title: Eosinophilic bowel disease controlled by the BB rat-derived lymphopenia/Gimap5 gene.
abstract: OBJECTIVE
  Many models of autoimmunity are associated with lymphopenia. Most involve a T-helper cell (Th)1-type disease, including the diabetic BioBreeding (BB) rat. To investigate the roles of identified susceptibility loci in disease pathogenesis, we bred PVG-RT1(u), lymphopenia (lyp)/lyp rats, congenic for the iddm1 (RT1(u)) and iddm2 (lyp, Gimap5(-/-)) diabetes susceptibility loci on the PVG background. Surprisingly, these rats developed a spontaneous, progressive, inflammatory bowel disease. To understand the disease pathogenesis, we undertook investigations at the genetic, histologic, and cellular levels.
  
  
  METHODS
  Genetically lymphopenic rats and congenic wild-type partners were compared for gross pathologic, histologic, and immunologic parameters, the latter including cytokines and autoantibodies.
  
  
  RESULTS
  Genetic analysis demonstrated that homozygosity at the lyp locus was required for disease. All rats developed disease, and the median age at humane killing was approximately 36 weeks. This panintestinal disease showed a conspicuous eosinophilic infiltrate in the submucosa and muscle layers, but the villi were unaffected. Diseased rats showed splenomegaly and massive enlargement of the mesenteric lymph nodes. This pathology resembles human eosinophilic gastroenteritis, and several further features indicate a Th2 basis. The rats developed high serum IgE and made IgG autoantibodies that detected a nonleukocytic cell present in the intestinal wall of all rats (including germ free).
  
  
  CONCLUSIONS
  The T-lymphopenic state associated with GIMAP5 deficiency renders rats generally susceptible to T-cell-mediated autoimmunity, but the immunoregulatory bias (Th1/Th2) of any disease depends on other genetic (or environmental) factors. In the present model, we suggest that defective peripheral tolerance to an intestine-specific autoantigen leads to uncontrolled inflammation of the intestinal wall.
authors.affiliation: The Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Cousins
authors.forename: Margaret
authors.initials: M
authors.lastname: Graham
authors.forename: Reuben
authors.initials: R
authors.lastname: Tooze
authors.forename: Christine
authors.initials: C
authors.lastname: Carter
authors.forename: J Ross
authors.initials: JR
authors.lastname: Miller
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Powrie
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Macpherson
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Butcher
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004751:Enteritis / Q000235:genetics* / Q000276:immunology; D004802:Eosinophilia / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006649:Histocompatibility Antigens / Q000235:genetics; D007073:Immunoglobulin E / Q000097:blood; D007422:Intestines / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics*; D051381:Rats; D011913:Rats, Inbred BB; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D006649:Histocompatibility Antigens; C038353:histocompatibility antigens RT, rat; D007073:Immunoglobulin E