title: Quantitative analysis of tissue inflammation and responses to treatment in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and review of literature.
abstract: OBJECTIVE
  Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation.
  
  
  METHODS
  We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORγt, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment.
  
  
  RESULTS
  The percentages of cells expressing the TH2-associated transcription factor GATA3 were higher in the IPEX patient before treatment than in controls, suggesting that TH2-type cells contribute to the tissue inflammation of the gut and kidneys in IPEX syndrome. Immunosuppressive treatment effectively decreased the number of effector cells in the kidneys and intestine of the IPEX patient.
  
  
  CONCLUSIONS
  This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain TH2-type immune effector cells, which decreased in number after immunosuppressive treatment was initiated and the clinical symptoms had improved.
authors.affiliation: Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Chih-An
authors.initials: CA
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wan-Chen
authors.initials: WC
authors.lastname: Chung
authors.affiliation: Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Yuan-Yow
authors.initials: YY
authors.lastname: Chiou
authors.affiliation: Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Yao-Jong
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yung-Chieh
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Seattle Children's Research Institute and Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.affiliation: Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: cshieh@mail.ncku.edu.tw.
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Shieh
mesh_terms: D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000151:congenital* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003967:Diarrhea / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000473:pathology; D040181:Genetic Diseases, X-Linked / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007154:Immune System Diseases / Q000151:congenital* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D007668:Kidney / Q000473:pathology; D008297:Male; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D000069283:Rituximab / Q000627:therapeutic use; D020825:T-Box Domain Proteins / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016559:Tacrolimus / Q000627:therapeutic use; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D007166:Immunosuppressive Agents; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000069283:Rituximab; D016559:Tacrolimus
keywords: T helper 2 cells; X-Linked syndrome; enteropathy; immune dysregulation; polyendocrinopathy; regulatory T cells