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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Université Paris Descartes, Paris, France.
Nicolette
N
Moes
Frédéric
F
Rieux-Laucat
Bernadette
B
Begue
Julien
J
Verdier
Bénédicte
B
Neven
Natacha
N
Patey
Troy T
TT
Torgerson
Capucine
C
Picard
Marie-Claude
MC
Stolzenberg
Corinne
C
Ruemmele
Edmond Hhm
EH
Rings
Jean-Laurent
JL
Casanova
Hugues
H
Piloquet
Armand
A
Biver
Anne
A
Breton
Hans D
HD
Ochs
Olivier
O
Hermine
Alain
A
Fischer
Olivier
O
Goulet
Nadine
N
Cerf-Bensussan
Frank M
FM
Ruemmele
D017668:Age of Onset; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000097:blood* / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000235:genetics; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D016366:Open Reading Frames; D010289:Parenteral Nutrition, Total; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016896:Treatment Outcome
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger