What is IPEX?
Overview
IPEX is a rare X-chromosome disorder in which affected boys develop severe autoimmunity that can target any organ. The gut, skin, and endocrine organs—particularly the pancreas and thyroid gland—are the most common targets.
Autoimmunity begins early in life and can be very severe. It tends to worsen and spread as individuals age, leading to a poor quality of life and early death in virtually all cases.
Treatment for IPEX is a combination of supportive care and immune suppression. Hematopoietic stem cell transplantation (HSCT), also referred to as bone marrow transplantation, is the only treatment where improvement is seen for this condition and should be considered early in most cases (Source)
Genetics
The immune system uses a variety of mechanisms to restrain autoimmune reactions. This includes a group known as regulatory T cells, or Treg cells.
These Tregs play a powerful role in controlling or restraining the actions of other immune cells. In fact, they are like a small police force that has the job of monitoring other immune cells to make sure that they don’t respond too strongly, or inappropriately target other cells in the person's body.
One of the key proteins required for Tregs to develop and function normally is called FOXP3. In people with IPEX, the X-chromosome gene responsible for creating FOXP3 is faulty, resulting in an uncontrolled Treg and autoimmune response.
The FOXP3 gene lives on the X chromosome, and is recessive. This means that a mother with a faulty X chromosome has a 50% chance of passing it to their child. Sons with that X chromosome are likely to have IPEX, while daughters will be asymptomatic and carry a similar 50% risk of passing the faulty gene down.
History
1982: First clinical description of "X-linked enteropathy" (Powell, J. Ped. 1982)
2001: Discovery of the FOXP3 natural mouse mutant, scurfy mouse (Brunkow, Nat. Gen 2001)
2001: FOXP3 mutation is reported to be the cause of IPEX (Baud, NEJMed 2001; Chatila, JCI 2000; Wildin, Nat Gen 2001; Bennett, Nat Gen 2001)
2003: Discovery of the immunological cause: impaired Treg cells (Fontenot, Nat Immunol 2003; Hori, Science 2003; Khattri, Nat Immun 2003)
2005: Human FOXP3 is expressed in 2 different isoforms in Treg and activated Teff (Allan S, JClin Inv 2005)
2006: Impaired Treg and Teff function in human FOXP3 mutated T cells (Bacchetta, JClin Inv 2006; d'Hennezel, NEJM 2009; Moes, Gastroenterology 2010)
2008: FOXP3 protein expression inconsistently correlate with disease severity (Gambineri, JACI 2008)
2009: Selective engraftment of wild-type CD4+CD25highFOXP3+T cells after alloHSCT (Seidel MG, Blood 2009) and in carrier mothers (Di Nunzio, Blood 2009)
2013: FOXP3 gene transfer converts IPEX Teff into functional Treg (Passerini, STMed 2013)
2015: FOXP3 mutations in Fetal Hydrops (Xavier-de-Silva, Clin Immunol 2015)
2018: Long-term follow up of IPEX syndrome patients after different therapeutic strategies: an international retrospective multicenter study (Barzaghi, JACI 2018)
2018: Clinical immunological and molecular heterogeneity. A broader disease spectrum (Gambineri E., Front Immunol 2018, Consonni F, Front Immunol 2021)
2019: LV-mediated wild-type FOXP3 expressing T cells rescue IPEX-mice model (Masiuk KE, Cell Stem Cell 2019, Sato Y., Clin Exp Immun 2020, Deville M., Blood 2021)
2020: Feasibility of CRISPR-based gene editing for FOXP3 repair (Goodwin, Sci Adv 2020)
2022: Rapamycin can restore Treg function in a FOXP3-independent manner (Passerini, JACI 2022)
2022: TSDR demethylation as Epigenetic immune indicator of disease activity (Narula, JACI 2023, Borna, STMed 2023)
2022-Ongoing: Autologous-engineered Treg-like cells gene therapy trial (NCT05241444)