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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]

Purpose: FOXP3 deficiency results in severe multisystem autoimmunity in both mice and humans, driven by the absence of functional regulatory T cells. Patients typically present with early and severe autoimmune polyendocrinopathy, dermatitis, and severe inflammation of the gut, leading to villous atrophy and ultimately malabsorption, wasting, and failure to thrive. In the absence of successful treatment, FOXP3-deficient patients usually die within the first 2 years of life. Hematopoietic stem cell transplantation provides a curative option but first requires adequate control over the inflammatory condition. Due to the rarity of the condition, no clinical trials have been conducted, with widely unstandardized therapeutic approaches. We sought to compare the efficacy of lead therapeutic candidates rapamycin, anti-CD4 antibody, and CTLA4-Ig in controlling the physiological and immunological manifestations of Foxp3 deficiency in mice. Method: We generated Foxp3-deficient mice and an appropriate clinical scoring system to enable direct comparison of lead therapeutic candidates rapamycin, nondepleting anti-CD4 antibody, and CTLA4-Ig. Results: We found distinct immunosuppressive profiles induced by each treatment, leading to unique protective combinations over distinct clinical manifestations. CTLA4-Ig provided superior breadth of protective outcomes, including highly efficient protection during the transplantation process. Conclusion: These results highlight the mechanistic diversity of pathogenic pathways initiated by regulatory T cell loss and suggest CTLA4-Ig as a potentially superior therapeutic option for FOXP3-deficient patients. [ABSTRACT FROM AUTHOR]

Treg deficiency causes a lethal, CD4+ T cell-driven autoimmune disease called IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, with X-linked inheritance) in humans and in the scurfy (SF) mouse, a mouse model of the disease. Feeding Limosilactobacillus reuteri DSM 17938 (LR 17938, LR) to SF mice reprograms the gut microbiota, reduces disease progression, and prolongs lifespan. However, the efficacy and mechanism of LR, compared with other probiotics, in producing these effects is unknown. We compared LR with Lacticaseibacillus rhamnosus GG (LGG), an extensively investigated probiotic. LR was more effective than LGG in prolonging survival. Both probiotics restored the fecal microbial alpha diversity, but they produced distinct fecal bacterial clusters and differentially modulated microbial relative abundance (RA). LR increased the RA of phylum_Firmicutes, genus_Oscillospira whereas LR reduced phylum_Bacteroidetes, genus_Bacteroides and genus_Parabacteroides, reversing changes attributed to the SF phenotype. LGG primarily reduced the RA of genus_Bacteroides. Both LR and LGG reduced the potentially pathogenic taxon class_cproteobacteria. Plasma metabolomics revealed substantial differences among 696 metabolites. We observed similar changes of many clusters of metabolites in SF mice associated with treatment with either LR or LGG. However, a unique effect of LR was to increase the abundance of plasma adenosine metabolites such as inosine, which we previously showed had immune modulatory effects. In conclusion: 1) different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency; and 2) when comparing different probiotics, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that “one size does not fit all” in the treatment of autoimmune disease. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare immune deficiency with a broad clinical presentation. IPEX syndrome causes dysfunctional regulatory T cells, increasing the risk of autoimmune diseases. In this case report, we describe a 7-year-old boy with lymphocytic interstitial pneumonia and bullous pemphigoid who was recently diagnosed with IPEX syndrome. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells expressing the transcription factor forkhead box P3 (Foxp3) play a requisite role in the maintenance of immunological homeostasis and prevention of peripheral self-tolerance breakdown. Although Foxp3 by itself is neither necessary nor sufficient to specify many aspects of the Treg cell phenotype, its sustained expression in Treg cells is indispensable for their phenotypic stability, metabolic fitness, and regulatory function. In this review, we summarize recent advances in Treg cell biology, with a particular emphasis on the role of Foxp3 as a transcriptional modulator and metabolic gatekeeper essential to an effective immune regulatory response. We discuss these findings in the context of human inborn errors of immune dysregulation, with a focus on FOXP3 mutations, leading to Treg cell deficiency. We also highlight emerging concepts of therapeutic Treg cell reprogramming to restore tolerance in the settings of immune dysregulatory disorders. [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]

Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition. [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 Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation. Highlights • Autoimmunity is a known manifestation of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. • Recurrent sinopulmonary infections and hypogammaglobinemia are not well recognized in IPEX syndrome. • IPEX, as other disorders involving regulatory T cells, can include a common variable immunodeficiency (CVID)-like presentation. • Expanded but dysregulated cTFH and B cell class switching defect could contribute to the development of hypogammaglobulinemia in some IPEX patients. [ABSTRACT FROM AUTHOR]

Abstract Primary immunodeficiency diseases (PIDs) consist of a large group of genetic disorders that affect distinct components of the immune system. PID patients are susceptible to infection and non-infectious complications, particularly autoimmunity. A specific group of monogenic PIDs are due to mutations in genes that are critical for the regulation of immunological tolerance and immune responses. This group of monogenic PIDs is at high risk of developing polyautoimmunity (i.e., the presence of more than one autoimmune disease in a single patient) because of their impaired immunity. In this review, we discuss the mechanisms of autoimmunity in PIDs and the characteristics of polyautoimmunity in the following PIDs: IPEX; monogenic IPEX-like syndrome; LRBA deficiency; CTLA4 deficiency; APECED; ALPS; and PKCδ deficiency. [ABSTRACT FROM AUTHOR]

Résumé Chez l’enfant, l’association de diarrhées et arthrites peut mener à divers diagnostics rares : les tufting enteropathies, avec perméabilité accrue de l’intestin ; les syndromes camptodactylies-arthropathies-coxa vara-péricardites, qui peuvent s’associer à des signes digestifs car la péricardite constrictive chronique facilite la survenue de lymphangiectasies intestinales ; les syndromes IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) par mutations du gène FOXP3 , peuvent rarement comporter une combinaison d’arthrites et des signes digestifs ; il en est de même dans des syndromes APECED (mutations de AIRE). Chez l’adulte, les achalasies de l’œsophage s’associent à des uvéites, et parfois à des rhumatismes psoriasiques ou un syndrome de Sjögren. Des ascites peuvent révéler des polyarthrites rhumatoïdes, et des entéropathies exsudatives compliquent certains syndromes de Sjögren. Des panniculites mésentériques ont été décrits en association avec des syndromes de Sjögren, des polyarthrites rhumatoïdes et des spondylarthrites ankylosantes. Le syndrome PPP (panniculite-pancréatite-polyarthrite) est dû à la libération systémique d’enzymes pancréatiques et a un pronostic sévère si le (faux)-kyste à l’origine de la libération des bolus d’enzymes ne peut être traité. En présence d’une polyarthrite indifférenciée, il faut s’étonner d’une cholestase chronique, et solliciter alors le dépistage d’anticorps anti-mitochondries et d’anticorps antinucléaires en gros grains, ou ciblant les pores nucléaires, en faveur d’une cholangite primitive, puis, en leur absence, rechercher par biopsie une cholangite sclérosante. Des arthrites peuvent révéler de graves hépatites auto-immunes (de type 1, avec anticorps anti-actine et/ou anti-SLA ou de type 2 avec anti-LKM1) à traiter rapidement par corticoïdes. Une hyperplasie nodulaire régénérative du foie peut compliquer des lupus, polyarthrites et syndromes de Felty. Abstract In children, the combination of diarrhoea and arthritis can disclose rare disorders: tufting enteropathies, with excessive gut permeability; camptodactyly-arthropathy-coxa vara-pericarditis, sometimes associated with digestive features secondary to intestinal lymphangiectasia induced by the chronic constrictive pericarditis; IPEX syndromes (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) due to FOXP3 genetic defects, sometimes include a combinaison of arthritis and digestive troubles; the same holds true for APECED syndromes (mutations of AIRE). In adults, esophagus achalasia is associated with uveitis, and less frequently with psoriatic arthritis or Sjögren's syndromes. Ascitis can herald rheumatoid arthritis, and exsudative enteropathies worsen some Sjögren's syndromes. Mesenteric panniculitis have been observed in Sjögren's syndromes, rheumatoid arthritis and ankylosing spondylitis. The PPP syndrome (panniculitis-pancreatitis-polyarthritis) is consecutive to the systemic release of pancreatic enzymes. Its prognosis is poor if (false)-cysts from which enzymes are periodically discharged cannot be quickly surgically removed. In patients with undifferentiated polyarthritis, chronic cholostasis must lead to the search of anti-mitochondrial antibodies and anti-nuclear dots (indicative of primitive cholangitis). If such auto-antibodies are not found, a liver biopsy can reveal sclerosing cholangitis. Some arthritis can antedate auto-immune hepatitis (type 1, with anti-actin and/or anti-SLA antibodies, or type 2, with anti-LKM1 antibodies) which require a quick treatment by high doses of corticosteroids. Nodular regenerative liver hyperplasia can complicate lupus, polyarthritis, and Felty's syndromes. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inherited disorder leading to severe organ-specific autoimmunity. IPEX is caused by hemizygous mutations in FOXP3 , which codes for a master transcription factor of regulatory T (T Reg ) cell development and function. We describe a four-year-old boy with typical but slightly delayed-onset of IPEX with autoimmune diabetes mellitus, enteropathy, hepatitis and skin disease. We found the unreported FOXP3 splice site mutation c.816+2T>A that leads to the loss of leucine-zipper coding exon 7. RNA-Seq revealed that FOXP3Δ7 leads to differential expression of FOXP3 regulated genes. After myeloablative conditioning the patient underwent allogeneic HSCT from a matched unrelated donor. HSCT led to the resolution of all IPEX symptoms including insulin requirement despite persisting autoantibody levels. After initial full donor engraftment nearly complete autologous reconstitution was documented, but donor-derived T Reg cells persisted with a lineage-specific chimerism of >70% and the patient remained in clinical remission. [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]

Purpose: The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder. Methods: Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (T) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing. Results: Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 -1G→A). T cell function was severely compromised by both DOCK8 mutations. Conclusion: DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic autoimmune disease characterized by early-onset life-threatening multisystemic autoimmunity. This rare hereditary disorder is caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor, which plays a key role in the differentiation and function of CD4 + CD25 + natural regulatory T cells (Tregs), essential for the establishment and maintenance of natural tolerance. We identified a novel mutation in the FOXP3 gene affecting the Phe367 residue of the protein (F367V) in a family with three male siblings affected by IPEX. Two other mutations affecting the FOXP3 Phe367 residue (F367L and F367C) have been described previously. This unique situation of three mutations affecting the same residue in FOXP3 led us to study the molecular impact of these mutations on the structure of FOXP3 protein. Structure analysis showed that Phe367 is involved in a rich interaction network related to both monomer and dimer structure stabilization, and is crucial for FOXP3 regulatory activity. The relevance of this location is confirmed by the results of SIFT and PolyPhen-2 pathogenicity predictions for F367V mutation. In summary, as assessment of the pathogenicity of a novel mutation is crucial to achieve a proper molecular diagnosis, we analysed the impact of mutations affecting the Phe367 residue using a combined approach that provides a mechanistic view of their pathogenic effect. [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]

The forkhead/winged-helix transcription factor FOXP3 confers suppressive ability to CD4 + FOXP3 + regulatory T (Treg) cells. Human Treg cells express several different isoforms of FOXP3 that differ in function. However, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. In order to study the function of the FOXP3Δ2Δ7 isoform in vivo we generated mice that exclusively expressed a Foxp3 isoform lacking exon 2 and 7. These mice exhibited multi-organ inflammation, increased cytokine production, global T cell activation, activation of antigen-presenting cells and B cell developmental defects, all features that are shared with mice completely deficient in FOXP3. Our results demonstrate that the mouse counterpart of human FOXP3Δ2Δ7 is unable to confer suppressive ability to Treg cells. [ABSTRACT FROM AUTHOR]

Background: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder is an autoimmune disease caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. These mutations affect the normal function of circulating regulatory T cells. IPEX is characterized by profound immune dysregulation leading to dermatitis, enteropathy, multiple endocrinopathies and failure to thrive. Different forms of renal injury have also been noted in these patients but these have been described to a very limited extent. Case-Diagnosis: Three patients with IPEX with characteristic renal findings and mutations in FOXP3, including one novel mutation, are described. Case presentations are followed by a review of the renal manifestations noted in IPEX and the range of therapeutic options for this disorder. Conclusions: We recommend that IPEX be considered in the differential diagnosis of young children who present with signs of immune dysregulation with a concomitant renal biopsy demonstrating immune complex deposition in a membranous-like pattern and/or interstitial nephritis. [ABSTRACT FROM AUTHOR]

FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions. [Display omitted] • FoxP3 forms a head-to-head (H-H) dimer, instead of a domain-swap dimer • H-H dimerization confers distinct DNA specificity and promotes Runx1 binding • H-H dimerization is unique to Foxp3, providing functional specialization • Disease mutation R337Q causes swap dimerization of FoxP3 and impairs its function FoxP3 is an essential transcription factor for regulatory T cells and overall immunologic homeostasis. We show that the forkhead DNA-binding domains of FoxP3 form a unique head-to-head dimer. This is important for DNA and cofactor binding and provides functional specificity. Furthermore, a disease mutation inducing alternative dimerization impairs Foxp3 function. [ABSTRACT FROM AUTHOR]

Purpose: IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) is a rare X-linked recessive life-threatening disorder characterized by autoimmunity and early death. Pulmonary complication related with IPEX has not been elucidated exactly. Here, we report 4 IPEX patients, 3 of which died from severe pulmonary disease. Methods: Clinical data and laboratory findings including autoantibodies, immunoglobulin levels as well as number of T, B and NK cells were evaluated. FOXP3 expression and T reg activity were analyzed. The FOXP3 gene was sequenced and RNA analysis was performed. Results: Patient I (PI) presented with nephrotic syndrome at 3 years of age and then developed autoimmune hepatitis without eczema, enteropathy or high IgE and died at 9 years of age due to acute respiratory distress syndrome (ARDS). Two cousins of PI had the same hypomorphic splice site mutation leading to a deletion of 27 amino acids, but normal FOXP3 protein expression and normal suppressive capacity of T reg in a proliferation inhibition assay. However, they exhibited typical symptoms such as eczema, diabetes and enteropathy with eosinophilia at early age (PII, PIII) and were transplanted in infancy. One of them had severe respiratory distress right after birth (PIII). Patient IV from another family presented with chronic diarrhea without autoimmune manifestations and died due to ARDS. Conclusion: Lung disease related to IPEX syndrome has not been reported before and this entity could be a critical factor in disease outcome. [ABSTRACT FROM AUTHOR]

Abstract: A major concept in autoimmunity is that disruption of Foxp3+ regulatory T cells (Tregs) predisposes to breach of tolerance. This is exemplified by the Foxp3-linked disorder termed IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) which affects newborn children. There has been considerable clinical interest in the role of non-depleting anti-CD4 antibodies as a means of upregulating the function of Foxp3+ Tregs in order to control detrimental inflammatory responses such as transplant rejection. However, according to the paradigm of a Treg-dependent mechanism of action, the effectiveness of anti-CD4 antibodies as a therapy for human autoimmune diseases is unclear considering that Treg function might be intrinsically impaired. Specifically, anti-CD4 therapy is expected to fail in patients suffering from the IPEX syndrome due to the lack of functional Foxp3+ Tregs. Taking advantage of natural Foxp3 mutant scurfy (sf) mice closely resembling the IPEX syndrome, and genetically engineered mice depleted of Foxp3+ Tregs, we report here that anti-CD4 treatment induces tolerance independent of Foxp3+ Tregs. This so far undefined mechanism is dependent on the recessive non-infectious tolerization of autoreactive T cells. Treg-independent tolerance alone is powerful enough to suppress both the onset and severity of autoimmunity and reduces clinically relevant autoantibody levels and liver fibrosis. Mechanistically, tolerance induction requires the concomitant activation of autoreactive T cells and is associated with the down-regulation of the co-stimulatory TNF-receptor superfamily members OX40 and CD30 sustaining CD4+ T cell survival. In the light of ongoing clinical trials, our results highlight an unexpected potency of anti-CD4 antibodies for the treatment of autoimmune diseases. Particularly, CD4 blockade might represent a novel therapeutic option for the human IPEX syndrome. [Copyright &y& Elsevier]

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]

Unlabelled: We report a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome with a novel splicing mutation of the FOXP3 gene. The patient is a boy, born at 39 + 2 weeks gestation with a birth weight of 3,280 g. The family history was unremarkable. He was well until 11 months of age, when he was diagnosed with type 1 diabetes mellitus. The level of urine C-peptide was 0.58 μg/day (normal range, 44-116 μg/day). Glutamic acid decarboxylase autoantibody was not detected, but a high level of anti-insulin antibody (50 IU/mL; normal range, <5 IU/mL) was noted. This patient presented with unusual clinical features, including pure red cell aplasia, membranous glomerulopathy, and posterior reversible encephalopathy syndrome after a vaccination against influenza A H1N1 virus. The diagnosis of IPEX was made when the patient was 11 years old, which is quite late compared with typical cases.Conclusion: Although IPEX syndrome is usually a disease of infancy, it should not be ruled out solely on the basis of age. IPEX presentation is so variable that it should be suspected in a male child with one or more autoimmune disorders and severe infections. [ABSTRACT FROM AUTHOR]

Abstract: FOXP3 is critical for the development and function of CD4+CD25bright natural regulatory T cells (nTreg). Individuals harboring mutations in FOXP3 develop immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). We describe a child diagnosed with IPEX who underwent a reduced intensity, T and B cell depleted, matched unrelated donor bone marrow transplant followed by clinical resolution. Using lineage-specific donor chimerism studies, we demonstrate that non-myeloablative HSCT resolves disease in the context of low level donor hematopoietic stem cell (HSC) engraftment. Despite low-levels of donor HSC, thymically-derived nTreg and to a lesser extent CD4+ and CD8+ T cells, exhibit a selective in vivo growth advantage for populations containing a functional FOXP3 gene. Moreover, nTreg from this patient show regulatory function directly ex vivo. These results have implications for improving clinical therapy for patients with IPEX and provide mechanistic insight into the in vivo development of human nTreg and unexpectedly, non-regulatory T cells. [Copyright &y& Elsevier]

Abstract: Intractable diarrhea is a major symptom of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and associated with autoantibodies against enterocytes. Although autoimmune enteropathy (AIE)-related 75kDa antigen (AIE-75) is a prominent autoantigen involved in the enteropathy associated with IPEX syndrome, some patients with this syndrome demonstrated autoantibody recognizing a 95kDa protein rather than AIE-75 in the small intestine. We, herewith, identified villin, an actin-binding protein, as the 95kDa antigen. Four of five sera from patients with IPEX syndrome reacted with a fusion protein of glutathione-S-transferase and full length villin (GST–villin), whereas only three of 98 control sera weakly reacted with GST–villin. Anti-AIE-75 antibody was detected in all five IPEX sera but not in normal or control disease sera. We conclude that both AIE-75 and villin appear to be brush border autoantigens in IPEX syndrome and could be used for the diagnosis of AIE in patients with presumptive IPEX syndrome. [Copyright &y& Elsevier]

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]

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). [ABSTRACT FROM AUTHOR]

Summary: In 10 years, the neonatal autoimmune enteropathy has been individualized from other causes of neonatal severe protracted diarrheas as a syndrome called Ipex for Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked. Thanks to linkage analyses in affected families, this rare paediatric syndrome with fatal outcome has been correlated to mutations of the foxp3 gene. Homozygous loss of function of foxp3 gene results in the absence of development of a crucial subpopulation of lymphocytes with CD4+CD25+ phenotype, called regulatory T-cells. The study of these lymphocytes allows a better understanding of the immune system homeostasis and of the physiopathology of Ipex syndrome, which is a prerequisite for treatment. Achieving ex vivo manipulation of such lymphocytes will end up on promising applications of cell therapy. [Copyright &y& Elsevier]

Abstract: FOXP3 is required for the generation and function of CD4+CD25+ regulatory T (Treg) cells. To elucidate the biological role of Treg cells, we used a monoclonal anti-FOXP3 antibody to examine the frequencies of Treg cells during child development. The percentages of CD4+CD25+FOXP3+ T cells were constant shortly from after birth through adulthood. CD4+CD25+FOXP3+ T cells in cord blood showed the naive CD45RA+CD45RO− phenotype, whereas adult CD4+CD25+FOXP3+ T cells expressed mostly the memory CD45RA−CD45RO+ phenotype. The age-dependent dominance of memory CD4+CD25+FOXP3+ T cells implies functional differences between naive and memory Treg cells. Notably, four patients with FOXP3 gene mutations revealed a paucity of CD4+CD25+FOXP3+ T cells. Importantly, one patient with a frame shift mutation, who showed typical symptoms of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), exhibited marked T cell activation, whereas others with missense mutations, who were clinically milder, did not. This observation suggests a possible genotype–phenotype correlation in IPEX. [Copyright &y& Elsevier]

Over the past decade, there has been an accelerated understanding of immune regulatory mechanisms. Peripheral immune regulation is linked to a collection of specialized regulatory cells of the CD4+ T cell lineage (i.e., CD4+ Tregs). This collection consists of Tregs that are either thymically derived (i.e., natural) or peripherally induced. Tregs are important for controlling potentially autoreactive immune effectors and immunity to foreign organisms and molecules. Their importance in maintaining immune homeostasis and the overall health of an organism is clear. However, Tregs may also be involved in the pathogenesis of malignancies as now compelling evidence shows that tumors induce or recruit CD4+ Tregs to block immune priming and antitumor effectors. Efforts are underway to develop approaches that specifically inhibit the function of tumor-associated Tregs which could lead to an increased capability of the body’s immune system to respond to tumors but without off-target immune-related pathologies (i.e., autoimmune disease). In this review, the biology of human CD4+ Tregs is discussed along with their involvement in malignancies and emerging strategies to block their function. [ABSTRACT FROM AUTHOR]

Abstract: It has long been observed that patients with autoimmune diseases also have immune deficiency. How these two opposite extremes of immunity can be found in the same individual is largely unclear. Here we review the evidence that a FoxP3 defect may provide a critical link between autoimmunity and immune deficiency. Disruption of FoxP3 results in severe autoimmune syndromes in both human and mice. Bone marrow chimera experiments indicate that FoxP3 defects in both hematopoietic and non-hematopoietic cells are required for the development of severe autoimmune disease. FoxP3 mutation in the hematopoietic cells impairs the development of regulatory T cells (Treg). Our data demonstrate that the mutation in non-hematopoietic cells results in deficient thymopoiesis. Defective T cell production may be an underlying cause of T cell hyperproliferation, which together with Treg defects, may lead to fatal autoimmune disease in mouse and man. [Copyright &y& Elsevier]

Naturally arising CD25 + CD4 + regulatory T cells play key roles in the maintenance of immunologic self-tolerance and negative control of various immune responses. The majority, if not all, of them are produced by the normal thymus as a functionally distinct T-cell subpopulation, and their generation is in part developmentally controlled. Genetic abnormality in the development and function of this population can indeed be a cause of autoimmune disease, immunopathology, and allergy in humans. This regulatory population can be exploited to prevent and treat autoimmune disease by strengthening and reestablishing immunologic self-tolerance. [ABSTRACT FROM AUTHOR]

A commentary about nutritional and immunosuppressive therapy. The authors describes a case of a 1-month-old male suffering from severe eczema. They explains the immunodusregulation, polyendocrinopathy, enteropathy, X-linked disorder. They mentions the therapeutic use of hematopoietic stem cell transplantation (HSCT). They believe an early and substantial control of inflammation with good nutrition is fundamental as a bridge to transplant.

Summary Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans -differentiated Treg cells. Graphical Abstract Highlights • IPEX mutation M370I leads to unrestrained Th2 immune response • M370I mutation generates Th2-like Treg cells expressing GATA3 and Th2 cytokines • M370I mutation induces de novo Foxp3 binding sites in the Th2 locus • M370I Treg cells have increased chromatin interaction at the Th2 locus Naturally occurring FOXP3 mutations provide unique opportunities to leverage clinical observations to increase our understanding of fundamental Treg cell biology. Van Gool et al. identify a mutation in the domain-swap interface of FOXP3 in IPEX patients and demonstrate a direct role for the mutant FOXP3 in reprogramming Treg cells to acquire a Th2-like phenotype, leading to Th2-mediated autoimmunity. [ABSTRACT FROM AUTHOR]