IL-9 Regulates Allergen-Specific Th1 Responses in Allergic Contact Dermatitis

Liu, Juan; Harberts, Erin; Tammaro, Antonella; Girardi, Nicholas; Filler, Renata; Fishelevich, Rita; Temann, Angela; Licona-Limón, Paula; Girardi, Michael; Flavell, Richard A.; Gaspari, Anthony A.

doi:10.1038/jid.2014.61

Cited by 77 publications

(65 citation statements)

References 36 publications

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“…39 Alternately, higher Th9 frequency in adults versus children with AD may be attributed to higher allergic contact dermatitis seen in this group, though this is speculative. 102 …”

Section: Discussionmentioning

confidence: 99%

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Czarnowicki

Esaki

Gonzalez

et al. 2015

Journal of Allergy and Clinical Immunology

192

171

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Background Identifying differences and similarities between CLA+ polarized T-cell subsets in pediatric vs. adult atopic dermatitis (AD) is critical for directing new treatments towards children. Objective To compare activation markers and frequencies of skin-homing (CLA+) vs. systemic (CLA−) “polar” CD4 and CD8 T-cell subsets in early pediatric AD, adult AD and controls. Methods Flow cytometry was used to measure CD69/ICOS/HLA-DR frequency in memory subsets as well as IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines, defining Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children <5 years and 42 adults with well-characterized moderate to severe AD, as well as age-matched controls (17 children and 25 adults). Results Selective ICOS activation (P<0.001) was seen in children. CLA+ Th2 T-cells were markedly expanded in both AD children and adults compared to controls, but decreases in CLA+ Th1 T-cells were greater in AD children (17% vs. 7.4%, P=0.007). Unlike in adults, no imbalances were detected in pediatric AD CLA− T-cells, nor were there altered frequencies of Th22 T-cells within CLA+ or CLA− compartments. Adults with AD had increased frequency of IL-22-producing CD4 and CD8 T-cells within the skin-homing population (9.5% vs. 4.5%; 8.6% vs. 2.4%, respectively; P<0.001) as well as increased HLA-DR activation (P<0.01). Conclusions These data suggest that Th2 activation within skin-homing T-cells may drive AD in children and that reduced counter-regulation by Th1 T-cells may contribute to excess Th2 activation. Th22 “spreading” of AD is not seen in young children and may be influenced by immune development, disease chronicity or recurrent skin infections. Clinical Implications Therapeutic approaches to treat AD in children may be best directed to correction of Th2/Th1 imbalance, while adults might also benefit from IL-22 targeted therapies.

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“…39 Alternately, higher Th9 frequency in adults versus children with AD may be attributed to higher allergic contact dermatitis seen in this group, though this is speculative. 102 …”

Section: Discussionmentioning

confidence: 99%

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Czarnowicki

Esaki

Gonzalez

et al. 2015

Journal of Allergy and Clinical Immunology

192

171

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“…Recent studies revealed a T-cell subset (Th9 cells) that predominantly produces IL-9 and is distinct from the classic Th1, Th2 and Th17 subsets (2-4). Several reports showed that Th9 cells could be involved in the pathogenesis of chronic allergic disorders such as asthma, allergic rhinitis and atopic dermatitis (23,24). Further studies indicated that serum levels of IL-9 are increased in patients with SLE and other autoimmune diseases such as systemic scleroderma (8,25,26).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-9 Is Associated with Elevated Anti-Double-Stranded DNA Antibodies in Lupus-Prone Mice

Yang

et al. 2015

Mol Med

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Interleukin (IL)-9, which is produced mainly by CD4 + T cells, is implicated in mast cell-related allergic diseases, although its involvement in systemic lupus erythematosus (SLE) pathogenesis remains unclear. Thus, we investigated the presence of IL-9 in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the role of IL-9 in lupus pathogenesis. Increased levels of IL-9 + lymphocytes were detected in the spleens and kidneys of MRL/lpr mice and increased IL-9 levels in the spleen correlated with PNA + germinal center (GC) cell expansion. The percentage of CD4 + IL-9 + (Th9) cells was increased in MRL/lpr mice and serum IL-9 levels were elevated and closely related to the production of antibodies against double-stranded DNA (dsDNA). IL-9 appears to promote B-cell proliferation and immunoglobulin production, which could be blocked by inhibition of signal transducer and activator of transcription 3 (STAT3). Treatment with neutralizing anti-IL-9 antibody in vivo decreased serum anti-dsDNA-antibody titers and alleviated lupus nephritis in MRL/lpr mice. Our findings indicate expansion of Th9 cells in lupus-prone MRL/lpr mice and the correlation of IL-9 with B-cell proliferation and autoantibody production. These findings suggest that IL-9 is a potential therapeutic target for SLE. autoantibody activity. IL-9 induced B-cell proliferation and immunoglobulin production in vitro, but this effect was blocked by signal transducer and activator of transcription 3 (STAT3) inhibition. Administration of neutralizing antibody against IL-9 in vivo relieved lupus nephritis in MRL/lpr mice. Further study indicated that IL-9 acts synergistically with IL-17 to promote immunoglobulin production in vitro and in vivo. Our data indicate that IL-9 is linked to B-cell activation and autoantibody production in lupus and that IL-9 is a potential therapeutic target for SLE. MATERIALS AND METHODS MiceFemale MRL/lpr and C57BL/6 mice (3 months old) were purchased from the Shanghai Laboratory Animal Center (Chinese Academy of Sciences) and maintained under pathogen-free conditions. The animal protocol was approved by the Institutional Animal Use Committee of the Shanghai Institute for Biological Sciences. Some experiments were performed as modified methods (15,16). MRL/lpr mice were randomized into two groups containing six mice each and were treated with intraperitoneal (IP) injections of phosphate-buffered saline, anti-IL-9 antibody (100 μg/mouse), or anti-IL-19 antibody (100 μg/mouse) plus anti-IL-17 antibody (100 μg/mouse), (eBioscience, San Diego, CA, USA) once every 4 wks for 12 wks, and gremial center formation and kidney injury was analyzed. All antibodies were obtained from eBioscience. To quantify protein in the urine, we collected the total volume of urine excreted over 24 h and measured urinary protein by enzyme-linked immunosorbent assay (ELISA) (Nanjing Jianchen Bioengineering Company, Nanjing, China). Cytokine and dsDNA Antibody DetectionELISA kits were used to evaluate mouse serum levels of IL-9 (eBioscience) and anti-dsDNA anti...

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“…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).…”

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confidence: 98%

“…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).…”

mentioning

confidence: 99%

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

Gutin¹,

Tammaro²,

Fishelevich³

et al. 2016

Dermatitis

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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...

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IL-9 Regulates Allergen-Specific Th1 Responses in Allergic Contact Dermatitis

Cited by 77 publications

References 36 publications

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)+ TH2/TH1 cell imbalance, whereas adults acquire CLA+ TH22/TC22 cell subsets

Interleukin-9 Is Associated with Elevated Anti-Double-Stranded DNA Antibodies in Lupus-Prone Mice

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

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