IPEX syndrome from diagnosis to cure, learning along the way

Abstract

In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality. The aim of this review was to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX syndrome. In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality. The aim of this review was to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX syndrome. In early 2003, 3 seminal studies demonstrated that (1) mutations in mouse Forkhead box protein 3 (FoxP3) caused CD4+ T-cell lymphoproliferation, scurfy hair, and wasting disease, leading to early death, and (2) Foxp3 is required for regulatory T (Treg)-cell development and its overexpression impaired normal CD4+ T-cell development and increased the frequency of CD4+ and CD8+ with suppressive function.1Hori S. Nomura T. Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3.Science. 2003; 299: 1057-1061Crossref PubMed Scopus (64) Google Scholar, 2Khattri R. Cox T. Yasayko S.A. Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells.Nat Immunol. 2003; 4: 337-342Crossref PubMed Scopus (2448) Google Scholar, 3Fontenot J.D. Gavin M.A. Rudensky A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.Nat Immunol. 2003; 4: 330-336Crossref PubMed Scopus (6340) Google Scholar These discoveries provided the primary mechanistic principle of the previously identified human disease, immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. IPEX syndrome is caused by pathogenic variants in FOXP3, designated as mutations throughout the text, and presents in affected infants with early-onset refractory diarrhea, diffuse eczema, and neonatal type 1 diabetes (T1D)4Chatila T.A. Blaeser F. Ho N. Lederman H.M. Voulgaropoulos C. Helms C. et al.JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.J Clin Invest. 2000; 106: R75-R81Crossref PubMed Google Scholar, 5Bennett C.L. Christie J. Ramsdell F. Brunkow M.E. Ferguson P.J. Whitesell L. et al.The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.Nat Genet. 2001; 27: 20-21Crossref PubMed Scopus (2781) Google Scholar, 6Wildin R.S. Ramsdell F. Peake J. Faravelli F. Casanova J.L. Buist N. et al.X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.Nat Genet. 2001; 27: 18-20Crossref PubMed Scopus (1533) Google Scholar (Fig 1). IPEX syndrome was first described in 1982 in a single-family tree for a total of 19 male members7Powell B.R. Buist N.R. Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy.J Pediatr. 1982; 100: 731-737Abstract Full Text PDF PubMed Scopus (368) Google Scholar; by 2002, an additional 14 cases were reported.8Wildin R.S. Smyk-Pearson S. Filipovich A.H. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome.J Med Genet. 2002; 39: 537-545Crossref PubMed Google Scholar In the latter cohorts, multiorgan pathology beyond the gut, pancreas, and skin involvement became evident, including kidney, blood, and liver. Although a certain degree of clinical heterogeneity was already described in these initial reports, it is now well established that IPEX syndrome comprises a broad spectrum of clinical manifestations having an impact on different organs, with different degrees of severity and evolution.9Barzaghi F. Passerini L. Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity.Front Immunol. 2012; 3: 211Crossref PubMed Scopus (278) Google Scholar,10Bacchetta R. Barzaghi F. Roncarolo M.G. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation.Ann N Y Acad Sci. 2018; 1417: 5-22Crossref PubMed Scopus (256) Google Scholar Despite the pathophysiologic importance of Treg-cell dysfunction in determining the disease, newly described immunologic abnormalities and complex epigenetic, transcriptional, and posttranslational modifications are emerging, which likely contribute to disease heterogeneity and evolution.11Grover P. Goel P.N. Piccirillo C.A. Greene M.I. FOXP3 and Tip60 structural interactions relevant to IPEX development lead to potential therapeutics to increase FOXP3 dependent suppressor T cell functions.Front Pediatr. 2021; 9607292Crossref Scopus (7) Google Scholar,12Narula M. Lakshmanan U. Borna S. Schulze J.J. Holmes T.H. Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google Scholar to have to early diagnosis of IPEX syndrome and for to hematopoietic stem cell transplantation is a treatment for IPEX it a with disease F. S. J.J. et of IPEX syndrome patients different an Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar In this the of and understanding of IPEX a disease that its remains and a significant of of with of as well as as gene are to the disease and improve the the of IPEX of the of pathology beyond in the and type of and and type of on a on protein function to of a the in and the role of a FOXP3 in and studies to the immune dysregulation and its and and of Treg-cell and and with the type of that patients with FOXP3 of in of in of Treg-cell hematopoietic stem cell gene therapy in a of the of pathology beyond in the and type of and and type of on a on protein function to of a the in and the role of a FOXP3 in and studies to the immune dysregulation and its and and of Treg-cell and and with the type of that patients with FOXP3 of in of in of Treg-cell hematopoietic stem cell gene therapy in a of its X-linked IPEX syndrome presents in the FOXP3 with different disease features and severity and 2 and 3 studies were published F. S. J.J. et of IPEX syndrome patients different an Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. S. S. et and molecular heterogeneity of patients with the of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Immunol. 2018; PubMed Scopus Google Scholar, R. F. J. S. C. et heterogeneity of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a 2018; PubMed Scopus Google Scholar, et dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: a Scopus Google Scholar, M. M. F. M. et and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and syndrome.J Allergy Clin Full Text Full Text PDF PubMed Scopus Google Scholar These studies provided a of the clinical aspects of the disease, including and of treatment of genetic and clinical features of IPEX syndrome features of patients with IPEX et F. S. J.J. et of IPEX syndrome patients different an Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google et S. M. S. S. et and molecular heterogeneity of patients with the of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Immunol. 2018; PubMed Scopus Google et R. F. J. S. C. et heterogeneity of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a 2018; PubMed Scopus Google et et dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: a Scopus Google et M. M. F. M. et and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and syndrome.J Allergy Clin Full Text Full Text PDF PubMed Scopus Google of were published in the 3 studies published in were published in the 3 studies published in of patients with FOXP3 of and disease and in in in of in in in The were published in the 3 studies published in in a studies that the clinical manifestations of IPEX syndrome are by enteropathy by diarrhea, the and and and The in with the of patients with IPEX syndrome with with as early as the first of and of patients with FOXP3 mutations and that with by enteropathy this the first of S. J. et and diagnosis of IPEX syndrome.J Clin Immunol. 2023; PubMed Scopus Google Scholar The endocrinopathy is In the of have been in pathology the of IPEX syndrome with and and increased skin and autoimmune were with frequency in the different In pathology been as an clinical in and P. R. N. polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: an of in PubMed Scopus Google Scholar, T.A. S. et involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) PubMed Google Scholar, T. F. M. in a with IPEX PubMed Scopus Google Scholar, L. An et novel FOXP3 in a with Scopus (2) Google Scholar, M. M. P. S. M. F. et manifestations with FOXP3 The of IPEX features and clinical Immunol. Scopus Google Scholar, P. L. J. M. N. features of in a PubMed Scopus Google Scholar involvement was in patients with IPEX syndrome with disease been with for the of as to it is now that the the of the autoimmune in IPEX syndrome. pathology in IPEX syndrome is by by and F. S. J.J. et of IPEX syndrome patients different an Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google S. M. S. S. et and molecular heterogeneity of patients with the of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Immunol. 2018; PubMed Scopus Google P. L. J. M. N. features of in a PubMed Scopus Google Scholar an autoimmune including the described were F. L. J. J. J. in the novel Immunol. Scholar Although are as our and in the of patients with Passerini L. Barzaghi F. C. C. et to and are in with IPEX PubMed Scopus Google Scholar In was with and review on neonatal IPEX syndrome manifestations in of of IPEX syndrome with neonatal diabetes and as the initial and a review of neonatal Clin Immunol. 2023; PubMed Scopus (1) Google Scholar In our of patients with 2 patients as first of IPEX syndrome in M. Lakshmanan U. Borna S. Schulze J.J. Holmes T.H. Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google of IPEX syndrome with neonatal diabetes and as the initial and a review of neonatal Clin Immunol. 2023; PubMed Scopus (1) Google of of disease in patients with IPEX disease disease et P. R. 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Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google Scholar Borna et J. J. et of regulatory and T that are in patients with FOXP3 2023; PubMed Scopus (2) Google in a primary type autoimmune autoimmune early immune protein (1) with of disease (2) with disease, and The latter were in the 2 described in with manifestations including and and and F. S. J.J. et of IPEX syndrome patients different an Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google S. M. S. S. et and molecular heterogeneity of patients with the of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) Immunol. 2018; PubMed Scopus Google Scholar in IPEX likely to the of and the of and to the of type 1 and and are in the patients with IPEX with patients with genetic autoimmune as autoimmune polyendocrinopathy M.E. Barzaghi F. 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F. et and molecular of a of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: box protein 3 and disease Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar The cell and immune cell are normal with the of a increase in CD4+ T with a even in and increased and as in with immune Although in normal to by in F. Passerini L. S. T. et of the FOXP3 of regulatory T in syndrome.J 2012; PubMed Scopus Google R. Passerini L. M. L. et regulatory and T cell in patients with FOXP3 Clin Invest. PubMed Scopus Google Scholar, M. C. et and regulatory T in the IPEX PubMed Google Scholar, L. Barzaghi F. R. C. F. et with regulatory T-cell function in IPEX Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar impaired suppressive been by it been for different FOXP3 been the in patients with IPEX F. Passerini L. S. T. et of the FOXP3 of regulatory T in syndrome.J 2012; PubMed Scopus Google R. Passerini L. M. L. et regulatory and T cell in patients with FOXP3 Clin Invest. PubMed Scopus Google Scholar, M. C. et and regulatory T in the IPEX PubMed Google Scholar, L. Barzaghi F. R. C. F. et with regulatory T-cell function in IPEX Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar The (1) Treg-cell cell and increase different (2) of are and are are in patients with IPEX the and are affected by patients on suppressive L. Barzaghi F. R. C. F. et with regulatory T-cell function in IPEX Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar patients on have of even normal in function to M. Lakshmanan U. S. L. Barzaghi F. et gene FOXP3 gene in IPEX PubMed Scopus Google Scholar the function for a FOXP3 M. Lakshmanan U. Borna S. Schulze J.J. Holmes T.H. Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google Scholar previously that patients with IPEX syndrome have a frequency of T in the that are the FOXP3 as with patients M. Lakshmanan U. Borna S. Schulze J.J. Holmes T.H. Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google J. J. et of regulatory and T that are in patients with FOXP3 2023; PubMed Scopus (2) Google F. Passerini L. S. T. et of the FOXP3 of regulatory T in syndrome.J 2012; PubMed Scopus Google Scholar The is a in of the FOXP3 its is a of established U. S. J. et in the human FOXP3 regulatory T T Immunol. PubMed Scopus Google Scholar, U. J. Schulze J.J. et al.Epigenetic immune cell in human for 2018; Scopus Google Scholar, S. N. T. et of the in regulatory T Immunol. PubMed Scopus Google Scholar of its the that FOXP3 on and a are the in to including U. S. J. et in the human FOXP3 regulatory T T Immunol. PubMed Scopus Google Scholar of of and of FOXP3 of been demonstrated in and F. Passerini L. Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity.Front Immunol. 2012; 3: 211Crossref PubMed Scopus (278) Google U. S. J. et in the human FOXP3 regulatory T T Immunol. PubMed Scopus Google J. S. U. et Foxp3 gene Immunol. PubMed Scopus Google Scholar, S. T. et of the Foxp3 to the of regulatory T the Immunol. PubMed Scopus Google Scholar, R. C. gene a of regulatory T cell by the Immunol. 2018; PubMed Scopus Google Scholar Treg-cell by of the cell of the a of in different including primary immune U. J. Schulze J.J. et al.Epigenetic immune cell in human for 2018; Scopus Google Scholar have in patients with IPEX syndrome and have that the frequency of the the CD4+ T is in patients with and IPEX syndrome and this frequency with disease of M. Lakshmanan U. Borna S. Schulze J.J. Holmes T.H. Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google J. J. et of regulatory and T that are in patients with FOXP3 2023; PubMed Scopus (2) Google Scholar patients with a FOXP3 in is normal of with the early of the a frequency of T is in affected have a to IPEX syndrome. the of in patients with for this J. J. et of regulatory and T that are in patients with FOXP3 2023; PubMed Scopus (2) Google Scholar that of the is a to gene on the dysregulation caused by FOXP3 In a have that the and the is to the of T that have the of have the of and are identified by immune These J. J. et of regulatory and T that are in patients with FOXP3 2023; PubMed Scopus (2) Google Scholar The of that the disease is to patients with FOXP3 of as was for patients with early-onset S. J. et and diagnosis of IPEX syndrome.J Clin Immunol. 2023; PubMed Scopus Google Scholar In this our in patients with IPEX with FOXP3 variants of with and The that FOXP3 was with increased with with of diabetes of increased in the of FOXP3 the early diagnosis of IPEX syndrome and with the and of novel variants of In patients with IPEX the of in the and an increased of and in patients M. Lakshmanan U. Borna S. Schulze J.J. Holmes T.H. Harre N. et al.Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.J Allergy Clin Immunol. 2023; 151: Full Text Full Text PDF PubMed Scopus (7) Google L. S. S. Barzaghi F. S. M. et box protein 3 mutations lead to increased cell and regulatory T-cell Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google F. S. et in the transcription factor Foxp3 T 2 function in regulatory T Full Text Full Text PDF PubMed Scopus Google Scholar have been that FOXP3 in IPEX syndrome the of and a broad of newly identified for the and as F. S. J.J. et of IPEX syndrome patients different an Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google Passerini L. Barzaghi F. C. C. et to and are in with IPEX PubMed Scopus Google

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