IPEX Syndrome Research Articles

Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals

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.

Foxp3-independent suppression of autoimmunity by anti-CD4-induced recessive tolerization of autoreactive T cells (P5222)

Abstract Non-depleting anti-CD4 monoclonal antibodies potently induce dominant infectious tolerance and Foxp3+ regulatory T cells (Tregs) have recently been implicated as a crucial underlying mechanism. However, it has not been explored whether anti-CD4 treatment has residual activity in the complete absence of Foxp3+ Tregs. Utilizing DEREG mice which allow for the inducible depletion of Foxp3+ Tregs by diphtheria toxin (DT), we found that the anti-CD4 clone YTS177.9 is able to fully inhibit CD4+ T cell activation in the absence of Foxp3+ Tregs in vitro. Moreover, anti-CD4 treatment of neonatal scurfy (sf) mice genetically devoid of functional Foxp3+ Tregs resulted in a rescue of the autoimmune phenotype. We thus discovered a novel Foxp3-independent mechanism of anti-CD4-induced tolerance. Foxp3-independent tolerance was recessive as opposed to classical dominant infectious tolerance requiring Foxp3+ Tregs. Given that anti-human CD4 antibodies are currently developed as therapeutics, our results provide valuable insights into anti-CD4-mediated tolerance and unexpectedly highlight a potential synergy of anti-CD4 antibodies with Foxp3+ Treg-modulating regimens for the treatment of human inflammatory diseases. Beyond, anti-CD4 antibodies might represent a novel therapeutic option for the human IPEX syndrome which is caused by Foxp3 mutations similar to the autoimmune disease of sf mice.

Characterization of the function and co-expression patterns of human FOXP3 isoforms and their role in IPEX syndrome development. (P4146)

Abstract IPEX syndrome is a rare and fatal X-linked recessive disorder due to mutations in the FOXP3 gene, which plays a critical role in the development and function of the regulatory T cells (Tregs) that maintain self-tolerance. Contrary to mice, humans possess three isoforms of FOXP3 with unknown function, and the expression of these isoforms is not restricted to Tregs. We determined the levels of expression and distribution of FOXP3 and other transcription factors isoforms in normal human T-cell subsets and in T cell subsets of patients with autoimmunity at the single-cell level by multiplex RT-qPCR and Flow cytometry and observed that expression of these isoforms is not restricted to Tregs, but can also be detected in naïve and activated/memory helper (Th) and in activated/memory CD8+ T cells. Distinct patterns of co-expression of the FOXP3 isoforms are modulated in response to inflammatory or autoimmune stimuli. Moreover, we observed that normal FOXP3 isoforms could induce bona fide regulatory function in Th cells. Our work supports the view that lack of FOXP3 expression in the effector T-cell populations in IPEX patients may contribute to the pathogenesis of the disease and suggests that FOXP3 deficiency can be corrected by gene transfer of the appropriate FOXP3 isoforms into conventional T-cells, which has important implication for the treatment of IPEX patients.

Intestinal Dysfunction in APECED Syndrome Could Mimic IPEX Syndrome

To the Editor: Classical diagnosis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome depends on the appearance of 2 of its 3 major criteria: mucocutaneous candidiasis, autoimmune hypoparathyroidism, and adrenal failure. A variety of clinical components may be seen in the clinical picture, however, and they may occur before onset of the 3 major criteria, resulting in diagnostic delay (1). Intestinal dysfunction is one such component of APECED syndrome and is observed in 18% to 22% of patients with APECED syndrome. A variety of causes are attributed to this intestinal dysfunction, such as celiac disease, cystic fibrosis, pancreatic insufficiency, intestinal infections with candida albicans, and loss of enteroendocrine cells caused by autoimmune attack (2,3). Mutations of the forkhead box P3 (FoxP3) gene result in impaired function of regulatory T cells, which leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome. In about one-third of patients, with clinical symptoms resembling IPEX syndrome, no mutation was found in the FoxP3 gene (4). So far, only 2 articles have been published about these IPEX-like patients. One of them suggested improvement of clinical symptoms with sirolimus usage in 2 IPEX and 5 IPEX-like patients (5). And a recently published article showed significant reduction in peripheral regulatory T cells in an impressive cohort of 28 IPEX-like patients (4). In that report, the authors declared exclusion of the Wiskott-Aldrich syndrome, Omenn syndrome, hyper-immunoglobulin E syndrome, and autoimmune lymphoproliferative syndrome, which were originally included in the differential diagnosis; however, APECED syndrome was not included in the differential diagnosis, despite its involvement in the same group of congenital diarrheal disorders as IPEX and IPEX-like syndromes, according to defects in the modulation of immune response (6). Additionally, a reduction in regulatory T cells in patients with APECED syndrome was previously discovered (7). Assessment of these patients for APECED syndrome could have occurred whether APECED syndrome was substantially part of the IPEX-like syndromes or not.

IPEX syndrome with membrano-proliferative nephrotic syndrome

A two-month old male infant initially presented with cutaneous candidiasis. He is the second child of nonconsanguineous healthy parents whose first born is a bright six year old school girl. This boy was born at term following an uncomplicated antenatal period with a birth weight of 2.9 kg. He was exclusively breast fed for six months. Initial tests for immunodeficiency including full blood count, HIV screening, CD 3,4,8,19,16 subsets, serum IgG, IgM and IgA levels were normal. IgE levels were not assessed due to non-availability of facilities.

Diagnostic Value of the Skin Lesions in Immune Dysregulation, Polyendocrinopathy, Enteropathy, X‐Linked Syndrome

We report a child with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome due to a de novo c.1190G>A (p.R397Q) mutation in exon 11 of the forkhead domain of the FOXP3 gene. He had chronic dermatitis with an eczematous and ichthyosiform appearance and had an allogeneic bone marrow transplantation. IPEX syndrome is a rare, often fatal recessive disease caused by mutations in the FOXP3 gene on the X chromosome (Xp11.23-q13.3).

IPEX Syndrome, FOXP3 and Cancer.

In this review, we introduce the IPEX syndrome and its relationship with germline mutations of the FOXP3 gene. We then describe the multiple functional roles of FOXP3 in regulatory T cells and epithelial cells as well as in IPEX syndrome and tumor progression. Potential mechanisms of FOXP3 inactivation and transcriptional regulation are discussed with recent advances. Finally, we point out current issues and a potential FOXP3-mediated therapeutic strategy as well as the reactivation of FOXP3 in patients with IPEX syndrome and cancer.

958 Fatal Human Bocavirus Infection in a Boy with Ipex-Like Syndrome and Vaccine-Acquired Rotavirus Enteritis Awaiting Stem Cell Transplantation

We report about a 21-month-old boy presenting with chronic diarrhea and obstructive lung disease since infancy. His older brother, the first male child of non-consanguine Egyptean parents, had died at...

Autoimmune Enteropathy: A Review and Update of Clinical Management

Autoimmune enteropathy (AIE) is a rare condition characterized by intractable diarrhea, histologic changes on small intestinal biopsy, and failed response to dietary manipulation that also may present with extraintestinal manifestations. In many patients, immunosuppressive therapies are necessary. Although AIE is more common in infants, adult involvement has also been documented. Much of what is known about AIE has been gathered from case reports and small case series; therefore, more research in this evolving field is needed. IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) and APECED (autoimmune phenomena, polyendocrinopathy, candidiasis, and ectodermal dystrophy) are systemic forms of AIE.

Interleukin-2 and type 1 diabetes: New therapeutic perspectives

A new sort of CD4+T cells, so-called regulatory T cells (Tregs), has been described in 1996. Tregs are suggested to have an important function consisting in controlling autoimmune reactions. In humans, absence of Tregs induces the IPEX syndrome characterized by the presence of several autoimmune diseases. These cells depend on interleukin-2 (IL-2) for proliferating and controlling the T effector cells (Teff) reaction, but they do not have the capacity to produce IL-2. In type 1 diabetes (T1DM), a hypothesis is that a lack of IL-2 in pancreas could prevent Tregs action and lead to beta cells destruction. In NOD mice, low dose IL-2 treatment at the initial time of diabetes can rescue insulin secretion by restoring proteins expression that are necessary for Tregs regulatory function in the pancreas. Using low doses instead of high doses IL-2 prevents Teff activation which also depends on IL-2. These results led to conduct a dose-effect trial in human T1DM. This trial aimed at determining the therapeutic condition, which induces Tregs activation without major side effects, in a therapeutic perspective to recover insulin secretion at the apparition of diabetes.

Structural and Biological Features of FOXP3 Dimerization Relevant to Regulatory T Cell Function

FOXP3 is a key transcription factor for regulatory Tcell function. We report the crystal structure of the FOXP3 coiled-coil domain, through which a loose or transient dimeric association is formed and modulated, accounting for the activity variations introduced by disease-causing mutations or posttranslational modifications. Structure-guided mutagenesis revealed that FOXP3 coiled-coil-mediated homodimerization is essential for Treg function invitro and invivo. In particular, we identified human FOXP3 K250 and K252 as key residues for the conformational change and stability of the FOXP3 dimer, which can be regulated by protein posttranslational modifications such as reversible lysine acetylation. These studies provide structural and mechanistic explanations for certain disease-causing mutations in the coiled-coil domain of FOXP3 that are commonly found in IPEX syndrome. Overall, the regulatory machinery involving homooligomerization, acetylation, and heteroassociation has been dissected, defining atomic insights into the biological and pathological characteristics of the FOXP3 complex.

Chronic Diarrhea in Children

Chronic Diarrhea in Children

The Biology of Autoimmune Response in the Scurfy Mice that Lack the CD4+Foxp3+ Regulatory T-Cells

Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans, endocrine and gastrointestinal inflammation are also observed, hence the disease is termed IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. The three week period of fatal MOI offers a useful autoimmune model in which the controls by genetics, T-cell subsets, cytokines, and effector mechanisms could be efficiently investigated. In this report, we will review published work, summarize our recent studies of Scurfy double mutants lacking specific autoimmune-related genes, discuss the cellular and cytokine controls by these genes on MOI, the organ-specificities of the MOI controlled by environments, and the effector mechanisms regulated by specific Th cytokines, including several newly identified control mechanisms for organ-specific autoimmune response.

A girl of IPEX syndrome with low expression of Foxp3

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked) syndrome is a rare immune disorder characterized by endocrinopathy such as insulin-dependent diabetes and hypothyroidism, intractable diarrhea, and recurrent infections. The mutation of the gene encoding a transcription factor, forkhead box P3 (FOXP3), leads to the dysfunction of regulatory T cells, resulting in systemic autoimmunity. IPEX syndrome is inherited in an X-linked recessive pattern. We report the case of a 12-year-old Japanese girl with IPEX syndrome. She developed severe and prolonged diarrhea with significant weight loss at age ten and was diagnosed with Crohn's disease by endoscopic and pathological finding at age twelve. Her diarrhea responded to corticosteroids, but recurred with tapering of corticosteroids. Eventually, infliximab was initiated to control her diarrhea with fair response. Having suffered from insulin-dependent diabetes since age two with hypothyroidism developing one year later, her clinical symptoms were quite reminiscent of IPEX syndrome. Although flow cytometry analysis revealed low expression of Foxp3 in CD4(+)CD25(+) T cells compared with healthy controls, no genetic mutation was found in the FOXP3 gene. In contrast to previously reported cases of IPEX syndrome without FOXP3 mutations, our patient was distinct in having had no episodes of recurrent infections.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A Paradigm of Immunodeficiency with Autoimmunity

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed.

Autoimmune Hepatitis Type 2 in a Child With IPEX Syndrome

Autoimmune Hepatitis Type 2 in a Child With IPEX Syndrome

Proteomics plus genomics approaches in primary immunodeficiency: the case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare syndrome due to a mutation in the forkhead box protein 3 gene (FOXP3) leading to an impaired regulatory T cell (T(reg) ) activity associated both with skewed T helper type 2 (Th2) response and autoreactive phenomena. The purpose of this study was to describe a combined proteomics and genomics approach to comprehensively evaluate clinical and immunological phenotypes of patients affected by IPEX. T cell receptor (TCR)-Vβ repertoire and peripheral blood lymphocytes phenotype from three brothers affected by IPEX were studied by flow cytometry. Specific immunoglobulin (Ig)E were evaluated by means of an allergenic molecules microarray [immuno solid-phase allergen chip (ISAC)]. Total RNA was extracted and hybridized to Affymetrix oligonucleotide arrays to obtain quantitative gene-expression levels. No FOXP3 protein was detectable within CD127(-) CD25(high) CD4(+) T cells from peripheral blood. A T cell-naive phenotype (CD62L(+) CD45R0(-)) associated with a reduction of both CD26 and CD7 expression and a TCR-Vβ 8 and 22 family expansions were found. B lymphocytes were mainly CD5(+) (B1) cells expressing a naive phenotype (tcl1(+) CD27(-)). The three IPEX patients had severe food allergy and specific IgE reactivity to cow's milk allergens, a hen's egg allergen and a wheat allergen. Gene expression profile analysis revealed a dysregulation associated mainly with Th1/Th2 pathways. The multiplexing evaluation reported in this study represents a comprehensive approach in the assessment of genetic conditions affecting the immune system such as the IPEX syndrome, paving the way for the development of diagnostic tools to improve the standard clinical and immunological profiling of the disease.

Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability

Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability

A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

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. 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.

Identification of FOXP3-negative regulatory T-like (CD4+CD25+CD127low) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disorder caused by mutations in the FOXP3 gene, which plays a key role in the generation of CD4(+)CD25(+)regulatory T (Treg) cells. We selected CD127 as the surface marker of Treg cells to illustrate the development and function of Treg cells in IPEX syndrome. CD4(+)CD25(+)FOXP3(+) T cells, the putative Treg cells, were almost completely absent in all patients. Importantly, a substantial number of CD4(+)CD25(+)CD127(low) T cells were observed in 3 IPEX patients with hypomorphic mutations in the FOXP3 gene. We demonstrated that CD4(+)CD25(+)CD127(low) T cells isolated from these 3 patients exhibited an appreciable suppressive activity on effector T cell proliferation, although less than that displayed by Treg cells from healthy controls. These results suggest that genetically altered FOXP3 can drive the generation of functionally immature Treg cells, but that intact FOXP3 is necessary for the complete function of Treg cells.