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

Abstract

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.

Requirements for the development of IL‐4‐producing T cells during intestinal nematode infections: what it takes to make a Th2 cell in vivo

“…In both cases, IL‐4 elevations were not reduced below levels detected in control N. brasiliensis ‐inoculated STAT6 –/– mice. We concluded at this point that the N. brasiliensis Th2 immune response was not further impaired by blockade of CD28 as well as STAT6 (54).…”

“…We hypothesized that a deficiency in both CD28 and STAT6 might inhibit the development of CD28‐independent in vivo Th2 responses. To test this possibility in vivo , we generated BALB/c mice that were simultaneously deficient for CD28 and STAT6 (54). We first examined the Th2 response to the intestinal nematode parasite N. brasiliensis .…”

“…Unexpectedly, by about 6 months of age, all the STAT6/CD28 –/– BALB/c mice spontaneously developed severe chronic dermatitis associated with alopecia, erythema, pruritus, blepharitis, and dense lymphoid infiltrates in the dermis and subcutaneous fat without eosinophils (54). Sibling single knockout STAT6 –/– or CD28 –/– BALB/c mice maintained normal haircoats and appearance, even when housed in the same cages with the affected STAT6/CD28 –/– mice.…”

The Role of HLA A2 and Cw2 in the Pathogenesis of Human Demodicosis

“…the cytotoxic effect of CD8+ T cells (big glandular lymphocytes), macrophage activation, which is regulated by T-helper-1-immune response or a T-helper-2-stimulated antibody synthesis [16]. In case of demodicosis, an incorrect response of the immune system could lead to severe immunopathological reactions instead of a reaction against the parasite, which we can observe in experimentally induced [25]or disease-related immunodeficiency [26, 28]. …”

Signal transducer and activator of transcription signals in allergic disease

“…44 The deficiency of STAT6 and CD28 results in chronic ectoparasite-induced inflammatory skin disease. 149 The importance of STAT1 in allergic inflammation was demonstrated by the inhibition of allergen-induced airway inflammation and airway hyperresponsiveness by decoy oligonucleotide specific for STAT1. 150 STAT3, STAT4, and STAT5 all play important roles in inflammation.…”