Most recent publications


M. Goodwin1*, E. Lee1,2*, U. Lakshmanan1, S. Shipp1, L. Froessl1, F. Barzaghi3,
L. Passerini3, M. Narula1, A. Sheikali1, C. M. Lee4, G. Bao5, C. S. Bauer6, H. K. Miller6, M. Garcia-Lloret7, M. J. Butte7, A. Bertaina1, A. Shah1, M. Pavel-Dinu1, A. Hendel1,8, M. Porteus1,2, M. G. Roncarolo1,2, R. Bacchetta

All publications


  • Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Science translational medicine Borna, Š., Lee, E., Nideffer, J., Ramachandran, A., Wang, B., Baker, J., Mavers, M., Lakshmanan, U., Narula, M., Garrett, A. K., Schulze, J., Olek, S., Marois, L., Gernez, Y., Bhatia, M., Chong, H. J., Walter, J., Kitcharoensakkul, M., Lang, A., Cooper, M. A., Bertaina, A., Roncarolo, M. G., Meffre, E., Bacchetta, R. 2023; 15 (727): eadg6822


    Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

    View details for DOI 10.1126/scitranslmed.adg6822

    View details for PubMedID 38117899

  • IPEX Syndrome from diagnosis to cure, learning along the way. The Journal of allergy and clinical immunology Bacchetta, R., Roncarolo, M. G. 2023


    In the past two decades, a significant number of studies have been published describing the molecular and clinical aspects of Immune dysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX). 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 immunological mechanisms. Despite these advances, Forkhead box P3 (FOXP3) mutations have devastating consequences, and treating patients with IPEX remains a challenge even with safer strategies for hematopoietic stem cell transplantation, and gene therapy becoming a promising reality. The aim of this review is to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX Syndrome.

    View details for DOI 10.1016/j.jaci.2023.11.021

    View details for PubMedID 38040040

  • FOXP3 deficiency, from the mechanisms of the disease to curative strategies. Immunological reviews Borna, S., Meffre, E., Bacchetta, R. 2023


    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.

    View details for DOI 10.1111/imr.13289

    View details for PubMedID 37994657

  • Epigenetic and Immunological Indicators of IPEX Disease in subjects with FOXP3 gene mutation. The Journal of allergy and clinical immunology Narula, M., Lakshmanan, U., Borna, S., Schulze, J. J., Holmes, T. H., Harre, N., Kirkey, M., Ramachandran, A., Tagi, V. M., Barzaghi, F., Grunebaum, E., Upton, J. E., Hong-Diep Kim, V., Wysocki, C., Dimitriades, V. R., Weinberg, K., Weinacht, K. G., Gernez, Y., Sathi, B. K., Schelotto, M., Johnson, M., Olek, S., Sachsenmaier, C., Roncarolo, M. G., Bacchetta, R. 2022


    Forkhead-Box-Protein-3 (FOXP3) is the master transcription factor in CD4+CD25hiCD127lo regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution and treatment choice.To study the type and extent of immunological abnormalities which remain ill-defined in IPEX, across genetic and clinical heterogeneity.We performed Treg-specific epigenetic quantification and immunological characterization of severe "typical" (n=6) and "atypical" or asymptomatic (n=9) IPEX patients.Increased number of cells with Treg-Specific Demethylated Region (TSDR) demethylation in FOXP3 is a consistent feature in IPEX patients, with i) highest values in those with typical IPEX, ii) increased values in subjects with pathogenic FOXP3 but still no symptoms, and iii) gradual increase over the course of disease progression. Large scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and Th2 polarization, with cytokines previously not associated with IPEX pathology, including CCL22, CCL17, CCL15, and IL-13, and the inflammatory markers TNFα, IL-1A, IL-8, sFasL, and CXCL9. Similarly, both Treg and Teff compartments, studied by CyTOF, were skewed towards the Th2 compartment, especially in typical IPEX.Elevated TSDR demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized Type 2 inflammatory immune response extends our understanding of IPEX diagnosis and heterogeneity.IPEX-specific epigenetic and immunologic changes provide invaluable tools that, complementing the genetic diagnosis, allow monitoring disease progression and enable early treatment interventions.

    View details for DOI 10.1016/j.jaci.2022.09.013

    View details for PubMedID 36152823

  • Towards gene therapy for IPEX syndrome. European journal of immunology Borna, S., Lee, E., Sato, Y., Bacchetta, R. 2022


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

    View details for DOI 10.1002/eji.202149210

    View details for PubMedID 35355253

  • Preclinical Safety and Efficacy Validation of CD4(LVFOXP3) Cells as an Innovative Cell-Based Gene Therapy Approach for IPEX Syndrome Sato, Y., Nathan, A., Wright, J., Tate, K., Wani, P., Fazeli, F., Timnak, A., Bhatia, N., Agarwal-Hashmi, R., Bertaina, A., Roncarolo, M., Bacchetta, R. CELL PRESS. 2021: 340
  • Thymic origins of autoimmunity-lessons from inborn errors of immunity. Seminars in immunopathology Bacchetta, R., Weinberg, K. 2021


    During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.

    View details for DOI 10.1007/s00281-020-00835-8

    View details for PubMedID 33532929

  • CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells SCIENCE ADVANCES Goodwin, M., Lee, E., Lakshmanan, U., Shipp, S., Froessl, L., Barzaghi, F., Passerini, L., Narula, M., Sheikali, A., Lee, C. M., Bao, G., Bauer, C. S., Miller, H. K., Garcia-Lloret, M., Butte, M. J., Bertaina, A., Shah, A., Pavel-Dinu, M., Hendel, A., Porteus, M., Roncarolo, M. G., Bacchetta, R. 2020; 6 (19)
  • Engineered Type-1 Regulatory T Cells as Cellular Therapy for Treatment of Immune Mediated Diseases Liu, J. M., Chen, P., Cieniewicz, B., Cepika, A., Bacchetta, R., Roncarolo, M. AMER ASSOC IMMUNOLOGISTS. 2020
  • Regulatory Type 1 T Cell Infusion in Mismatched Related or Unrelated Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Agarwal, R., Bacchetta, R., Bertaina, A., Chen, P., Saini, G., Shiraz, P., Bhatia, N., Roncarolo, M. ELSEVIER SCIENCE INC. 2020: S272–S273

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