title: Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein.
abstract: OBJECTIVE
  Controversy exists as to whether patients with inflammatory bowel disease have an underlying immunodeficiency. We have focused on a murine model of the Wiskott-Aldrich syndrome, an immunodeficiency in which autoimmunity can manifest in the form of an inflammatory bowel disease-like illness. Wiskott-Aldrich syndrome protein (WASP) deficiency in mice results in similar clinical features. Herein, we characterized the colitis in WASP-deficient mice.
  
  
  METHODS
  WASP-deficient mice were followed clinically and histologically. Immunologic studies were performed to determine the pathogenic cell population(s), the predominant cytokine expression pattern, and the role of cytokine(s) in colitis pathogenesis.
  
  
  RESULTS
  All WASP-deficient mice develop colitis by 6 months of age. Lymphocytes are required for disease induction, and CD4(+) T cells from WASP-deficient mice are sufficient to induce disease in lymphocyte-deficient hosts. Lamina propria preparations from WASP-deficient mice demonstrated elevations in interferon-gamma, interleukin (IL)-4, and IL-13 levels but decreased IL-6 and no difference in IL-17 expression in comparison with wild-type controls. Treatment with neutralizing antibody to IL-4, but not to interferon-gamma, abrogated colitis development. However, mice deficient in both WASP and IL-4 showed no difference in histologic colitis scores at 24 weeks of age compared with WASP-deficient mice.
  
  
  CONCLUSIONS
  These results demonstrate a critical role for lymphocytes and a relative T helper 2 cytokine predominance in the colitis associated with WASP-deficient mice. This is the only model of colitis with elevated T helper 2 cytokines and aberrant natural regulatory T cell function and is unique in having a human disease counterpart with similar defects.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Deanna D
authors.initials: DD
authors.lastname: Nguyen
authors.forename: Michel H
authors.initials: MH
authors.lastname: Maillard
authors.forename: Vinicius
authors.initials: V
authors.lastname: Cotta-de-Almeida
authors.forename: Emiko
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Ivan
authors.initials: I
authors.lastname: Fuss
authors.forename: Cathryn
authors.initials: C
authors.lastname: Nagler
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizoguchi
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006965:Hyperplasia; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016207:Cytokines; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D020381:Interleukin-17; D015850:Interleukin-6; C499308:Rag2 protein, mouse; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D015847:Interleukin-4; D007371:Interferon-gamma