show that a screening CG test can be used as a tool to reduce diagnostic delays, improve long-term prognosis and reduce the healthcare costs of antibody deficiency.
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http://dx.doi.org/10.2174/1389201019666180808163311DOI Listing
February 2019

Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer.

Front Immunol 2018 13;9:1595. Epub 2018 Jul 13.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy.

Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.
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http://dx.doi.org/10.3389/fimmu.2018.01595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053489PMC
July 2018

Biweekly Hizentra® in Primary Immunodeficiency: a Multicenter, Observational Cohort Study (IBIS).

J Clin Immunol 2018 07 28;38(5):602-609. Epub 2018 Jun 28.

Immunoallergology Unit, Department Medical-Geriatric, AOU Careggi, Brambilla, 3, 50134, Florence, Italy.

Immunoglobulin G (IgG) replacement therapy is a standard treatment for patients with primary immunodeficiency diseases (PIDs). Hizentra®, a 20% human subcutaneous IgG (SCIG), is approved for biweekly administration for PIDs. The aim of the multicenter IBIS study was to prospectively investigate the efficacy of biweekly Hizentra® compared with previous IVIG or SCIG treatment regimens in patients with PIDs. The study consisted of a 12-month retrospective period followed by 12-month prospective observational period. The main endpoints included pre-infusion IgG concentrations, proportion of patients with serious bacterial infections (SBIs), other infections, hospitalizations due to PID-related illnesses, and days with antibiotics during the study periods. Of the 36 patients enrolled in the study, 35 patients continued the study (mean age 26.1 ± 14.4 years; 68.6% male). The mean pre-infusion IgG levels for prior immunoglobulin regimens during the retrospective period (7.84 ± 2.09 g/L) and the prospective period (8.55 ± 1.76 g/L) did not show any significant variations (p = 0.4964). The mean annual rate of SBIs/patient was 0.063 ± 0.246 for both prospective and retrospective periods. No hospitalizations related to PIDs were reported during the prospective period versus one in the retrospective period. All patients were either very (76.5%) or quite (23.5%) satisfied with biweekly Hizentra® at the end of the study. In conclusion, the IBIS study provided real-world evidence on the efficacy of biweekly Hizentra® in patients with PIDs, thus verifying the data generated by the pharmacometric modeling and simulation study in a normal clinical setting.
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http://dx.doi.org/10.1007/s10875-018-0528-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061090PMC
July 2018

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective.

Front Physiol 2018 7;9:167. Epub 2018 Mar 7.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.

Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.
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http://dx.doi.org/10.3389/fphys.2018.00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846016PMC
March 2018

Chronic Diarrhea in Common Variable Immunodeficiency: a Case Series and Review of the Literature.

J Clin Immunol 2018 01 14;38(1):67-76. Epub 2017 Nov 14.

Department of Translational Medical Sciences, Allergy and Clinical Immunology. Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced immunoglobulin serum levels and absent or impaired antibody production. Clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies, also involve various segments of the gastrointestinal tract. Chronic diarrhea is one of the most common gastrointestinal symptoms and may cause a wide spectrum of potentially life-threatening conditions as malabsorption and protein-energy malnutrition. We describe three female CVID adult patients presenting with chronic diarrhea, weight loss, and protein-energy malnutrition due to different underlying conditions. Our review of the literature explores the various gastrointestinal involvements in CVID and points out several histopathological findings proper of the disease, thus highlighting the relevance of the endoscopic and histological assessment in CVID patients presenting with chronic diarrhea.
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http://dx.doi.org/10.1007/s10875-017-0461-zDOI Listing
January 2018

Immunoglobulin replacement therapy in primary and secondary antibody deficiency: The correct clinical approach.

Int Immunopharmacol 2017 Nov 12;52:136-142. Epub 2017 Oct 12.

Department of Translational Medical Sciences, Allergy and Clinical Immunology, University of Naples Federico II, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.

Immunoglobulin therapy is the administration of human polyvalent IgG and represents the most effective treatment to prevent recurrent infections in antibody deficiency patients. Primary antibody deficiency represents the main indication of immunoglobulin replacement therapy and includes a wide range of disorders characterized by impaired antibody production in response to pathogens and recurrent infections. However, not all primary antibody deficiency patients require immunoglobulin replacement. Indeed, immunoglobulin preparations are expensive and, once prescribed, usually result in lifelong therapy. Moreover, many patients significantly benefit from a long-term antibiotic prophylaxis and a prompt begin of antibiotic therapy in case of infectious events. Even more controversial is the decision to initiate immunoglobulin replacement therapy in secondary antibody deficiency, a heterogeneous and expanding group including B-cell lymphoproliferative syndromes, protein losing states and therapeutic agents. This review seeks to define the indication to immunoglobulin replacement in primary and secondary antibody deficiency disorders, distinguishing those in which the beginning of immunoglobulin therapy is always indicated at the same time as the diagnosis has been made, from those lacking of defined indication to replacement therapy. In addition, we propose a clinical approach, mainly based on the evaluation of infectious history, vaccine response and bronchiectasis finding, to support the decision to initiate immunoglobulin therapy in an individual patient.
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http://dx.doi.org/10.1016/j.intimp.2017.09.005DOI Listing
November 2017

Total and High Molecular Weight Adiponectin Expression Is Decreased in Patients with Common Variable Immunodeficiency: Correlation with Ig Replacement Therapy.

Front Immunol 2017 31;8:895. Epub 2017 Jul 31.

Department of Translational Medical Sciences, Allergy and Clinical Immunology, University of Naples Federico II, Naples, Italy.

Adiponectin (Acrp30) is an adipokine widely studied for its beneficial metabolic properties. It circulates as low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) oligomers. The latter exerts the most potent biological effects. Acrp30 attracted renewed interest with the finding that it was associated with the development and progression of immune disorders. The mechanisms underlying this association and the role of Acrp30 in the pathophysiology of immune-mediated conditions remain unknown. Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic activation of the immune system, impaired antibody production, and imbalanced cytokine production. In the attempt to shed light on the expression of Acrp30 in CVID, we: (a) investigated total Acrp30 and its oligomerization state in CVID patients undergoing maintenance Ig replacement therapy; (b) assessed the effects of Ig replacement therapy on Acrp30 expression in treatment-naïve CVID patients, namely, patients not treated before diagnosis, before and after the first Ig administration; and (c) evaluated the correlation between Acrp30 levels and clinical phenotypes of the disease. As controls, we analyzed healthy subjects and patients affected by a non-immunodeficiency chronic inflammatory demyelinating polyneuropathy (CIDP), before and after Ig infusion. We found that total Acrp30 and HMW oligomers were decreased in CVID but not in CIDP patients versus controls. Moreover, Acrp30 levels were correlated with IgA levels and were associated with two CVID phenotypes, namely, autoimmune cytopenia and enteropathy. Receiver operating characteristic curve analysis indicated that Acrp30 modulation is specific for CVID patients. Acrp30 and HMW levels quickly and dramatically increased after Ig infusion only in eight treatment-naïve CVID patients but not in five CIDP patients. This finding indicates that Ig administration is not able to induce an increase of Acrp30, but the specific cellular and/or molecular background proper of CVID seems to be essential. In conclusion, our data indicate that Acrp30 is specifically related to CVID activity. Further studies are required to understand the biological role of Acrp30 and its possible use as disease biomarker in CVID.
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http://dx.doi.org/10.3389/fimmu.2017.00895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534466PMC
July 2017