Simultaneous deficiency in CD28 and STAT6 results in chronic ectoparasite-induced inflammatory skin disease.
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.
Liu
Qian
Q
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
Arseculeratne
Cristin
C
Liu
Zhugong
Z
Whitmire
Jeannette
J
Grusby
Michael J
MJ
Finkelman
Fred D
FD
Darling
Thomas N
TN
Cheever
Allen W
AW
Swearengen
James
J
Urban
Joseph F
JF
Gause
William C
WC
D000052:Acanthosis Nigricans / Q000188:drug therapy; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D004478:Ectoparasitic Infestations / Q000276:immunology* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D007306:Insecticides / Q000494:pharmacology; D051379:Mice; D008924:Mite Infestations / Q000188:drug therapy; D008925:Mites / Q000187:drug effects; D009559:Nippostrongylus / Q000276:immunology; D050800:STAT6 Transcription Factor; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology / Q000469:parasitology*; D017206:Strongylida Infections / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D018106:CD28 Antigens; D007306:Insecticides; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators