Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 139; no. 3; p. 770
• Main Authors: Moes, Nicolette, Rieux-Laucat, Frédéric, Begue, Bernadette, Verdier, Julien, Neven, Bénédicte, Patey, Natacha, Torgerson, Troy T, Picard, Capucine, Stolzenberg, Marie-Claude, Ruemmele, Corinne, Rings, Edmond Hhm, Casanova, Jean-Laurent, Piloquet, Hugues, Biver, Armand, Breton, Anne, Ochs, Hans D, Hermine, Olivier, Fischer, Alain, Goulet, Olivier, Cerf-Bensussan, Nadine, Ruemmele, Frank M
• Format: Journal Article
• Language: English
• Published: United States 01.09.2010
• Subjects: Age of Onset; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - mortality; Autoimmune Diseases - therapy; Case-Control Studies; CD4 Lymphocyte Count; Cells, Cultured; Child; Child, Preschool; Coculture Techniques; Down-Regulation; Female; Flow Cytometry; Forkhead Transcription Factors - blood; Forkhead Transcription Factors - genetics; Humans; Immunosuppressive Agents - therapeutic use; Infant; Infant, Newborn; Interleukin-2 Receptor alpha Subunit - blood; Interleukin-2 Receptor alpha Subunit - genetics; Intestinal Diseases - genetics; Intestinal Diseases - immunology; Intestinal Diseases - mortality; Intestinal Diseases - therapy; Male; Microscopy, Confocal; Mutation; Open Reading Frames; Parenteral Nutrition, Total; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - blood; Severity of Illness Index; T-Lymphocytes, Regulatory - immunology; Treatment Outcome
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2010.06.006

Little is known about the pathophysiology of early onset forms of autoimmune enteropathy (AIE). AIE has been associated with mutations in FOXP3-a transcription factor that controls regulatory T-cell development and function. We analyzed the molecular basis of neonatal or early postnatal AIE using clinical, genetic, and functional immunological studies. Gastroenterological and immunological features were analyzed in 9 boys and 2 girls with AIE that began within the first 5 months of life. FOXP3 and IL2RA were genotyped in peripheral blood monocytes. FOXP3 messenger RNA and protein expression were analyzed using reverse-transcription polymerase chain reaction, flow cytometry, and confocal immunofluorescence of CD4(+) T cells. Regulatory T-cell function (CD4(+)CD25(+)) was assayed in coculture systems. AIE associated with extraintestinal autoimmunity was severe and life-threatening; all patients required total parenteral nutrition. Regulatory T cells from 7 patients had altered function and FOXP3 mutations that resulted in lost or reduced FOXP3 protein expression; 2 infants had reduced regulatory T-cell activity and reduced levels of FOXP3 protein, although we did not detect mutations in FOXP3 coding region, poly-A site, or promoter region (called FOXP3-dependent AIE). Two patients had a normal number of regulatory T cells that expressed normal levels of FOXP3 protein and normal regulatory activity in in vitro coculture assays (called FOXP3-independent AIE). No mutations in IL2RA were found. Most cases of AIE are associated with alterations in regulatory T-cell function; some, but not all, cases have mutations that affect FOXP3 expression levels. Further studies are needed to identify mechanisms of AIE pathogenesis.