ELEONORA GAMBINERI, MD UNIVERSITY of FLORENCE DEPARTMENT of PEDIATRICS “A. MEYER” CHILDREN’S HOSPITAL FLORENCE, ITALY. ESID Prague Spring Meeting May 14 and 15, 2007 Prague. A FAMILY AFFECTED BY ATYPICAL IPEX SYNDROME .
UNIVERSITY of FLORENCE
DEPARTMENT of PEDIATRICS
“A. MEYER” CHILDREN’S HOSPITAL
ESID Prague Spring Meeting
May 14 and 15, 2007
A FAMILY AFFECTED BY
ATYPICAL IPEX SYNDROME
A rare genetic disorder of immune regulation characterized by overwhelming systemic autoimmunity
It is caused by mutations in the FOXP3 gene , located on X-chromosome, key molecular factor driving T cell tolerance and crucially important for CD4+CD25+ regulatory T cell development and function
FOXP3What does FOXP3 do?
IPEXCD4+CD25+ Regulatory T Cells
Make up 5-10% of the normal CD4+ T cell population.
Characterized by expression of CD4 and CD25bright at baseline and of intracytoplasmatic expression of FOXP3. They are positive for Cytotoxic T Lymphocyte associated Antigen-4 (CTLA-4) e Glucocorticoid-Induced Tumor-necrosis factor receptor-Related protein (GITR); recently, it has been reported that they have low expression of CD127.
Require activation and cell contact to repress proliferation of other T cells but do not appear to proliferate themselves after activation.
CLINICAL & LABORATORY FEATURES
BASIC Clinical & Laboratory Features:
Other Clinical & Laboratory Features:
Bacchetta et al 2006
ATG>ATA Bacchetta et al 2006
ATG>AGG Myers AK et al 2006
Owen CJ et al 2003
Torgerson TR et al 2007
Chatila TA et al 2000
T108M & 454+4A>G
De Benedetti F et al 2006
Locations of FOXP3 mutations reported
From Ochs HD et al.Immunol Rev. 2005 Feb;203:156-64. Review.
Male born to healthy unrelated parents after 37 wks of pregnancy, complicated with diabetes and IUGR.
At birth, weight was 2580g. The neonatal period was unremarkable.
At age of 1 month he was admitted to our hospital for vomiting and severe bloody diarrhea
Lab evaluation resulted negative for common GI infections, total protein were low (3.6 g/dl) and anemia was present (Hb 10g/dl)
Severe and intractable diarrhea persisted and because of his progressive clinical deterioration total parenteral nutrition as well as treatments of support were started.
Intestinal biopsies showed histological findings compatible with autoimmune enteropathy
Clinical improvement was slowly obtained when immunosuppressive therapy was started (high-dose intravenous corticosteroids combined to oral cyclosporin)
Although absence of any endocrine dysfunction and skin lesions, due to life threatening enteropathy, a diagnostic procedure for IPEX syndrome was considered.
Unfortunately the patient died prematurely at age of 5 month while he was on immunosuppression
Bennet C.et al. Curr Opin Pediatr, 2001
Gambineri E.et al.Curr Opin Rheumatol, 2003
FOXP3 PROTEIN EXPRESSION by Flow Cytometry
Chronic diarrhea since infancy
No symptoms reported
FOXP3 PROTEIN EXPRESSION
by Flow Cytometry
Disruption of exonic splicing enhancer (ESE) motifs and modification of SR protein binding sites
in mutated of FOXP3
F3R2 and F4R1
FOXP3 cDNA fragments @ PCR amplification
IS IPEX UNDERESTIMATED OR MISDIAGNOSED?
IS REALLY FOXP3 RESPONSIBLE FOR THE DISEASE?
WHAT IS MODULATING THE PHENOTYPE VARIABILITY?
University of Florence, Department of Pediatrics
“A. MEYER” Children’s Hospital - Florence, Italy
Immunology Lab: Gastroenterology Unit:
Lucia Bianchi, PhD Paolo Lionetti,MD
Sara Ciullini Mannurita, BS Francesca Bronzini,MD
Anna Maria Grazia Gelli, PhD
Chiara Azzari, MD, PhD
Perroni Lucia - Genoa
Tommasini Alberto - Trieste
Badolato Raffaele - Brescia
Bacchetta Rosa, Roncarolo Maria Grazia - Milan