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Infection and Immunity, July 2004, p. 3706-3715, Vol. 72, No. 7
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.7.3706-3715.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Simultaneous Deficiency in CD28 and STAT6 Results in Chronic Ectoparasite-Induced Inflammatory Skin Disease

Qian Liu,1 Cristin Arseculeratne,1 Zhugong Liu,1 Jeannette Whitmire,1 Michael J. Grusby,2 Fred D. Finkelman,3 Thomas N. Darling,4 Allen W. Cheever,5 James Swearengen,6 Joseph F. Urban,7 and William C. Gause1*

Department of Microbiology and Immunology,1 Department of Dermatology,4 Laboratory of Animal Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,6 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115,2 University of Cincinnati College of Medicine and Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio 45220,3 Biomedical Research Institute, Rockville, Maryland 20852,5 Immunology Disease Resistance Laboratory, Livestock and Poultry Sciences Institute, U.S. Department of Agriculture, Beltsville, Maryland 20705-23507

Received 30 January 2004/ Returned for modification 9 March 2004/ Accepted 12 March 2004

A mouse lacking CD28, a T-cell costimulatory molecule, and STAT6, a transcription factor that mediates interleukin-4 (IL-4) signaling, was developed from parental CD28- and STAT6-deficient mice. STAT6/CD28–/– BALB/c mice that were 8 weeks old had a normal phenotype, and IL-4 production was induced following infection with nematode parasites. Unexpectedly, when they were between 4 and 8 months old, all mice examined spontaneously developed severe chronic dermatitis associated with pronounced numbers of Demodex ectoparasites. In addition, pronounced CD4 and CD8 T-cell infiltrates in the dermis and subcutaneous fat, increased serum immunoglobulin G2a levels, and lymphadenopathy associated with increased gamma interferon and IL-12 expression were observed. Single-knockout siblings lacking either CD28 or STAT6 had a phenotype similar to that of BALB/c wild-type controls. To distinguish whether the ectoparasite Demodex or the Th1 immunity was the proximal cause of the inflammatory skin disease, STAT6/CD28–/– mice were treated with a miticide that eliminated the ectoparasites. This treatment markedly reduced the severity of the dermatitis and the associated lymphoid infiltrates. These findings suggest that ubiquitous ectoparasites, which are generally considered to be commensal, may contribute to disease when specific molecules required for an effective Th2 response are blocked.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-1958. Fax: (301) 295-1545. E-mail: Wgause{at}usuhs.mil.

Editor: W. A. Petri, Jr.

Infection and Immunity, July 2004, p. 3706-3715, Vol. 72, No. 7
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.7.3706-3715.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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