Chronic Allergic Contact Dermatitis Research Articles

Inflammatory plasma signature of chronic hand eczema: Associations with aetiological and clinical subtypes.

Chronic hand eczema (CHE) is a highly prevalent, heterogeneous, skin disease that encompasses different aetiological and clinical subtypes. Severe CHE without atopic dermatitis has been associated with systemic inflammation; yet it remains unknown if specific CHE subtypes leave distinct, systemic, molecular signatures. To characterize the inflammatory plasma signature of different aetiological and clinical CHE subtypes. We assessed expression levels of 266 inflammatory and cardiovascular disease risk plasma proteins as well as filaggrin gene mutation status in 51 well-characterized CHE patients without concomitant atopic dermatitis and 40 healthy controls. Plasma protein expression was compared between aetiological and clinical CHE subgroups and controls both overall and according to clinical CHE severity. Correlation analyses for biomarkers, clinical and self-reported variables were performed. Very severe, chronic allergic contact dermatitis (ACD) on the hands was associated with a mixed Type 1/Type 2 systemic immune activation as compared with controls. Circulating levels of Type 1/Type 2 inflammatory biomarkers correlated positively with clinical disease severity among CHE patients with ACD. No biomarkers were found, that could discriminate between aetiological subtypes, for example, between ACD and irritant contact dermatitis. Hyperkeratotic CHE showed a distinct, non-atopic dermatitis-like, systemic footprint with upregulation of markers associated with Type 1 inflammation and tumour necrosis factor alpha, but not Type 2 inflammation. Increased levels of CCL19 and CXCL9/10 could discriminate hyperkeratotic CHE from both vesicular and chronic fissured CHE, whereas no difference was found between the latter two subtypes. Profiling of systemic biomarkers showed potential for identifying certain CHE subtypes. Peripheral blood levels of inflammatory biomarkers were associated and correlated with the clinical disease severity of chronic ACD on the hands, underlining that this is a systemic disease. We question whether hyperkeratotic CHE should be classified as eczema.

Veronica persica Ethanol Extract Ameliorates Dinitrochlorobenzene-Induced Atopic Dermatitis-like Skin Inflammation in Mice, Likely by Inducing Nrf2/HO-1 Signaling.

Atopic dermatitis (AD) is chronic allergic contact dermatitis with immune dysregulation. Veronica persica has pharmacological activity that prevents asthmatic inflammation by ameliorating inflammatory cell activation. However, the potential effects of the ethanol extract of V. persica (EEVP) on AD remain elusive. This study evaluated the activity and underlying molecular pathway of EEVP in two AD models: dinitrochlorobenzene (DNCB)-induced mice and interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated human HaCaT keratinocytes. EEVP attenuated the DNCB-induced increase in serum immunoglobulin E and histamine levels, mast cell counts in toluidine-blue-stained dorsal skin, inflammatory cytokine (IFN-γ, interleukin [IL]-4, IL-5, and IL-13) levels in cultured splenocytes, and the mRNA expression of IL6, IL13, IL31 receptor, CCR-3, and TNFα in dorsal tissue. Additionally, EEVP inhibited the IFN-γ/TNF-α-induced mRNA expression of IL6, IL13, and CXCL10 in HaCaT cells. Furthermore, EEVP restored the IFN-γ/TNF-α-induced downregulation of heme oxygenase (HO)-1 in HaCaT cells by inducing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. A molecular docking analysis demonstrated that EEVP components have a strong affinity to the Kelch-like ECH-associated protein 1 Kelch domain. In summary, EEVP inhibits inflammatory AD by attenuating immune cell activation and inducing the Nrf2/HO-1 signaling pathway in skin keratinocytes.

Pharmacological Profile of Difamilast, a Novel Selective Phosphodiesterase 4 Inhibitor, for Topical Treatment of Atopic Dermatitis.

PDE4 inhibitors are expected to be anti-inflammatory agents based on their mechanism of action, but the application of this drug class is limited by a narrow therapeutic window due to adverse effects associated with gastrointestinal function. Difamilast, a novel selective phosphodiesterase 4 (PDE4) inhibitor, demonstrated significant efficacy without adverse reactions such as nausea and diarrhea in patients with atopic dermatitis (AD) and was recently approved in Japan. In this study, we investigated the pharmacological and pharmacokinetic properties of difamilast to provide nonclinical data to help understand the clinical effects. Difamilast selectively inhibited recombinant human PDE4 activity in assays. The IC50 of difamilast against PDE4B, a PDE4 subtype that plays an important role in the inflammatory response, was 0.0112 μM, representing a 6.6-fold decrease compared with the IC50 against PDE4D (0.0738 μM), a subtype that can trigger emesis. Difamilast inhibited TNF-α production in human (IC50 = 0.0109 μM) and mouse (IC50 = 0.0035 μM) peripheral blood mononuclear cells and improved skin inflammation in a mouse model of chronic allergic contact dermatitis. These effects of difamilast on TNF-α production and dermatitis were superior to those of other topical PDE4 inhibitors: CP-80633, cipamfylline, and crisaborole. In pharmacokinetic studies using miniature pigs and rats, the concentrations of difamilast in the blood and brain after topical application were not sufficient to support pharmacological activity. This nonclinical study contributes to explain the efficacy and safety of difamilast with a sufficient therapeutic window in the clinical trials. SIGNIFICANCE STATEMENT: This is the first report on the nonclinical pharmacological profile of difamilast ointment, a novel topical PDE4 inhibitor that demonstrated utility in clinical trials in patients with atopic dermatitis. Difamilast, which has high PDE4 selectivity (especially for the PDE4B subtype), ameliorated chronic allergic contact dermatitis in mice after topical application, with a pharmacokinetic profile in animals that suggests few systemic side effects; thus, difamilast is a promising new therapeutic treatment for atopic dermatitis.

287 Targeting the inhibitory receptor Siglec-8 on mast cells represents an attractive approach to reduce MRGPRX2-mediated mast cell activation

Abstract Atopic dermatitis (AD) is a debilitating type 2 inflammatory disease of the skin characterized by pruritus. Mast cells (MCs) and eosinophils (eos) are elevated in AD tissue. Siglecs are inhibitory receptors found on immune cells, with Siglec-8 selectively expressed on MCs and eos. Engagement of Siglec-8 with antibody results in broad inhibition of MC activation (IgE-dependent and -independent pathways). MCs and eos are key drivers of itch. Crosstalk between skin MCs and sensory neurons contributes to non-histaminergic itch via activation of Mas-related G-protein receptor X2 (MRGPRX2). MRGPRX2-mediated MC activation has been implicated in chronic urticaria and allergic contact dermatitis, however, this mechanism has not been studied in the pathogenesis of AD. We hypothesize that activation of MCs through MRGPRX2 contributes to chronic inflammation and itch in patients with AD. Supernatants were collected from intact ex vivo cultured lesional and non-lesional skin biopsies from donor-matched patients with AD or healthy volunteers. Following ex vivo culture, secreted mediators were quantified using ELISA and meso-scale discovery (MSD). Biopsies were enzymatically digested and MRGPRX2 expression and function were measured using flow cytometry and MSD. Acute MRGPRX2 activation in vivo and the effects of a Siglec-8 monoclonal antibody (mAb), compared with isotype control, were studied in Siglec-8 transgenic mice. MC and eosinophil numbers were increased in lesional biopsies from patients with AD compared with patient-matched non-lesional and healthy volunteer control biopsies. MCs from AD lesional biopsies showed significant evidence of activation and degranulation compared to MCs in non-lesional biopsies. Levels of MC-specific proteases, inflammatory and pruritic mediators were significantly elevated in supernatants from ex vivo cultured lesional biopsies, including CPA3, CCL17 (TARC), IL-8, IL-13 and IL-31. Levels of MRPGRX2 ligands in supernatants from AD lesional biopsies were significantly elevated. Ex vivo challenge of healthy skin tissue with MRGPRX2 ligands partially replicated the AD lesional microenvironment. Lastly, intradermal injection of MRGPRX2 ligands in Siglec-8 transgenic mice induced inflammation and itch, which were inhibited with a Siglec-8 mAb. MRGPRX2-mediated MC activation contributes to inflammation in patients with AD through the release of chemotactic, proteolytic, pruritic and inflammatory factors. Therapeutic strategies that broadly target MCs, such as a lirentelimab (AK002) and a Siglec-8 mAb, may decrease the severity of AD.

Assessment of Comorbidities Associated With Allergic Contact Dermatitis in the United States: A Retrospective Claims-Based Study.

Allergic contact dermatitis (ACD) is a common dermatologic disease. Patch testing remains the criterion standard for diagnosis. In clinical practice, avoidance may be limited by patient occupation or noncompliance, the pervasive nature of the culprit agent, or barriers to expert care because of socioeconomic, cultural, or geographic factors. Thus, ACD is frequently chronic and/or recurrent; however, the comorbidities associated with ACD are not well characterized. The aim of the study is to identify associations between ACD and psychiatric, sleep health, cardiovascular, and infectious conditions. In this study, we used a large US claims database to identify comorbidities associated with ACD diagnosed after patch testing, including psychiatric, sleep health, cardiovascular, and infectious conditions. We also stratified these associations by chronicity of disease. We identified associations between ACD and psychiatric, sleep-related, cardiovascular, and infectious comorbidities. We also found that more chronic ACD was associated with more infectious comorbidities. All of these associations remained significant on further subanalysis when patients with AD and venous stasis were excluded. Allergic contact dermatitis is associated with multiple comorbidities. Further study is required to corroborate these findings, determine causality, and to explore the impact of possible interventions in the workup and management of this common and often debilitating disease.

S1 guideline: Differential diagnosis of acute and chronic redness of the lower legs.

Acute or chronic redness of the lower leg is a frequent reason for visits to clinics and practices. The differential diagnosis is often challenging. The aim of this guideline is to define criteria and procedures for the differential diagnosis of acute or chronic, unilateral or bilateral redness of the lower leg. Finding the correct diagnosis is essential for selecting an appropriate treatment and can help to reduce the inappropriate use of antibiotics. The guideline committee identified the most relevant differential diagnoses: 1. erysipelas, 2. stasis dermatitis, 3. hyperergic ictus reaction, 4. superficial and deep vein thrombosis, 5. gout, 6. chronic allergic contact dermatitis, and 7. acute toxic or allergic contact dermatitis. Algorithms/diagnostic pathways, each of which can be broken down into anamnesis, clinical examination, and diagnostics, have been developed for these seven diagnoses. In addition, the guideline group identified over 40 other relevant diagnoses and summarized their characteristics in a table to facilitate further differential diagnoses.

Active implications for dermatologists in 'SARS-CoV-2 ERA': Personal experience and review of literature.

Linked articles: COVID‐19 SPECIAL FORUM. J Eur Acad Dermatol Venereol 2020; 34: e346–e380.

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation

Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33's direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33-Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.

Immune-modulation via IgD B-cell receptor suppresses allergic skin inflammation in experimental contact hypersensitivity models despite of a Th2-favoured humoral response

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common skin inflammatory conditions. B and T cells are strongly implicated in allergic contact hypersensitivity (CHS) conditions. Activation of IgD B-cell receptor (BCR) by anti-IgD stimulation depletes mature B cells and modulates T-helper cell type 1/2 (Th1/2) responses in vivo. It is not known whether these effects by anti-IgD exacerbates or ameliorates chronic skin inflammations. This study investigated the effects of anti-IgD and B-cell depleting anti-CD20 antibody on skin inflammation in CHS murine models. Chronic CHS were induced by challenges with allergens trimellitic anhydride (TMA) or 2,4 dinitrochlorobenzene (DNCB). Mice were treated with an anti-IgD or anti-CD20 at various time-points following allergen challenges. This study revealed that early therapeutic treatments with anti-IgD at 4 h after allergen challenge significantly reduced skin inflammation in both TMA- and DNCB-induced CHS models (P < 0.05). In contrast, anti-CD20 treatment exacerbated skin inflammation in DNCB-induced CHS despite of an extensive B cell depletion (P < 0.05). Anti-IgD treatment depleted mature CD19+IgD+ B cells but enhanced allergen-specific IgM and total IgE productions, suggesting a Th2-favoured humoral response. Anti-IgD reduced neutrophilic infiltrations but increases accumulation of mast cells in dermal tissues. The anti-inflammatory effects of anti-IgD were supported by evidence of an increase in the percentage of regulatory B cells and T cells. Collectively, this study demonstrates that immune-modulation by anti-IgD treatment suppresses Th2-mediated allergic skin inflammation in murine models despite a skew toward a Th2-favvoured humoral response and therefore may present a novel treatment for chronic human AD and ACD.

Interleukin-17 and interleukin-23 expression in chronic allergic contact dermatitis

Interleukin-17 and interleukin-23 expression in chronic allergic contact dermatitis

Hand-biting Lesions in a Child — a Challenging Diagnosis

AbstractBackground:Self-induced skin lesions, especially in young children, can create confusion within pediatricians, dermatologists, or other medical care providers, leading to different diagnoses, unnecessary investigations, and delaying the correct therapeutic psychiatric evaluation.Case report:We report the case of a 4-year-old boy who was referred to Dermatology after being hospitalized in the Allergy Department for a chronic allergic contact dermatitis. He had been previously diagnosed with chronic hand dermatitis, atopic dermatitis, and psoriasis, and treated with no favorable outcome. Scaly erythematous plaques were noticed on the dorsal aspects of both hands and on the lateral folds of the fingers. The skin lesions were distributed in a non-symmetrical way. A diagnosis of self-injurious behavior was presumed, and psychiatric evaluation was asked. The child was transferred to the Psychiatry Department, and a diagnosis of schizophrenia was concluded.

Histamine suppresses T helper 17 responses mediated by transforming growth factor-β1 in murine chronic allergic contact dermatitis

Allergic skin diseases are caused by the introduction of antigen into the skin. Repeated application of antigens prompts the development of atopic dermatitis (AD) and chronic allergic contact dermatitis (CACD). Histamine facilitates the development of chronic lesions in CACD. T helper (Th)17 cells are less prevalent in the chronic lesional skin compared to acute lesional skin in AD and CACD. The present experiment determined the effects of histamine in regulating Th17 in a murine model of CACD. CACD was induced by repeated epicutaneous challenge of 2,4,6-trinitro-1-chlorobenzene in histidine decarboxylase (HDC) (-/-) mice. Th17 response were analyzed by transforming growth factor (TGF)-β1, interleukin (IL)-17 and IL-22 levels in lesional skin. TGF-β1 was injected into the dermis of CACD-developing mice. Histamine H1 or H4 receptor antagonist were orally administrated in CACD-developing mice. IL-17 and IL-22 levels were lower in HDC (+/+) mice compared to HDC (-/-) mice. TGF-β1 levels were also lower in HDC (+/+) mice compared to HDC (-/-) mice. TGF-β1 injection increased IL-17 and IL-22 levels in the lesional skin of HDC (+/+) mice. Histamine H1 or H4 receptor antagonist administration also increased TGF-β1, IL-17 and IL-22 levels in the lesional skin of HDC (+/+) mice. In conclusion, histamine suppresses Th17 function in murine CACD. This effect was induced by the down-regulation of TGF-β1 through histamine H1 and H4 receptors.

Eczema in Psoriatico: An Important Differential Diagnosis Between Chronic Allergic Contact Dermatitis and Psoriasis in Palmoplantar Localization

Differential diagnosis of palmoplantar non-pustular psoriasis and chronic allergic contact dermatitis (ACD) and the combination of these conditions, termed "eczema in psoriatico" (EIP), is difficult, especially in cases of isolated involvement. A blind re-evaluation of 63 archived formalin-fixed palmoplantar samples, previously diagnosed clinically as either psoriasis or chronic ACD, was performed. Samples were allocated to histopathological diagnoses of psoriasis, contact dermatitis or EIP. Immunohistological stainings were performed for better characterization. Immunochemistry of EIP revealed features that overlapped contemporarily with psoriasis (cytokeratin 17 (CK17), Ki67, interleukin (IL)-8, IL-17, IL-23) and with ACD (CD1a, major histocompatibility complex (MHC) class I, MHC class II, epidermal T-cell subsets). Surprisingly, a significantly much higher number of dermal CD8+ T cells was found in EIP than in ACD and psoriasis. In conclusion, this study provides insight into the immunohistological differentiation of palmoplantar psoriasis, chronic ACD and EIP.

Same old peristomal dermatitis, but what's causing it?

Introduction Prevalence of peristomal dermatoses ranges between 6-80% 1 and more commonly affects patients with urostomies and ileostomies, than with colostomies. Most common causes include irritant contact dermatitis from urine/faeces, mechanical dermatitis, chronic papillomatous dermatitis, seborrheic dermatitis and allergic contact dermatitis. We report an unusual case of allergic contact dermatitis to printing ink on stoma bag which has not knowingly been reported before. Case description A 66-year-old male, presented with a pruritic rash under colostomy bag, not responding to topical emollients and steroids. Examination findings were of an eczematous rash with no obvious leak at stoma site or from bag. He was not on any medication such as Nicorandil which might be contributing to peristomal dermatitis/ulceration. Provisional diagnoses were allergic contact dermatitis and irritant contact dermatitis. First patch test for standard european battery was negative. Histopathology had shown eczematoid spongiotic dermatitis, consistent with allergic/irritant contact dermatitis. He was treated with several emollients, topical Trimovate®, Betnovate® and topical 0.1%Tacrolimus; however, it had made no significant difference even by occlusion with hydrocolloid dressing. Subsequently he was patch tested with colostomy bag tied on to forearm for a week. It was divided in five patches: 1.Inner sticky pad 2.Outer sticky pad 3.Bag 4.Printed area of bag and 5.Joined area of bag. Surprisingly he had shown strongly positive reaction only to number 4 but not to any other part of the bag. It was thought that he was allergic to that particular ink and not to bag itself as he did not show any reaction to un-branded part of the bag. He was advised to cover the printed under surface of the colostomy bag with Micropore® and to continue Hydromol® as barrier emollient and Mometasone furoate ointment for flare ups. His problem completely resolved with covering inked part of colostomy bag with Micropore® and he was discharged back to GP. Enquiry had been made to manufacturer regarding materials used in ink, as patch test for standard European battery were negative, however manufacturer of the colostomy bag had passed it on to the manufacturer of the ink and no further information had been received to this date. Conclusion Allergic contact dermatitis had been reported secondary to ostomy bag/pouch, sealing rings, strapping, deodorizers, adhesives, skin cleansers and topical emollients and ointments. Patch testing had always been the key investigation in these cases. Most reported cases had shown sensitivity to ‘epoxy resin' which is a component of stoma bag itself. Allergic contact dermatitis had also been reported to karaya gum seal ring 2 , colophony & benzyl peroxide 3 , tinuvin P® / 2-benzotriazol 4 , di-aminodiphenylmethane and rubber seal surrounding the bag 5 . Other cases had shown sensitivity to adhesive tapes, polyisobutylene (adhesive ring of ostomy bag), adhesive remover wipes, stomahesive paste®, dansac® soft paste, gantrez ES®, balsam of Peru, cinnamic aldehyde, geraniol, benzyl alcohol, isoeugenol, propylene glycol and DOR ostomy deodorant® 6 . However, so far we had not noted any case report showing sensitivity to printing ink on colostomy bag. It is unfortunate that we are still unable to get the information on components of ink however, in suspected cases it would be worth covering the printed under surface of colostomy bag to overcome possible allergic contact dermatitis. Recommending manufacturers of stoma care products to avoid printing on the surface in contact with the skin would also be another feasible alternative. Take-home message 1.Allergic contact dermatitis is one of the common causes of peristomal dermatitis. 2.Patch test is important if allergic/irritant contact dermatitis is suspected. 3.Stoma bag can be used directly for patch testing if commercially available patch tests batteries do not show any positive result. 4.Although quite rare, patients can develop sensitivity to printing ink on stoma bag and covering printed surface can be considered if clinically suspected.

Effects of Licochalcone E Derivatives on the Production of Inflammatory Mediators Induced by LPS

Licochalcone E is a retrochalcone isolated from the roots of Glycyrrhiza inflate. We previously reported that licochalcone E inhibited IL-12p40 production and attenuated chronic allergic contact dermatitis (ACD). Among the derivatives of licochalcone E, compound #74 ((E)-3-(5-Bromo-4-hydroxy-2-methoxyphenyl)-1-(4-ethoxyphenyl)prop-2-en-1-one) inhibited the production of IL-12p40, TNF-α, and IL-6, and NF-κB signaling pathway from LPS stimulated RAW264.7 macrophages. The effect of compound #74 (0.5, 1, and 5%) on ACD model was very weak.

Tetradecanol reduces EL-4 T cell growth by the down regulation of NF-κB mediated IL-2 secretion

Tetradecanol is a straight-chain saturated fatty alcohol purified from Dendropanax morbifera leaves. We found that tetradecanol (30μM) reduced specifically the growth of T cells such as EL-4 T cell and isolated murine CD4+ T cells. In this study, we investigated the effects of tetradecanol on the regulation of interlukin-2 (IL-2), a potent T cell growth factor. Tetradecanol significantly inhibited IL-2 secretion in EL-4 T cells activated with phorbol 12-myristate 13-acetate (PMA) plus ionomycin (Io) and also in isolated murine CD4+ T cells activated with anti-CD3 and anti-CD28 antibodies. Next, we examined the effect of tetradecanol on the transcriptional activity related to IL-2 production in T cells. Tetradecanol decreased PMA/Io-induced promoter activity of NF-κB in EL-4 T cells, but did not show any significant effects on the promoters of activator protein 1 (AP-1) and nuclear factor of activated T cells (NF-AT). Tetradecanol inhibited IκBα degradation and nuclear translocation of NF-κB subunit, p65 in PMA/Io–activated EL-4 T cells. These results suggest that tetradecanol might have immunosuppressive effects on T cell mediated disorders. Using a chronic allergic contact dermatitis model induced by repeated application of oxazolone, we showed that tetradecanol reduced ear thickness induced by oxazolone.

Histamine H4 Receptor in Allergic Dermatitis

Allergic dermatitis, the common skin disease, includes chronic allergic contact dermatitis (CACD) and atopic dermatitis (AD), the Th2 dominant diseases. Histamine aggravates CACD in mice. Histamine H4 receptor (HH4R) is expressed on eosinophils, mast cells, T cells, natural killer cells, antigen presenting cells, basophils, keratinocytes and sensory neurons and is suggested to be related to allergic dermatitis. Administration of the HH4R antagonist JNJ7777120 is effective to the murine CACD models. Furthermore, combination of JNJ7777120 and the histamine H1 receptor antagonist olopatadine hydrochloride is a potent therapeutic target in chronic inflammatory skin diseases such as CACD and AD, since combined therapy is more effective than monotherapy.

Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure.

Allergic contact dermatitis is a chronic T cell-driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient KitW-sh/W-sh (Sash) and MCPT5-Cre+iDTR+ mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-γ, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-γ-producing CD8+ tissue-resident memory T (TRM) cells. The CD8+ T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous TRM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8+ TRM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition.

Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib

The janus kinase-inhibitor oclacitinib is licensed for the control of pruritus associated with allergic skin diseases in dogs. Strikingly, it has been clinically reported that abrupt withdrawal of oclacitinib leads to a rebound pruritus in dogs. Therefore, the primary objective of this study was to mimic the rebound phenomenon of oclacitinib using a chronic pruritic mouse model of allergic contact dermatitis. Chronic allergic contact dermatitis was induced by repetitive toluene-2,4-diisocyanate (TDI) challenge in BALB/c mice. Oclacitinib was orally administered twice daily at 45mg/kg for 7 days, with concurrent TDI challenge, and then treatment of oclacitinib was abruptly discontinued. Scratching bouts following TDI challenge were evaluated to day 15. Additionally, dorsal root ganglia (DRG) and affected skin were isolated from mice receiving oclacitinib and from mice 24h after oclacitinib withdrawal and were used to determine pruritogen induced Ca2+ signals in sensory neurons, the number of activated dendritic cells (DCs) within DRG, and the cytokine profiles of affected skin. Mice treated with oclacitinib showed a significant decrease in scratching bouts during treatment, then following abrupt withdrawal scratching bouts were significantly increased. Furthermore, following abrupt withdrawal more DRG neurons were activated by pruritogenic cytokines, TNFα positive DCs were significantly increased, and affected skin revealed a significant increase of TNFα and TSLP. In conclusion, while oclacitinib significantly reduced itch during treatment the abrupt withdrawal led to a rapid rebound phenomenon which can be explained by an increase in pruritogenic cytokines and fast peripheral sensitization.

Histamine and Histamine Receptors in Allergic Dermatitis.

In this chapter we will first introduce the pathophysiological process of several skin diseases including allergic dermatitis, a common skin disease, including chronic allergic contact dermatitis (CACD), and atopic dermatitis (AD). In CACD and AD patients, repeated skin exposure to antigens contributes to the development of chronic eczematous lesions. Repeated application of haptens on mice allows emulation of the development of CACD in humans. Further, we will focus on H1, H2, and H4 histamine receptors and their effects on CACD and AD. Histamine-deficient mice, with a knockout histidine decarboxylase (HDC) gene, were used to investigate the role of histamine in CACD and AD. Histamine induces infiltration of inflammatory cells, including mast cells and eosinophils, and elevates Th2 cytokine levels in CACD. Histamine promotes the development of eczematous lesions, elevates IgE serum levels, and induces scratching behavior in CACD. The administration of H1 or H4 receptor antagonists was effective to ameliorate these symptoms in murine CACD models. The combination of H1 and H4 receptor antagonists is a potential therapeutic target for chronic inflammatory skin diseases such as CACD and AD, since combined therapy proved to be more effective than monotherapy.