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Clinical Research on Primary Immunodeficiency Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 17305

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Special Issue Editors

Prof. Dr. Claudio Pignata

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Guest Editor

Section of Pediatrics, Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
Interests: primary immunodeficiencies; severe combined immunodeficiencies; T cell immunity; thymus; FOXN1; ataxia telanigiectasia; high throughput sequencing

Dr. Giuliana Giardino

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Guest Editor

University of Naples Federico II, Section of Pediatrics, Department of Translational Medical Sciences, Naples, Italy
Interests: primary immunodeficiencies; severe combined immunodeficiencies; T cell immunity; thymus; FOXN1, Di George syndrome; adenosine deaminase deficiency; high throughput sequencing; gene therapy

Special Issue Information

Dear Colleagues,

Primary immunodeficiency disorders (PIDs) represent a group of genetically determined diseases of the immune system, typically characterized by increased susceptibility to infections, but also by immune dysregulation and malignancy. In the last few years, the application of the high throughput sequencing (HTS) technology to PIDs diagnosis has expedited our understanding of the genetic basis of PIDs, leading to the identification of more than 300 novel genetic defects resulting in novel and broadened clinical phenotypes. The introduction of the HTS technology in the clinical setting led to the great opportunities to speed the diagnostic process, which is crucial to establish proper treatment, prevent disease complications and improve the outcome, and to promote novel and tailored treatments. Indeed, the identification of specific genes and their related molecular immunologic pathways has improved the knowledge of the pathogenic mechanisms underlying PIDs leading to the development of targeted therapy, aimed at correcting a specific gene defect or an impaired signaling pathway. In this special issue, we aim to exploit recent advances in the field of PIDs. In particular, the issue will be focused on the definition of advantages and limitations of novel diagnostic approaches to PIDs, on the description of novel clinical phenotypes of more recently characterized PIDs or unusual unexplained observations, and on the definition of novel tailored therapeutic approaches to PIDs.

Prof. Claudio Pignata
Dr. Giuliana Giardino
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

primary immunodeficiency disorders
high throughput sequencing
immune dysregulation
autoimmunity
HSCT
gene therapy
gene editing
precision medicine

Published Papers (5 papers)

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Research

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14 pages, 1279 KiB

Open AccessArticle

Activated Phosphoinositide 3-Kinase Delta Syndrome 1: Clinical and Immunological Data from an Italian Cohort of Patients

by Giulio Tessarin, Stefano Rossi, Manuela Baronio, Luisa Gazzurelli, Michael Colpani, Alessio Benvenuto, Fiammetta Zunica, Fabio Cardinale, Baldassarre Martire, Letizia Brescia, Giorgio Costagliola, Laura Luti, Gabriella Casazza, Maria Cristina Menconi, Francesco Saettini, Laura Palumbo, Maria Federica Girelli, Raffaele Badolato, Gaetana Lanzi, Marco Chiarini, Daniele Moratto, Antonella Meini, Silvia Giliani, Maria Pia Bondioni, Alessandro Plebani and Vassilios Lougaris Show full author list Hide full author list

J. Clin. Med. 2020, 9(10), 3335; https://doi.org/10.3390/jcm9103335 - 17 Oct 2020

Cited by 23 | Viewed by 3120

Abstract

Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients’ clinical management and their quality of life. Full article

(This article belongs to the Special Issue Clinical Research on Primary Immunodeficiency Diseases)

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14 pages, 2662 KiB

Open AccessArticle

Systemic Redox Imbalance in Patients with Chronic Granulomatous Disease

by Edyta Heropolitanska-Pliszka, Klaudia Berk, Mateusz Maciejczyk, Jolanta Sawicka-Powierza, Ewa Bernatowska, Beata Wolska-Kusnierz, Malgorzata Pac, Nel Dabrowska-Leonik, Barbara Piatosa, Aleksandra Lewandowicz-Uszynska, Joanna Karpinska, Anna Zalewska and Bozena Mikoluc

J. Clin. Med. 2020, 9(5), 1397; https://doi.org/10.3390/jcm9051397 - 09 May 2020

Cited by 7 | Viewed by 3265

Abstract

The aim of our study was to evaluate redox status, enzymatic and non-enzymatic antioxidant barriers, oxidative damage of proteins, lipids and DNA, as well as concentration of coenzyme Q10 and vitamins A and E in patients with chronic granulomatous disease (CGD). The study was performed on fifteen Caucasian individuals (median age 24 years and seven months) diagnosed with CGD. The mutation in the NCF1 gene was confirmed in ten patients, and in the CYBB gene in five patients. We demonstrated high levels of total oxidant status (TOS) and oxidative stress index (OSI), lipids (↑8-isoprostanes (8-isoP), ↑4-hydroxynonenal (4-HNE)), proteins (↑advanced oxidation protein products (AOPP)) and DNA (↑8-hydroxy-2’-deoxyguanosine (8-OHdG)) oxidation products in CGD individuals as compared to sex- and age-matched healthy controls. We showed enhanced serum enzymatic activity of catalase (CAT) and superoxide dismutase-1 (SOD) and significantly decreased coenzyme Q10 concentration. Our study confirmed redox disturbances and increased oxidative damage in CGD patients, and indicated the need to compare redox imbalance depending on the type of mutation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The question regarding effectiveness of antioxidant therapy in patients with CGD is open, and the need to establish guidelines in this area remains to be addressed. Full article

(This article belongs to the Special Issue Clinical Research on Primary Immunodeficiency Diseases)

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12 pages, 2238 KiB

Open AccessArticle

The Usefulness of Scintigraphic Studies in the Assessment of Asymptomatic Bowel Disease in Patients with Primary Antibody Diseases

by Cinzia Milito, Francesco Cinetto, Valentina Megna, Giuseppe Spadaro, Isabella Quinti and Mauro Liberatore

J. Clin. Med. 2020, 9(4), 949; https://doi.org/10.3390/jcm9040949 - 30 Mar 2020

Cited by 1 | Viewed by 1680

Abstract

Enteropathy may be the first presentation of immunodeficiency or it may occur during the course of the disease and in association with malabsorption in patients affected by primary antibody diseases. For these patients, immunoglobulin G (IgG) replacement therapy prevents infectious and non-infectious complications. Nonetheless some patients cannot achieve optimal IgG trough levels, even when treated with high Ig doses in absence of protein-losing syndromes. We investigated seven patients affected by common variable immunodeficiencies (CVIDs) and treated with high Ig doses (600–800 mg/kg/month) showing low IgG trough level. Patients underwent abdominal scintigraphy with human polyclonal immunoglobulin G labeled with 99mTc and with white blood cells labeled by 111 Indium-oxinate to investigate asymptomatic bowel inflammation. A concentration of labeled leukocytes in abdominal segments greater than that observed with human polyclonal immunoglobulin G was evident only in one patient. In five patients a slight concentration of both radiopharmaceuticals was reported, due to mild intestinal inflammatory response. These data might be related to mild increase of capillary permeability in the absence of inflammation leukocyte mediated. This study discloses a new cause of IgG-accelerated catabolism due to inflammatory bowel conditions without diarrhea in CVID patients. Full article

(This article belongs to the Special Issue Clinical Research on Primary Immunodeficiency Diseases)

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15 pages, 2300 KiB

Open AccessArticle

Clinical, Immunological, and Functional Characterization of Six Patients with Very High IgM Levels

by Vera Gallo, Emilia Cirillo, Rosaria Prencipe, Alessio Lepore, Luigi Del Vecchio, Giulia Scalia, Vincenzo Martinelli, Gigliola Di Matteo, Carol Saunders, Anne Durandy, Viviana Moschese, Antonio Leonardi, Giuliana Giardino and Claudio Pignata

J. Clin. Med. 2020, 9(3), 818; https://doi.org/10.3390/jcm9030818 - 17 Mar 2020

Cited by 5 | Viewed by 3353

Abstract

Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in PIK3R1. In a second case, the ITPKB gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies. Full article

(This article belongs to the Special Issue Clinical Research on Primary Immunodeficiency Diseases)

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Review

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9 pages, 950 KiB

Open AccessReview

Chromothripsis and DNA Repair Disorders

by Lusine Nazaryan-Petersen, Victoria Alexandra Bjerregaard, Finn Cilius Nielsen, Niels Tommerup and Zeynep Tümer

J. Clin. Med. 2020, 9(3), 613; https://doi.org/10.3390/jcm9030613 - 25 Feb 2020

Cited by 16 | Viewed by 5248

Abstract

Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of TP53 have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements. Full article

(This article belongs to the Special Issue Clinical Research on Primary Immunodeficiency Diseases)

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