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Summary: Inborn errors of immunity (IEI) present a unique paradigm in the realm of gene therapy, emphasizing the need for precision in therapeutic design. As gene therapy transitions from broad‐spectrum gene addition to careful modification of specific genes, the enduring safety and effectiveness of these therapies in clinical settings have become crucial. This review discusses the significance of IEIs as foundational models for pioneering and refining precision medicine. We explore the capabilities of gene addition and gene correction platforms in modifying the DNA sequence of primary cells tailored for IEIs. The review uses four specific IEIs to highlight key issues in gene therapy strategies: X‐linked agammaglobulinemia (XLA), X‐linked chronic granulomatous disease (X‐CGD), X‐linked hyper IgM syndrome (XHIGM), and immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX). We detail the regulatory intricacies and therapeutic innovations for each disorder, incorporating insights from relevant clinical trials. For most IEIs, regulated expression is a vital aspect of the underlying biology, and we discuss the importance of endogenous regulation in developing gene therapy strategies. [ABSTRACT FROM AUTHOR]

Summary: FOXP3 gene is a key transcription factor driving immune tolerance and its deficiency causes immune dysregulation, polyendocrinopathy, enteropathy X‐linked syndrome (IPEX), a prototypic primary immune regulatory disorder (PIRD) with defective regulatory T (Treg) cells. Although life‐threatening, the increased awareness and early diagnosis have contributed to improved control of the disease. IPEX currently comprises a broad spectrum of clinical autoimmune manifestations from severe early onset organ involvement to moderate, recurrent manifestations. This review focuses on the mechanistic advancements that, since the IPEX discovery in early 2000, have informed the role of the human FOXP3+ Treg cells in controlling peripheral tolerance and shaping the overall immune landscape of IPEX patients and carrier mothers, contributing to defining new treatments. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) is characterized by failure to thrive, severe chronic diarrhea, neonatal type 1 diabetes or thyroiditis, and eczematous dermatitis. We report a patient with infantile onset IPEX syndrome who developed vitiligo, alopecia, and chronic diarrhea. Awaiting stem cell transplant, he had multiple episodes of sepsis and succumbed at the age of 10 months. The constellation of symptoms is important to prompt clinicians to suspect this rare syndrome as early hematopoietic stem cell transplantation is the only cure for IPEX patients. [ABSTRACT FROM AUTHOR]

Immune dysregulation polyendocrinopathy enteropathy X linked (IPEX) syndrome is an uncurable disease of the immune system, with immune dysregulation that is caused by mutations in FOXP3. Current treatment options, such as pharmacological immune suppression and allogeneic hematopoietic stem cell transplantation, have been beneficial but present limitations, and their life‐long consequences are ill‐defined. Other similar blood monogenic diseases have been successfully treated using gene transfer in autologous patient cells, thus providing an effective and less invasive therapeutic. Development of gene therapy for patients with IPEX is particularly challenging because successful strategies must restore the complex expression profile of the transcription factor FOXP3, ensuring it is tightly regulated and its cell subset‐specific roles are maintained. This review summarizes current efforts toward achieving gene therapy to treat immune dysregulation in IPEX patients. [ABSTRACT FROM AUTHOR]

Hyper IgE syndromes comprise a group of rare primary immunodeficiency disorders characterized by a triad of atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels. Job syndrome or autosomal dominant hyper IgE syndrome because of heterozygous loss‐of‐function mutations with dominant negative effect in signal transducer and activator of transcription‐3 is the prototype of these disorders. However, several other genetically characterized immunodeficiency disorders have been identified over the past decade and joined the umbrella of hyper IgE syndromes including autosomal recessive mutations in the DOCK8,ZNF431 and PGM3 genes and heterozygous mutations with dominant negative effect in the CARD11 gene. Moreover, a number of phenotypically distinct immunodeficiency disorders can mimic hyper IgE syndromes, adding to the diagnostic challenge. Herein, we will concisely review these disorders, their molecular bases, highlighting key distinguishing clinical and laboratory findings and therapeutic options. [ABSTRACT FROM AUTHOR]

Summary: Recently, several studies have investigated a number of rare monogenic autoimmune disorders, in which the causative genetic defects were identified and found to affect the development or function of regulatory T cells (Tregs). The studies of these disorders have facilitated a deeper understanding of the mechanisms involved in immune regulation and tolerance. Furthermore, these studies have highlighted the importance of Tregs in maintaining homeostasis at the mucosal interface between the host and microbiome. Here, we offer our perspective on these monogenic autoimmune disorders, highlighting their overlapping clinical features with inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Abstract: Immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus‐derived regulatory T (tTreg) cells. tTreg cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments. [ABSTRACT FROM AUTHOR]

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease. [ABSTRACT FROM AUTHOR]

This case describes a patient with immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome with diffuse eczematous dermatitis and severe, intractable pruritus. Despite a bone marrow transplant and immunosuppressive therapy, his skin findings and pruritus persisted. Off‐label dupilumab provided significant improvement and almost complete clearance of the dermatitis and pruritus. This is the first known report of dupilumab being used in a patient with IPEX syndrome. [ABSTRACT FROM AUTHOR]

Aim To evaluate in vivo the performance of the iPex and Root ZX electronic apex locators ( EALs) in the presence of several irrigant solutions: 2.5% sodium hypochlorite (NaOCl) and 2% chlorhexidine ( CHX). Methodology Thirty-two single-rooted human teeth that were scheduled for extraction were selected. Teeth with metallic restorations, fractures, root resorption, pulp necrosis or open apices were not included The working length ( WL) was determined electronically for the root canals with the iPex and Root ZX EALs in the presence of two different irrigant solutions, 2.5% NaOCl and 2% CHX. After the teeth had been extracted, a size 10 K-file was used to determine the reference working length ( RWL), which was established at 0.5 mm short of the major foramen. In each case, the RWL was subtracted from the electronic measurements. Positive values indicated electronic measurements that exceeded the RWL (long measurements), whereas negative values indicated measurements that were short of the RWL. The values obtained with the different irrigants and EALs were compared using the paired t-test. Significance was set at P < 0.05. Results The accuracy of the iPex nor Root ZX EAL was not affected by 2.5% NaOCl or 2% CHX ( P > 0.05). However, significant differences were observed between the readings of the iPex and Root ZX, irrespective of whether 2.5% NaOCl or 2% CHX was used as the irrigant ( P < 0.05). The iPex was less accurate than the Root ZX in determining the RWL. Conclusions The accuracy of neither the iPex nor Root ZX EAL was affected by the irrigant used. However, the iPex was less accurate than the Root ZX in determining the RWL both for 2.5% NaOCl and for 2% CHX. [ABSTRACT FROM AUTHOR]

Aim To evaluate ex vivo the accuracy of the iPex multi-frequency electronic apex locator (NSK Ltd, Tokyo, Japan) for working length determination in primary molar teeth. Methodology One calibrated examiner determined the working length in 20 primary molar teeth (total of 33 root canals). Working length was measured both visually, with the placement of a K-file 1 mm short of the apical foramen or the most coronal limit of root resorption, and electronically using the electronic apex locator iPex, according to the manufacturers' instructions. Data were analysed statistically using the intraclass correlation (ICC) test. Results Comparison of the actual and the electronic measurements revealed high correlation (ICC = 0.99) between the methods, regardless of the presence or absence of physiological root resorption. Conclusions In this laboratory study, the iPex accurately identified the apical foramen or the apical opening location for working length measurement in primary molar teeth. [ABSTRACT FROM AUTHOR]

Autoimmune disease affects a significant proportion of the population. The etiology of most autoimmune diseases is largely unknown, but it is thought to be multifactorial with both environmental and genetic influences. Rare monogenic autoimmune diseases, however, offer an invaluable window into potential disease mechanisms. In this review, we will discuss the autoimmune polyglandular syndrome (APS1), the immunedysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), and autoimmune lymphoproliferative syndrome (ALPS). Significantly, the information gained from the study of these diseases has provided new insights into more common autoimmune disease and have yielded new diagnostics and therapeutic opportunities. [ABSTRACT FROM AUTHOR]