Elevation of IL-9 in Extreme Patch Test Reactions Suggests It Is an Inflammatory Mediator in Allergic Contact Dermatitis

Abstract

Interleukin 9 is a cytokine classically considered to be associated with the Th2 lymphocyte subset; however, an IL-9 producing T-cell subset, Th9, has recently been recognized and implicated in the pathogenesis of allergic inflammation. 1,2 Despite the known role of this cytokine in various forms of allergic inflammation, the role of IL-9 specifically in allergic contact dermatitis (ACD) has not been fully established. A recent collaborative study conducted by the Departments of Dermatology at the University of Maryland School of Medicine and the University of Rome has contributed to our evolving understanding of the role of IL-9 in ACD by demonstrating that IL-9 serves a regulatory role by modulating allergen-specific IFN-F production by Th1 cells. In the study, a 5-fold increase in gene expression of IL-9 as well as a 2-to 3-fold increase in the Th9 transcription factor PU.1 was present in skin biopsies from 7 patients with positive patch test results to nickel. Furthermore, approximately 4% of the infiltrating CD3 + /CD4 + T cells in positive patch test biopsies from 5 patients with ACD to different allergens were found to be Th9 cells. A robust, dose-dependent production of IL-9 in vitro by peripheral blood mononuclear cells derived from 7 nickel-allergic patients was observed in response to increasing doses of nickel. It was also demonstrated that IL-9 acts to regulate allergen-specific Th1 lymphocyte responses indirectly by enhancing IL-4 production by Th2 lymphocytes. These in vitro data were confirmed in a contact hypersensitivity model using IL-9 j / j mice, which demonstrated enhanced Th1 lymphocyte immune responses when compared with wildtype mice. Surprisingly, irritant contact dermatitis was impaired in IL-9 j/j mice compared with wild-type mice, suggesting a role for IL-9 in promoting an inflammatory response during contact dermatitis. 3 This prompted us to study IL-9 production in extreme cases of ACD at the protein level (ex vivo).We studied 5 extreme bullous patch test reactions (3+) elicited by patch testing with paraphenylenediamine in highly allergic patients. Blister fluid was aspirated at the 48-or 72-hour readings and studied for IL-9 content using an IL-9Yspecific enzyme linked immunosorbent assay. 3 High levels of IL-9 were identified in all 5 ACD specimens (1589 T 459 pg/mL; n = 5). In addition, we measured IL-9 levels in 3 normal human serum controls and blister fluid from 3 different control blistering skin diseases: an ischemic blister, an edema blister, and bullous pyoderma gangrenosum (PG). Interleukin 9 levels were undetectable in all of these samples with the exception of PG, in which IL-9 was mildly elevated (199 pg/mL) (Fig. 1).Significantly elevated levels of IL-9 in extreme patch test reactions suggest that IL-9 may serve as an inflammatory mediator in ACD. The cellular source of IL-9 in the blister fluid is currently unknown, possibly T cells, mast cells, or another cell type. Although further studies are necessary to clarify the role of IL-9 as an inflammatory mediator in AC...

Dust mite induces multiple polar T cell axes in human skin

“…HDM‐positive responses showed striking induction of IL‐9 and IL‐5, even greater than in AD tissues, and more characteristic of hapten‐induced DTH reactions . IL‐9, a Th9 cytokine, promotes proliferation and differentiation of mast‐ and T cells and has a regulatory role in ACD, through direct effects on Th1 .…”

“…Based on past data on HDM APT response, including its strong association with T cell infiltration and cytokine increases, 27,30 HDM-positive responses showed striking induction of IL-9 and IL-5, even greater than in AD tissues, and more characteristic of hapten-induced DTH reactions. 37,41,52,75 IL-9, a Th9 cytokine, promotes proliferation and differentiation of mast-and T cells 76 and has a regulatory role in ACD, through direct effects on Th1. 77 HDM stimulates IL-9 production via protease-activated receptor-2 (PAR-2), present on eosinophils.…”

“…S4-S6) 49,50. HDM produced a robust and significant induction of IL-9, a cytokine characteristically increased by contact allergens (P < .01;Figure3) 37,51,52. Th17-related markers (IL-8, IL-23p40, PI3, CCL20, LCN2) were strongly upregulated in HMD tissues vs controls (P < .05;Figure 3), showing greater similarity to nickel responses rather than to AD lesions, which showed lesser Th-17 skewing (Fig.…”

TH9 cells in skin disorders

“…IL-9 is upregulated in positive skin patch reactions in patients with allergic contact dermatitis [54, 55]. IL-9 expression seems to be a general pathogenetic event in allergic contact dermatitis, as increased levels of IL-9 were found in reactions to a variety of different contact allergens, including metals, drugs, and polymers [54].…”

“…However, there is circumstantial evidence that IL-9 may serve as a proinflammatory mediator in ACD: In contact allergic patients, IL-9 expression in both the skin and in peripheral blood mononuclear cells (PBMCs) seems to correlate with the strength of the allergen stimulus: In vitro stimulation of PBMCs with nickel leads to a dose-dependent production of IL-9 in nickel-allergic patients and elevated levels of IL-9 were found in blister fluids of highly positive patch test reactions but not in fluids of other blistering skin conditions [54, 55]. Moreover, PBMCs of allergic patients but not those of tolerant individuals secrete IL-9 after allergen stimulation [57].…”