Primary Immunodeficiencies: Pathogenetic Advances, Diagnostic and Management Challenges

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

Deadline for manuscript submissions: closed (25 April 2023) | Viewed by 37572

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Special Issue Editors


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Guest Editor
Section of Clinical and Laboratory Immunology, Department of Clinical and Experimental Medicine, Division of Pediatrics, University of Pisa, Pisa, Italy
Interests: primary immunodeficiency disorders; autoinflammatory disorders; pediatric immunology; autoimmunity; biologic drugs

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Guest Editor
Section of Pediatric Hematology and Oncology, Santa Chiara Hospital, Pisa, Italy
Interests: inborn errors of immunity; autoimmune diseases; primary immunodeficiency disorders; immune dysregulation; autoimmune cytopenia; lymphoproliferation
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Special Issue Information

Dear Colleagues,

In the last decade, the research advances in the field of pediatric immunology brought a dramatic improvement in the diagnosis of primary immunodeficiency disorders. The use of new genetic panels allowed the identification of a considerable number of monogenic causes of primay immunodeficiency, each one featuring a peculiar clinical and immunological phenotype.

Moreover, the discovery and molecular characterization of the monogenic causes of primary immunodeficiencies helped to better understand the complex pathogenic and clinical overlap between immunodeficiency, immune dysregulation, autoimmunity and autoinflammation. The risk of lynphoproliferation and non-hematologic malignancies in children with primary immunodeficiencies has also been deeply analyzed, providing interesting information for long-term follow-up and clinical management.

Finally, the increasing knowledge on the genetic and immunological background underlying single conditions, together with the collection of data from the literature and international registries, opened up the opportunity to use targeted treatments and genetic therapy and better define the role of hematopoietic stem cell transplantaion in pediatric immunodeficiency disorders.

The present Special Issue aims to provide an update on the intriguing field of primary immunodeficiency disorders in childhood, with a particular focus on the clinical, immunological and molecular diagnostic aspects and on the most relevant improvements in the therapeutic approach to such conditions.

Dr. Rita Consolini
Dr. Giorgio Costagliola
Guest Editors

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Keywords

  • new primary immunodeficiency disorders
  • diagnosis of primary immunodeficiency disorders
  • screening for primary immunodeficiency disorders
  • immunodeficiency disorders with immune dysregulation
  • immunodeficiency and autoimmunity
  • immunodeficiency and autoinflammation
  • new therapies for primary immunodeficiencies
  • genetic therapy for primary immunodeficiency disorders
  • hematopoietic stem cell transplantation for primary immunodeficiency disorders

Published Papers (14 papers)

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Editorial

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3 pages, 184 KiB  
Editorial
Primary Immunodeficiencies: Pathogenetic Advances, Diagnostic and Management Challenges
by Giorgio Costagliola and Rita Consolini
J. Clin. Med. 2023, 12(14), 4651; https://doi.org/10.3390/jcm12144651 - 13 Jul 2023
Viewed by 687
Abstract
The field of immunology is rapidly progressing, with new monogenic disorders being discovered every year [...] Full article

Research

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11 pages, 763 KiB  
Article
The Evolutionary Scenario of Pediatric Unclassified Primary Antibody Deficiency to Adulthood
by Mayla Sgrulletti, Giorgio Costagliola, Giuliana Giardino, Simona Graziani, Elisabetta Del Duca, Silvia Di Cesare, Gigliola Di Matteo, Rita Consolini, Claudio Pignata and Viviana Moschese
J. Clin. Med. 2023, 12(13), 4206; https://doi.org/10.3390/jcm12134206 - 22 Jun 2023
Cited by 1 | Viewed by 995
Abstract
Background: Unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. Since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological [...] Read more.
Background: Unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. Since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological scenario of unPAD children to adulthood and identification of biomarkers of primary immune deficiency (PID) persistence. Methods: A total of 23 pediatric unPAD patients underwent clinical and immunological FU for a mean time of 14 years (range 3–32 years, median 16 years). Results: UnPAD diagnosis may change over time. At the last FU, 10/23 (44%) children matched the diagnosis of transient hypogammaglobulinemia of infancy and 13/23 (56%) suffered from a persistent PID. In detail, an unPAD condition was confirmed in 7/23 (30%) patients, whereas 3/23 (13%), 2/23 (9%), and 1/23 (4%) were reclassified as common variable immunodeficiency, selective IgA deficiency, and isolated IgM deficiency, respectively. Low IgA, low specific antibody response to pneumococcus, and lower respiratory tract infections at diagnosis were independently associated with IEI persistence. Conclusions: Long-term monitoring of unPAD patients is required to define their outcome and possible evolution towards a definitive IEI diagnosis. Full article
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14 pages, 907 KiB  
Article
Incidence, Management Experience and Characteristics of Patients with Giardiasis and Common Variable Immunodeficiency
by Irene Díaz-Alberola, Juan Francisco Gutiérrez-Bautista, Andrea Espuch-Oliver, José María García-Aznar, Per Anderson, Pilar Jiménez, Carmen Hidalgo-Tenorio and Miguel Ángel López-Nevot
J. Clin. Med. 2022, 11(23), 7007; https://doi.org/10.3390/jcm11237007 - 27 Nov 2022
Cited by 5 | Viewed by 3618
Abstract
Common variable immunodeficiency (CVID) is an antibody immunodeficiency with a wide variety of clinical and immunological manifestations, and whose genetic cause is found in about 25% of diagnosed cases. Giardia lamblia is one of the main causes of gastrointestinal infections in CVID. 5-Nitroimidazoles [...] Read more.
Common variable immunodeficiency (CVID) is an antibody immunodeficiency with a wide variety of clinical and immunological manifestations, and whose genetic cause is found in about 25% of diagnosed cases. Giardia lamblia is one of the main causes of gastrointestinal infections in CVID. 5-Nitroimidazoles are the most used first-line treatment, but nitroimidazole-refractory giardiasis is increasing. Nevertheless, only a few cases of refractory giardiasis in CVID have been reported. This study aimed to determine the incidence of Giardia infection in our CVID cohort, shows our management experience and describes patients’ phenotypic features. Clinical data collection, immunological, immunogenetics and microbiology assays were performed, and previous cases of giardiasis in CVID were reviewed. The incidence of symptomatic giardiasis was 12.9%. The main immunological features were undetectable or decreased IgA levels and reduced switched memory B cells. A probable PTEN pathogenic variant was detected in one. Three patients responded to metronidazole but suffered reinfections, and one was a refractory giardiasis eradicated with innovative quinacrine plus paromomycin combination. This work could contribute to the decision-making and therapeutic management of future patients with CVID and giardiasis, highlighting the importance of the early detection and treatment of infections in patients with CVID to ensure a good quality of life. Full article
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12 pages, 1728 KiB  
Article
Common Variable Immunodeficiency Associated with a De Novo IKZF1 Variant and a Low Humoral Immune Response to the SARS-CoV-2 Vaccine
by Irene Díaz-Alberola, Andrea Espuch-Oliver, José María García-Aznar, Christian Ganoza-Gallardo, María Aguilera-Franco, Antonio Sampedro, Pilar Jiménez and Miguel Ángel López-Nevot
J. Clin. Med. 2022, 11(9), 2303; https://doi.org/10.3390/jcm11092303 - 20 Apr 2022
Cited by 3 | Viewed by 2295
Abstract
Background and Aims: Common variable immunodeficiency (CVID) comprises a group of diseases with heterogeneous clinical and immunological manifestations. Several mutations have been identified in genes encoding proteins essential for immune function. Our aim was to phenotypically and genotypically characterize a patient diagnosed with [...] Read more.
Background and Aims: Common variable immunodeficiency (CVID) comprises a group of diseases with heterogeneous clinical and immunological manifestations. Several mutations have been identified in genes encoding proteins essential for immune function. Our aim was to phenotypically and genotypically characterize a patient diagnosed with CVID and study his response to the SARS-CoV-2 vaccine. Methods: We performed a next-generation sequencing analysis, a CMIA, and an ELISA to analyze the humoral and cellular response to the SARS-CoV-2 vaccine, respectively. We also employed flow cytometry and immunoturbidimetry to assess the patient’s global immune status. Results: We found a low humoral but positive cellular response to the SARS-CoV-2 vaccine. NGS screening revealed a transition from guanine to adenine at position c.485 of the IKZF1 gene in heterozygosity, giving rise to the R162Q variant, which was not present in his parents. Conclusions: The R162Q variant of the IKZF1 gene has been associated with CVID type 13, but always with an autosomal dominant inheritance with high penetrance. Therefore, we present for the first time a case of CVID associated with a de novo heterozygous R162Q variant in the IKZF1 gene in a patient with a low humoral immune response to the complete COVID-19 vaccination program. Full article
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15 pages, 282 KiB  
Article
Clinical, Immunological, and Genetic Findings in a Cohort of Patients with the DiGeorge Phenotype without 22q11.2 Deletion
by Antonino Maria Quintilio Alberio, Annalisa Legitimo, Veronica Bertini, Giampiero I. Baroncelli, Giorgio Costagliola, Angelo Valetto and Rita Consolini
J. Clin. Med. 2022, 11(7), 2025; https://doi.org/10.3390/jcm11072025 - 5 Apr 2022
Cited by 4 | Viewed by 1824
Abstract
Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype [...] Read more.
Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype that is highly suggestive of this syndrome but without the 22q11.2 deletion. The cardinal features of 22q11.2DS, such as congenital heart defects, hypoparathyroidism, and facial dysmorphisms, were observed in the majority of the patient cohort. The unusual features are described in detail. The immunologic assessment showed various degrees of immunodeficiency of the T-cell compartment, notably a reduction in the thymic output. Half of the patient cohort exhibited a reduction in total dendritic cells. Array comparative genomic hybridization (CGH) revealed six patients harboring copy number variations (CNVs) never reported in normal subjects. The gene content of these CNVs was carefully analyzed to understand the mechanisms leading to 22q11.2DS phenocopies. According to these results, we suggested that array-CGH should be used as a first-tier tool for patients resembling 22q11.2DS. Full article
9 pages, 1183 KiB  
Article
Assessment of COVID-19 Incidence and the Ability to Synthesise Anti-SARS-CoV-2 Antibodies of Paediatric Patients with Primary Immunodeficiency
by Karolina Pieniawska-Śmiech, Anna Kuraszewicz, Joanna Sado, Karol Śmiech and Aleksandra Lewandowicz-Uszyńska
J. Clin. Med. 2021, 10(21), 5111; https://doi.org/10.3390/jcm10215111 - 30 Oct 2021
Cited by 10 | Viewed by 1748
Abstract
Background: Data regarding the course of SARS-CoV-2 infection in children with primary immunodeficiency (PID) is insufficient. The purpose of the study was to evaluate the morbidity and clinical course of COVID-19 and the ability to produce anti-SARS-CoV-2 IgG antibodies in children with PID. [...] Read more.
Background: Data regarding the course of SARS-CoV-2 infection in children with primary immunodeficiency (PID) is insufficient. The purpose of the study was to evaluate the morbidity and clinical course of COVID-19 and the ability to produce anti-SARS-CoV-2 IgG antibodies in children with PID. Methods: In this retrospective study, medical records of 99 patients aged 0–18 were evaluated. The patients were divided into three groups: PID group (68.69%), control group (19.19%) and patients with ongoing or previous paediatric inflammatory multisystem syndrome (12.12%). Data such as morbidity, clinical outcome, and IgG anti-SARS-CoV-2 antibody titres were assessed. Results: A confirmed diagnosis of SARS-CoV-2 infection has been established in 26.47% of patients with PID. Among patients with PID infected with SARS-CoV-2, only three cases were hospitalised. Mortality in the PID group was 0%. Throughout an observation period of 1 year, 47.06% of patients with PID were tested positive for the anti-SARS-CoV-2 antibody. Conclusions: In the study group, in most cases the disease had a mild and self-limiting course. Remarkably, even though IgG deficiency was the most prevalent form of PID in the study group, the patients were able to respond satisfactorily to the infection in terms of anti-SARS-CoV-2 IgG. Full article
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15 pages, 579 KiB  
Article
Spectrum of Disease Manifestations in Patients with Selective Immunoglobulin E Deficiency
by César Picado, Iñaki Ortiz de Landazuri, Alexandru Vlagea, Irina Bobolea, Ebymar Arismendi, Rosanel Amaro, Jacobo Sellarés, Joan Bartra, Raimon Sanmarti, José Hernandez-Rodriguez, José-Manuel Mascaró, Jordi Colmenero, Eva C. Vaquero and Mariona Pascal
J. Clin. Med. 2021, 10(18), 4160; https://doi.org/10.3390/jcm10184160 - 15 Sep 2021
Cited by 12 | Viewed by 3550
Abstract
Background: Selective IgE deficiency (SIgED) has been previously evaluated in selected patients from allergy units. This study investigates the effects of SIgED on the entire population in a hospital setting and sought to delineate in detail the clinical aspects of SIgED. Methods: A [...] Read more.
Background: Selective IgE deficiency (SIgED) has been previously evaluated in selected patients from allergy units. This study investigates the effects of SIgED on the entire population in a hospital setting and sought to delineate in detail the clinical aspects of SIgED. Methods: A retrospective study of the data obtained from electronic medical records of 52 adult patients (56% female) with a mean age of 43 years and IgE levels of <2.0 kU/L with normal immunoglobulin (Ig) IgG, IgA, and IgM levels, seen at our hospital, without selection bias, from 2010 to 2019. Results: Recurrent upper respiratory infections were recorded in 18 (34.6%) patients, pneumonia was recorded in 16 (30.7%) patients, bronchiectasis was recorded in 16 (30.7%) patients, and asthma was recorded in 10 (19.2%) patients. Eighteen patients (34.6%) suffered autoimmune clinical manifestations either isolated (19%) or combining two or more diseases (15%), Hashimoto’s thyroiditis being the most frequent (19%), which was followed by arthritis (10%) and thrombocytopenia and/or neutropenia (5.7%). Other less frequent associations were Graves’ disease, primary sclerosing cholangitis, Sjögren’s syndrome, and autoimmune hepatitis. Eczematous dermatitis (15.3%), chronic spontaneous urticaria (17.3%), and symptoms of enteropathy (21%) were also highly prevalent. Thirty percent of patients developed malignancies, with non-Hodgkin lymphomas (13.4%) being the most prevalent. Conclusions: The clinical manifestations of SIgED encompass a variety of infectious, non-infectious complications, and malignancy. Since it cannot be ruled out that some type of selection bias occurred in the routine assessment of IgE serum Ievels, prospective studies are required to better characterize SIgED and to determine whether it should be added to the list of antibody deficiencies. Full article
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16 pages, 1516 KiB  
Article
Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells
by Ewa Więsik-Szewczyk, Elżbieta Rutkowska, Iwona Kwiecień, Marcelina Korzeniowska, Dariusz Sołdacki and Karina Jahnz-Różyk
J. Clin. Med. 2021, 10(15), 3356; https://doi.org/10.3390/jcm10153356 - 29 Jul 2021
Cited by 10 | Viewed by 2162
Abstract
Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID [...] Read more.
Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases. Full article
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Review

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9 pages, 1868 KiB  
Review
Eosinophilic Gastrointestinal Diseases in Inborn Errors of Immunity
by Martina Votto, Matteo Naso, Ilaria Brambilla, Silvia Caimmi, Maria De Filippo, Amelia Licari, Gian Luigi Marseglia and Riccardo Castagnoli
J. Clin. Med. 2023, 12(2), 514; https://doi.org/10.3390/jcm12020514 - 8 Jan 2023
Cited by 4 | Viewed by 1834
Abstract
Inborn errors of immunity (IEI) are disorders mostly caused by mutations in genes involved in host defense and immune regulation. Different degrees of gastrointestinal (GI) involvement have been described in IEI, and for some IEI the GI manifestations represent the main and characteristic [...] Read more.
Inborn errors of immunity (IEI) are disorders mostly caused by mutations in genes involved in host defense and immune regulation. Different degrees of gastrointestinal (GI) involvement have been described in IEI, and for some IEI the GI manifestations represent the main and characteristic clinical feature. IEI also carry an increased risk for atopic manifestations. Eosinophilic gastrointestinal diseases (EGIDs) are emerging disorders characterized by a chronic/remittent and prevalent eosinophilic inflammation affecting the GI tract from the esophagus to the anus in the absence of secondary causes of intestinal eosinophilia. Data from the U.S. Immunodeficiency Network (USIDNET) reported that EGIDs are more commonly found in patients with IEI. Considering this element, it is reasonable to highlight the importance of an accurate differential diagnosis in patients with IEI associated with mucosal eosinophilia to avoid potential misdiagnosis. For this reason, we provide a potential algorithm to suspect an EGID in patients with IEI or an IEI in individuals with a diagnosis of primary EGID. The early diagnosis and detection of suspicious symptoms of both conditions are fundamental to prevent clinically relevant complications. Full article
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25 pages, 386 KiB  
Review
Diagnostic Challenges in Patients with Inborn Errors of Immunity with Different Manifestations of Immune Dysregulation
by Karolina Pieniawska-Śmiech, Gerard Pasternak, Aleksandra Lewandowicz-Uszyńska and Marek Jutel
J. Clin. Med. 2022, 11(14), 4220; https://doi.org/10.3390/jcm11144220 - 20 Jul 2022
Cited by 12 | Viewed by 2781
Abstract
Inborn errors of immunity (IEI), formerly known as primary immunodeficiency disorders (PIDs), are inherited disorders caused by damaging germline variants in single genes, which result in increased susceptibility to infections and in allergic, autoimmune, autoinflammatory, nonmalignant lymphoproliferative, and neoplastic conditions. Along with well-known [...] Read more.
Inborn errors of immunity (IEI), formerly known as primary immunodeficiency disorders (PIDs), are inherited disorders caused by damaging germline variants in single genes, which result in increased susceptibility to infections and in allergic, autoimmune, autoinflammatory, nonmalignant lymphoproliferative, and neoplastic conditions. Along with well-known warning signs of PID, attention should be paid to signs of immune dysregulation, which seem to be equally important to susceptibility to infection in defining IEI. The modern diagnostics of IEI offer a variety of approaches but with some problems. The aim of this review is to discuss the diagnostic challenges in IEI patients in the context of an immune dysregulation background. Full article
13 pages, 639 KiB  
Review
Epigenetic Alterations in Inborn Errors of Immunity
by Roberta Romano, Francesca Cillo, Cristina Moracas, Laura Pignata, Chiara Nannola, Elisabetta Toriello, Antonio De Rosa, Emilia Cirillo, Emma Coppola, Giuliana Giardino, Nicola Brunetti-Pierri, Andrea Riccio and Claudio Pignata
J. Clin. Med. 2022, 11(5), 1261; https://doi.org/10.3390/jcm11051261 - 25 Feb 2022
Cited by 10 | Viewed by 1837
Abstract
The epigenome bridges environmental factors and the genome, fine-tuning the process of gene transcription. Physiological programs, including the development, maturation and maintenance of cellular identity and function, are modulated by intricate epigenetic changes that encompass DNA methylation, chromatin remodeling, histone modifications and RNA [...] Read more.
The epigenome bridges environmental factors and the genome, fine-tuning the process of gene transcription. Physiological programs, including the development, maturation and maintenance of cellular identity and function, are modulated by intricate epigenetic changes that encompass DNA methylation, chromatin remodeling, histone modifications and RNA processing. The collection of genome-wide DNA methylation data has recently shed new light into the potential contribution of epigenetics in pathophysiology, particularly in the field of immune system and host defense. The study of patients carrying mutations in genes encoding for molecules involved in the epigenetic machinery has allowed the identification and better characterization of environment-genome interactions via epigenetics as well as paving the way for the development of new potential therapeutic options. In this review, we summarize current knowledge of the role of epigenetic modifications in the immune system and outline their potential involvement in the pathogenesis of inborn errors of immunity. Full article
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27 pages, 33230 KiB  
Review
The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies
by Paulina Mertowska, Sebastian Mertowski, Martyna Podgajna and Ewelina Grywalska
J. Clin. Med. 2022, 11(4), 947; https://doi.org/10.3390/jcm11040947 - 11 Feb 2022
Cited by 5 | Viewed by 2779
Abstract
Transcription factors are an extremely important group of proteins that are responsible for the process of selective activation or deactivation of other cellular proteins, usually at the last stage of signal transmission in the cell. An important family of transcription factors that regulate [...] Read more.
Transcription factors are an extremely important group of proteins that are responsible for the process of selective activation or deactivation of other cellular proteins, usually at the last stage of signal transmission in the cell. An important family of transcription factors that regulate the body’s response is the FOX family which plays an important role in regulating the expression of genes involved in cell growth, proliferation, and differentiation. The members of this family include the intracellular protein Foxp3, which regulates the process of differentiation of the T lymphocyte subpopulation, and more precisely, is responsible for the development of regulatory T lymphocytes. This protein influences several cellular processes both directly and indirectly. In the process of cytokine production regulation, the Foxp3 protein interacts with numerous proteins and transcription factors such as NFAT, nuclear factor kappa B, and Runx1/AML1 and is involved in the process of histone acetylation in condensed chromatin. Malfunctioning of transcription factor Foxp3 caused by the mutagenesis process affects the development of disorders of the immune response and autoimmune diseases. This applies to the impairment or inability of the immune system to fight infections due to a disruption of the mechanisms supporting immune homeostasis which in turn leads to the development of a special group of disorders called primary immunodeficiencies (PID). The aim of this review is to provide information on the role of the Foxp3 protein in the human body and its involvement in the development of two types of primary immunodeficiency diseases: IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome) and CVID (Common Variable Immunodeficiency). Full article
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20 pages, 1479 KiB  
Review
Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications
by Giorgio Costagliola, Susanna Cappelli and Rita Consolini
J. Clin. Med. 2021, 10(20), 4729; https://doi.org/10.3390/jcm10204729 - 15 Oct 2021
Cited by 23 | Viewed by 5661
Abstract
During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency [...] Read more.
During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity. Full article
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22 pages, 935 KiB  
Review
The Epidemiology and Clinical Presentations of Atopic Diseases in Selective IgA Deficiency
by Izabela Morawska, Sara Kurkowska, Dominika Bębnowska, Rafał Hrynkiewicz, Rafał Becht, Adam Michalski, Hanna Piwowarska-Bilska, Bożena Birkenfeld, Katarzyna Załuska-Ogryzek, Ewelina Grywalska, Jacek Roliński and Paulina Niedźwiedzka-Rystwej
J. Clin. Med. 2021, 10(17), 3809; https://doi.org/10.3390/jcm10173809 - 25 Aug 2021
Cited by 17 | Viewed by 4084
Abstract
Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency disease (PID), with an estimated occurrence from about 1:3000 to even 1:150, depending on population. sIgAD is diagnosed in adults and children after the 4th year of age, with immunoglobulin A level below [...] Read more.
Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency disease (PID), with an estimated occurrence from about 1:3000 to even 1:150, depending on population. sIgAD is diagnosed in adults and children after the 4th year of age, with immunoglobulin A level below 0.07 g/L and normal levels of IgM and IgG. Usually, the disease remains undiagnosed throughout the patient’s life, due to its frequent asymptomatic course. If symptomatic, sIgAD is connected to more frequent viral and bacterial infections of upper respiratory, urinary, and gastrointestinal tracts, as well as autoimmune and allergic diseases. Interestingly, it may also be associated with other PIDs, such as IgG subclasses deficiency or specific antibodies deficiency. Rarely sIgAD can evolve to common variable immunodeficiency disease (CVID). It should also be remembered that IgA deficiency may occur in the course of other conditions or result from their treatment. It is hypothesized that allergic diseases (e.g., eczema, rhinitis, asthma) are more common in patients diagnosed with this particular PID. Selective IgA deficiency, although usually mildly symptomatic, can be difficult for clinicians. The aim of the study is to summarize the connection between selective IgA deficiency and atopic diseases. Full article
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