Eosinophilic bowel disease controlled by the BB rat-derived lymphopenia/Gimap5 gene.
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.
Cousins
Lesley
L
The Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Graham
Margaret
M
Tooze
Reuben
R
Carter
Christine
C
Miller
J Ross
JR
Powrie
Fiona M
FM
Macpherson
Gordon G
GG
Butcher
Geoffrey W
GW
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*
D001323:Autoantibodies; D006649:Histocompatibility Antigens; C038353:histocompatibility antigens RT, rat; D007073:Immunoglobulin E