Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 2005 Nov;116(5):1106-15
Date
11/09/2005Pubmed ID
16275384DOI
10.1016/j.jaci.2005.08.046Scopus ID
2-s2.0-27644519459 (requires institutional sign-in at Scopus site) 208 CitationsAbstract
BACKGROUND: Regulatory T cells have been proposed to play an important role in regulating allergic inflammation. The transcription factor Foxp3 is a master switch gene that controls the development and function of natural and adaptive CD4(+)CD25(+) regulatory T (T(R)) cells. In human subjects loss-of-function Foxp3 mutations trigger lymphoproliferation, autoimmunity, and intense allergic inflammation in a disease termed immune dysregulation polyendocrinopathy enteropathy-X-linked syndrome.
OBJECTIVE: We sought to examine the evolution and attributes of allergic inflammation in mice with a targeted loss-of-function mutation in the murine Foxp3 gene that recapitulates a known disease-causing human Foxp3 mutation.
METHODS: Foxp3 mutant mice were generated by means of knock-in mutagenesis and were analyzed for histologic, immunologic, and hematologic abnormalities. The role of signal transducer and activator of transcription 6 (Stat6) in disease pathogenesis was analyzed by using Stat6 and Foxp3 double-mutant mice.
RESULTS: Foxp3 mutant mice developed an intense multiorgan inflammatory response associated with allergic airway inflammation, a striking hyperimmunoglobulinemia E, eosinophilia, and dysregulated T(H)1 and T(H)2 cytokine production in the absence of overt T(H)2 skewing. Concurrent Stat6 deficiency reversed the hyperimmunoglobulinemia E and eosinophilia and delayed mortality, which is consistent with a pathogenic role for allergic inflammation in Foxp3 deficiency.
CONCLUSION: Allergic dysregulation is a common and fundamental consequence of loss of CD4(+)CD25(+) T(R) cells caused by Foxp3 deficiency in different species. Abnormalities affecting T(R) cells might contribute to a variety of allergic diseases.
Author List
Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J, MartÃn MG, Chatila TAAuthor
Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCytokines
Disease Models, Animal
Eosinophilia
Forkhead Transcription Factors
Hypergammaglobulinemia
Hypersensitivity
Immunoglobulin E
Inflammation
Mice
Mice, Knockout
Respiratory System
STAT6 Transcription Factor
Th1 Cells
Th2 Cells
