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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]

Background: Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects.Objective: The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period.Methods: C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro.Results: Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4+ T cells.Conclusions: Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases. [ABSTRACT FROM AUTHOR]

The Crafoord Prize in Polyarthritis ranks as one of the most prestigious prizes and can be awarded only if the Royal Swedish Academy of Sciences decides the likelihood of prize worthy progress in the field, and at most every 4th year. This has happened only four times since 1982. This year the 5th Laureates were Shimon Sakaguchi, Fred Ramsdell, and Alexander Rudensky with the motivation “for their discoveries relating to regulatory T cells, which counteract harmful immune reactions in arthritis and other autoimmune diseases”. Here I review the history of their contributions and its impact in rheumatology. [ABSTRACT FROM AUTHOR]

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in the FOXP3 gene. Patients usually present with a clinical triad of intractable diarrhea, diabetes, and eczema. In this patient, FOXP3 protein expression was normal, but FOXP3 Sanger sequencing confirmed the clinical suspicion of IPEX by detecting a previously unreported missense variant. Early recognition of IPEX is important, because hematopoietic stem cell transplantation can be curative. [ABSTRACT FROM AUTHOR]

We present the case of a 21-year-old male patient with a history of autoimmune nephritis, peripheral eosinophilia, eosinophilic esophagitis, and enteropathy who developed subacute worsening cardiomyopathy with systolic dysfunction. Diagnostic studies revealed a one-codon deletion in the FoxP3 gene, which led to the diagnosis of immune dysregulation polyendocrinopathy, enteropathy X-linked syndrome. Unfortunately, this patient suffered from cardiopulmonary arrest with resulting anoxic encephalopathy before diagnosis confirmation. Here, we discuss the key issues surrounding the diagnostic and therapeutic approaches to this patient's condition. [ABSTRACT FROM AUTHOR]

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a primary immunodeficiency with autoimmunity caused by mutations in forkhead box P3 (FOXP3), which encodes a transcription factor involved in regulatory T (Treg) cell function. The mechanistic basis for how different mutations in FOXP3 cause distinct manifestations of IPEX remains unclear. Objective: To determine whether 3 different point mutants of FOXP3 that cause severe or mild IPEX differ in their ability to reprogram conventional T cells into Treg cells. Methods: Human CD4+ T cells were transduced with wild-type or point mutant forms of FOXP3, and changes in cell surface marker expression, cytokine production, proliferation and suppressive capacity were assessed. Ex vivo TH17 cells were also transduced with different forms of FOXP3 to monitor changes in IL-17 production. Results: The forkhead mutant F373A failed to upregulate CD25 and CCR4, did not suppress cytokine production, and induced suppressive activity less effectively than wild-type FOXP3. In contrast, although the forkhead mutant R347H was also defective in upregulation of CD25, it suppressed the production of cytokines, conferred suppressive capacity on CD4+ T cells, and suppressed IL-17 production. F324L, a mutant outside the forkhead domain associated with mild IPEX, was equivalent to wild-type FOXP3 in all aspects tested. Conclusion: Mutations in FOXP3 that cause IPEX do not uniformly abrogate the ability of FOXP3 to regulate transcription and drive the development of Treg cells. These data support the notion that factors in addition to functional changes in Treg cells, such as alterations in conventional T cells, are involved in the pathogenesis of IPEX. [ABSTRACT FROM AUTHOR]

IgE antibodies play a central role in the pathogenesis of atopic diseases and in host immunity against parasitic infections. IgE has potent activities on mast cells and basophils. IgE class switching is a very tightly controlled process, and serum IgE levels are very low compared with other immunoglobulin isotypes. Transcription factors that activate or inhibit the IgE gene promoter, as well as TH1 and TH2 cytokines are important in the regulation of IgE levels. Hyper-IgE syndrome; Wiskott-Aldrich syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX); Omenn syndrome; and atypical complete DiGeorge syndrome are primary immune deficiencies that are associated with elevated serum IgE levels. Increased IgE levels in IPEX, Wiskott-Aldrich syndrome and Omenn syndrome are likely related to increased TH2 cytokine production caused by decreased a number or function of CD4+CD25+forkhead box protein P3+ regulatory T cells. The link between signal transducer and activator of transcription 3 mutations and elevated serum IgE levels in hyper-IgE syndrome is unclear. Insight into IgE regulation provided by the study of primary immune deficiencies with elevated IgE has important implications for allergic diseases. [Copyright &y& Elsevier]

The article provides clues for considering monogenic diabetes mellitus (DM) and genetic testing whenever facing a child with DM. DM is a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genes play an important role in the development of DM. Type 1 DM accounts for more than 95% of childhood and adolescence diabetes in most Western countries. Type 2 DM is considered a polygenic disorder with multiple genes located on different chromosomes. Meanwhile, monogenic DM results from the presence of one or more mutations in a single gene. Almost all cases of monogenic DM result from mutations in genes causing Β-cell loss or Β-cell dysfunction.

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) results in systemic autoimmunity from birth and can be caused by mutations in the transcription factor forkhead box P3 (FOXP3). Objective: To determine if Foxp3 is required for the generation of IL-10–expressing T regulatory cells. Methods: CD4 lymphocytes were isolated from patients with IPEX-like syndromes and activated with antibodies to CD3 and CD46 to generate IL-10–expressing T regulatory cells. Results: We describe a patient with clinical manifestations of IPEX that had a normal Foxp3 gene, but who had CD25 deficiency due to autosomal recessive mutations in this gene. This patient exhibited defective IL-10 expression from CD4 lymphocytes, whereas a Foxp3-deficient patient expressed normal levels of IL-10. Conclusion: These data show that CD25 deficiency results in an IPEX-like syndrome and suggests that although Foxp3 is not required for normal IL-10 expression by human CD4 lymphocytes, CD25 expression is important. Clinical implications: Any patient with features of IPEX but with a normal Foxp3 gene should be screened for mutations in the IL-2 receptor subunit CD25. [Copyright &y& Elsevier]

Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. Phenotype and function of FOXP3 -mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18 , glucocorticoid-induced TNF-receptor–related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor–related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment. [ABSTRACT FROM AUTHOR]

Background Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant ( P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen. [ABSTRACT FROM AUTHOR]