Clinically uninvolved but not healthy-The skin of patients with atopic dermatitis is primed for itch and inflammation.

BACKGROUND: Atopic dermatitis (AD) is a highly prevalent inflammatory skin disorder characterized by episodic exacerbations and remissions. Why the clinically healthy skin of AD patients becomes rapidly inflamed and very pruritic is poorly understood. OBJECTIVE: To investigate cowhage- and histamine-induced itch and skin expression levels of their target receptors in lesional and non-lesional skin of AD, compared to the skin of patients with psoriasis, chronic spontaneous urticaria (CSU) and healthy subjects. METHODS: Patients with AD, psoriasis and chronic spontaneous urticaria (CSU) as well as healthy control subjects (HC) (n = 20 each) were assessed for differences in itch parameters, neurogenic flare reaction and local blood flow responses to skin provocations with cowhage and histamine. Skin biopsies from 10 AD, 10 psoriasis,11 CSU and 12 HC were obtained to assess expression of protease-activated receptors 2 and 4 (PAR-2, PAR-4), histamine H1 and H4 receptors (H1R, H4R), and mast cells. RESULTS: Provocation of non-lesional skin of AD patients with cowhage resulted in prolonged itch (p = 0.020), which was not observed in psoriasis and CSU. Significantly prolonged and more intense cowhage- and histamine-induced itch (for duration, peak and overall intensity) was also observed in lesional AD skin. Diminished neurogenic flare reaction and blood flow after histamine provocation were shown in AD and psoriasis patients. Non-lesional AD skin along with lesional AD and psoriasis skin showed an increased expression of PAR-2 and PAR-4, H1R and H4R. Mast cell number was higher in lesional AD and psoriasis skin (p = 0.006 and p = 0.006, respectively). CONCLUSION: The non-lesional skin of AD patients markedly differs from healthy skin in cowhage-induced itch responses and the expression of receptors for proteases and histamine. Proactive therapeutic interventions that downregulate these receptors may prevent episodic exacerbation in AD.

A comprehensive, tri-national, cross-sectional analysis of characteristics and impact of pruritus in psoriasis.

BACKGROUND: Pruritus is prevalent in psoriasis but still many features of pruritus, its response to therapy and its burden in psoriasis remain to be better characterized. OBJECTIVE: To investigate characteristics and burden of pruritus in an international cohort of patients with psoriasis. METHODS: This cross-sectional study included a total of 634 patients and 246 controls from Germany, Poland and Russia. Physicians examined and interviewed participants, recording clinical characteristics, such as severity, therapy and localization of psoriatic lesions. Participants filled out self-reported questionnaires including questions on pruritus severity and impact, characteristics, and response to therapy, and quality of life (QoL). Localization patterns of pruritus and skin lesions were visualized using body heat maps. RESULTS: Most patients (82%) experienced pruritus throughout their disease, and 75% had current pruritus. The majority of patients (64%) perceived pure pruritus, and those who reported additional painful and/or burning sensations (36%) reported overall stronger pruritus. The scalp was the most frequently reported localization of pruritus, even in the absence of skin lesions. Body surface area (BSA) of pruritus was not linked to pruritus intensity, but to BSA of psoriatic lesions (rho = 0.278; P < 0.001). One third of patients (31%) reported impaired sex-life, and 4% had suicidal ideations due to pruritus. In up to one third of patients, psoriasis therapies had little or no effect on pruritus. The only therapeutic option offered to some of these patients were antihistamines, which appeared to be effective in most cases. CONCLUSION: Pruritus is highly prevalent in psoriasis and is linked to a significant burden. Current psoriasis therapies are frequently insufficient to control pruritus. Managing psoriasis should include the assessment and control of itch. Efficient antipruritic therapies should be developed and be made available for patients with psoriasis.

Mammary analogue secretory carcinoma presenting with cervical lymphadenopathy: A rare case report with review of the literature.

INTRODUCTION: Mammary analogue secretory carcinoma is a rare malignant tumor of the salivary glands that typically involves the major glands. The aim of the current study is to report a rare case of mammary analogue secretory carcinoma that presented with left cervical lymphadenopathy. CASE REPORT: A 59-year-old lady presented with left cervical lymphadenopathy. Tissue biopsy and immunohistochemistry revealed metastatic carcinoma, favoring ovarian origin. Staging workup was performed and, ultimately, the patient was treated as having a carcinoma of unknown primary. After showing partial response to therapy, left side neck dissection was performed. Based on better assessment of the histologic picture and a broader panel of immunohistochemistry performed on the excision specimen, the final diagnosis was that of mammary analogue secretory carcinoma. DISCUSSION: Mammary analogue secretory carcinoma is usually an indolent salivary gland carcinoma, with the majority of patients presenting with a slow-growing, painless mass measuring approximately 2 cm in size, and a reported duration ranging from 2 months to several years. In certain cases, pain and facial paralysis have been reported. It could also be found incidentally during radiologic assessment for thyroid illness or routine dental screening. CONCLUSION: Diagnosing mammary analogue secretory carcinoma is challenging, and this should be in the differential diagnosis list of metastatic carcinomas to cervical lymph nodes.

Prevalence and factors associated with sleep disturbance in adult patients with psoriasis.

BACKGROUND: Sleep, which is crucial for restoring of physiological functions and health, is reportedly impaired in psoriasis. The role of different potential sleep confounding factors, including detailed pruritus characteristics, and the complex interplay between psychological variables (anxiety and depression), pruritus and sleep disturbance in psoriasis remain insufficiently investigated. OBJECTIVES: To investigate sleep characteristics and to identify clinical, demographic and psychological factors associated with sleep disturbance in psoriasis. METHODS: This cross-sectional study included 334 psoriasis patients (response rate 86%) and 126 control subjects (response rate 82%). Measures included sleep quality [Pittsburgh Sleep Quality Index (PSQI)], psoriasis severity, pruritus characteristics, including average pruritus intensity [visual analogue scale (VAS)], severity of comorbidities, anxiety and depression (Hospital Anxiety and Depression Scale - HADS) and quality of life (Dermatology Life Quality Index - DLQI, and Short Form 12 - SF12). RESULTS: Fifty-nine per cent of patients and 34% of control subjects (P < 0.001) suffered from sleep disturbance (PSQI > 5). Patients slept 1 h less than control subjects (median 6 vs. 7 h, P < 0.001). Patients without pruritus had less impaired sleep (global PSQI) than patients with strong (P < 0.001) and very strong pruritus (P < 0.001). Anxiety (HADS-A) and depression (HADS-D) levels were the strongest predictors of sleep impairment, followed by pruritus exacerbation at night, age, female sex, pruritus exacerbation in the morning, average pruritus intensity (VAS), diagnosed depression and gastroesophageal reflux disease, altogether explaining 32%-37% of the variance in global sleep quality. Both anxiety (HADS-A) and depression (HADS-D) were significant mediators explaining the association between pruritus intensity (VAS) and sleep impairment in 42% and 37% respectively. CONCLUSIONS: Sleep disturbance in patients with psoriasis is highly prevalent. Patients with psoriasis should be assessed for sleep impairment, pruritus, anxiety and depression. Reduction in pruritus should be considered as an important therapeutic goal, along with therapies aimed at reducing anxiety and depression.

Characterization of cowhage-induced pruritus in inflamed and non-inflamed skin.

BACKGROUND AND OBJECTIVE: Pruritus is a major symptom of many inflammatory diseases and impacts greatly the quality of life in patients. We aimed to specify the characteristics of experimentally induced pruritus in normal skin and in experimentally induced inflammatory dermatitis in healthy volunteers. METHODS: Skin inflammation was induced by the repeated application of sodium lauryl sulphate (SLS 2%) on the volar forearms of 30 healthy volunteers. Inflammatory dermatitis intensity was assessed using the eczema score adapted from Frosch and Kligman. Non-histaminergic pruritus was induced by cowhage spicules rubbed on the volar forearms and recorded for 30 min on a 10-cm visual analogue scale (VAS) in both non-inflamed and inflamed skin. RESULTS: Induction of inflammatory dermatitis by SLS resulted in a mild inflammatory dermatitis with an inflammation score of 2.3 ± 0.1 within 7 days of treatment. Cowhage-induced pruritus was of markedly higher intensity (P < 0.001), and all but two individuals had higher maximum pruritus intensity in inflamed skin as compared to non-inflamed skin, whereas the kinetics of the pruritus response were similar. The quality of cowhage-induced pruritus was significantly different with more 'burning' and 'painful sensations' in inflamed skin (P < 0.01). Maximum pruritus intensity in inflamed skin strongly correlated with maximum pruritus intensity in non-inflamed skin (r = 0.51, P = 0.004). Skin hydration, skin barrier integrity and dermatitis severity did not correlate with pruritus intensity. CONCLUSION: Taken together, pruritus in inflamed skin is perceived as more intense, painful and burning. This may explain, in part, why pruritus is a major driver of quality-of-life impairment in patients with chronic inflammatory skin conditions such as atopic dermatitis.

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.

BACKGROUND: In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES: This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS: Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS: Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION: This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.

In chronic spontaneous urticaria, IgE against staphylococcal enterotoxins is common and functional.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema. Despite the known effectiveness of omalizumab therapy, the relevant IgE antigens are largely unknown. Recently, increased rates of elevated levels of IgE towards Staphylococcus aureus enterotoxins (SEs) were described in CSU. AIM: To assess the prevalence and functional relevance of IgE to SEs in CSU. METHOD: We investigated serum levels of IgE against SEs in 49 CSU patients and in 15 CSU patients additional specific IgE to SE components and basophil histamine release (BHR). Sera of 15 healthy controls (HCs) served as control group. RESULTS: Twenty-five (51%) of the CSU patients had detectable levels of SE-IgE as compared to 5 (33%) of HCs. Specific IgE to one of the SEs, Staphylococcus enterotoxin B (SEB), was present in 5 (33%) of 15 randomly selected CSU patients vs 3 (20%) of HC. Total IgE serum levels in CSU patients were significantly correlated with SE-IgE (r = .52, P < .001) and SEB-IgE (r = .54, P = .04) serum concentrations. Interestingly, SEB-IgE levels were strongly correlated with disease activity (UASday) in CSU patients (r = .657, P = .01). Furthermore, BHR in response to SEB was significantly higher in basophils loaded with the serum of CSU patients compared to HC (P < .05) and was clinically correlated with duration of disease (r > .51, P < .05). DISCUSSION: IgE against SEs may contribute to the pathogenesis of CSU in a subpopulation of patients. Its role and relevance in the pathophysiology of CSU need to be further analysed.

Comparison and interpretability of the available urticaria activity scores.

The urticaria activity score (UAS) is the gold standard for assessing disease activity in patients with chronic spontaneous urticaria (CSU). Two different versions, the UAS7 and UAS7TD , are currently used in clinical trials and routine care. To compare both versions and to obtain data on their interpretability, 130 CSU patients applied both versions and globally rated their disease activity as none, mild, moderate, or severe. UAS7 and UAS7TD values correlated strongly (r = .90, P < .001). Interquartile ranges for UAS7 and UAS7TD values for mild, moderate, and severe CSU were 11-20 and 10-24, 16-30 and 16-32, and 27-37 and 28-40. UAS7 values were slightly, but significantly lower as compared to UAS7TD values (mean difference: 1.6 ± 4.6, P < .001). This difference was driven by lower wheal subscores (2.1 ± 3.5, P < .001) and was most pronounced in patients with severe CSU (2.5 ± 5.6, P < .01). The UAS7/UAS7TD ratio was 0.96 ± 0.21 and did not differ significantly between mild, moderate, and severe CSU. Since the results of both UAS versions are comparable, we recommend the use of the UAS7, which is less burdensome in administration and scoring.

The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change.

BACKGROUND: Omalizumab is an effective and well-tolerated treatment for chronic spontaneous urticaria (CSU). Markers and predictors of response are largely unknown, but needed to optimize omalizumab treatment. Omalizumab targets IgE, and IgE levels may be linked to the effects of treatment. We evaluated whether response rates to treatment with omalizumab in patients with CSU are linked to their baseline IgE levels, their IgE levels after omalizumab treatment, and the ratio of on treatment IgE and baseline IgE levels. METHODS: Chronic spontaneous urticaria (CSU) patients (n = 113) were treated with omalizumab 300 mg/4 weeks for 12 weeks, when their treatment responses, that is, no, partial, or complete response, were assessed by use of the urticaria activity score, physician and patient visual analog scale, and treatment effectiveness score. Total IgE levels were measured before treatment (bIgE) with omalizumab and 4 weeks thereafter (w4IgE). RESULTS: Nonresponders to omalizumab had significantly lower bIgE levels (17.9, 17.0-55.0 IU/mL) than partial responders (82.0, 46.2-126.5 IU/mL, P = .008) and complete responders (73.7, 19.45-153.8 IU/mL, P = .032). Nonresponders also had lower w4IgE levels and lower ratios of w4IgE/bIgE levels than partial and complete responders (P < .001). Nonresponse to omalizumab was best predicted by patients' w4IgE/bIgE ratios, significantly better than by bIgE levels (P = .016). CONCLUSIONS: In CSU, total IgE levels and their change predict the response to treatment with omalizumab. The assessment of pre- and post-treatment IgE levels and their ratio may help to improve the management of CSU in patients who require omalizumab treatment.

C-reactive protein is linked to disease activity, impact, and response to treatment in patients with chronic spontaneous urticaria.

BACKGROUND: Elevated levels of C-reactive protein (CRP), a sensitive marker of inflammation, have been consistently reported in chronic spontaneous urticaria (CSU). Here, we retrospectively analyzed data from 1253 CSU patients from 2 centers to answer the following questions: (i) What is the prevalence of elevated levels of CRP in CSU? (ii) Why do CSU patients show elevated levels of CRP? (iii) Are elevated CRP levels relevant? METHODS: Serum levels of CRP were measured by the nephelometric method. We collected information regarding various laboratory tests including ESR, CBC with differential, D-dimer, fibrinogen, C3, C4, IL-6, etc. For most patients, we also collected data on age, gender, duration of CSU, presence of angioedema, activity (UAS at the time of blood sampling and for 7 days), quality of life (CU-Q2oL and/or DLQI), comorbidities and possible causes of CSU, and autologous serum skin test (ASST) response. The efficacy of second-generation antihistamines was evaluated on the day of blood collecting. RESULTS: One-third of CSU patients had elevated levels of CRP. Higher levels of CRP were associated with ASST positivity (P = .009) and arterial hypertension (P = .005), but not with other possible causes or comorbidities of CSU. C-reactive protein correlated with urticaria activity (P < .001), quality of life impairment (P = .026), and inflammatory and coagulation markers (P < .001). C-reactive protein levels were significantly higher in nonresponders to antihistamines as compared to responders (P < .001). CONCLUSION: Elevated levels of CRP are common and relevant in CSU patients. The assessment of CRP levels may help to optimize the management of patients with CSU.

Cholinergic urticaria patients of different age groups have distinct features.

BACKGROUND: Cholinergic urticaria (CholU) is a common skin disease characterized by the development of pinpoint-sized weals and severe itch upon physical exercise. Little is known about the epidemiology of CholU. CholU can occur at any age and has the highest prevalence among young adults. As of now, it is unclear whether patients of different age show differences in the clinical manifestation of CholU, duration of disease, comorbidities or response to treatment. METHODS: Here, we analysed the demographic data and clinical characteristics including disease duration and comorbidities of 200 patients with CholU, 12-76 years of age. RESULTS: We identified two distinct types of CholU, one with early onset (EO, 71%) and one with late onset (LO, 29%). Patients with EO and LO CholU markedly differ in key characteristics: patients with EO, who had a disease onset before the age of 36, showed no gender preponderance and had a significantly higher rate of concomitant atopic dermatitis (16.9% vs 5.2%; P = .028) and higher IgE levels (295.5 vs 267.1 IU/mL; P = .020) as compared to patients with LO, who were mainly female (69%), had a shorter duration of disease (33.3 vs 63.7 months; P = .005), a higher rate of concomitant other forms of urticaria (48.3% vs 33.1%; P = .044) and a higher rate of psychiatric comorbidities (12.1% vs 1.4%; P = .001). CONCLUSION: There are two subtypes of CholU patients with different gender ratios, disease duration and comorbidities. These findings suggest that two distinct underlying pathogenetic pathways are relevant in these two subgroups of patients with CholU.

Skin provocation tests may help to diagnose atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. OBJECTIVE: To test whether the results of skin provocation with cowhage, an established model of histamine-independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD. METHODS: Twenty-two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. RESULTS: Patients with AD, compared with healthy controls, exhibited significantly smaller histamine-induced flares (P < 0.01) and markedly longer itch persistence after provocation with cowhage (P < 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic (ROC) curve 0.78 and 0.80, respectively). The persistence of cowhage-induced itch for at least 30 min and a histamine-induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD. If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. CONCLUSION: The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage-induced itch and diminished histamine-induced flare in nonlesional skin may support diagnosis of AD.

Serum neuron specific enolase - a novel indicator for neuropsychiatric systemic lupus erythematosus?

OBJECTIVE: Neuropsychiatric (NP) lupus, a common manifestation of systemic lupus erythematosus (SLE), is still insufficiently understood, in part, because of the lack of specific biomarkers. Neuron specific enolase (NSE), an important neuronal glycolytic enzyme, shows increased serum levels following acute brain injury, and decreased serum levels in several chronic disorders of the nervous system, including multi infarct dementia, multiple sclerosis and depression. The aim of the study was to evaluate serum NSE levels in SLE patients with and without nervous system involvement, and in healthy controls, and to assess the correlation of NSE serum levels of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) with clinical parameters. METHODS: The study comprised 47 SLE patients and 28 controls. SLE activity was assessed using the Systemic Lupus Activity Measure (SLAM). A neurologist and a psychiatrist examined all patients. NP involvement was diagnosed according to strict NPSLE criteria proposed by Ainiala and coworkers, as modification to American College of Rheumatology (ACR) nomenclature and case definitions. NSE serum levels were determined by use of an immunoassay. RESULTS: Mean NSE serum concentrations in patients with NPSLE were significantly lower than in non-NPSLE patients (6.3 ± 2.6 µg/L vs. 9.7 ± 3.3 µg/L, p < 0.01) and in controls (8.8 ± 3.3 µg/L, p < 0.05). There were significant negative correlations between NSE serum levels and SLE activity (r = -0.42, p < 0.05) and the number of NPSLE manifestations diagnosed (-0.37; p = 0.001). CONCLUSION: Decreased serum concentrations of NSE may reflect chronic neuronal damage with declined metabolism of the nervous tissue in patients with NPSLE.

Impact of psoriasis severity on family income and quality of life.

BACKGROUND: Psoriasis is a common disease and the costs of its therapy, medical care and loss of productivity are a major financial burden for patients and society. The financial status of psoriasis patients and its relationship with disease severity and quality of life (QoL) remains ill characterized. OBJECTIVE: The aim of this study was to assess the economic status of psoriasis patients and to investigate its correlation with disease severity and its impact on QoL. METHODS: A total of 83 (45 male) psoriasis patients, treated at a Polish specialty clinic, were assessed for their financial and employment status. QoL was measured with a generic (WHOQOL-BREF) and a skin disease-related QoL instrument (dermatology life quality index--DLQI). The effects of demographic and clinical variables, including disease severity measured by Psoriasis Area and Severity Index (PASI), on the family income of patients were analyzed by multiple logistic regression. The mediating effect of family income between PASI and QoL was assessed by using the Baron and Kenny's procedure. RESULTS: Patients' family income correlate negatively with psoriasis severity (Spearman's rho = -0.356; P < 0.01). Disease severity in patients with a family income below the social minimum was significantly higher (PASI: 20.5 ± 12.2) than in patients with a higher family income (PASI: 11.7 ± 7.7, P < 0.001). We found that education, disease severity and age predict 50% of the variability in family income (P < 0.001). Disease severity showed the second strongest impact on income after education (P < 0.01). Family income was found to link disease severity to global QoL impairment (P < 0.05). CONCLUSION: Disease severity negatively affects the financial status of psoriasis patients, which in turn, is a mediator of global QoL impairment. Our findings are alarming and call for long-term solutions that equalize employment opportunities for patients with psoriasis.

Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge.

BACKGROUND: The most intriguing function attributed to interleukin-31 (IL-31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL-31 was tested in vivo only in animal models. METHODS: Ten patients with AD and 10 healthy controls were challenged with IL-31 and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h. RESULTS: All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-31- and two of the NaCl-challenged subjects reported immediate itch at the provocation site (short lasting, for 2-6 min). Nine subjects (five patients with AD) reported late itch responses to IL-31 challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-31-induced itch start time, duration and intensity between patients with AD and healthy volunteers. CONCLUSION: IL-31 does not induce immediate itch responses in humans. The late onset of IL-31-induced itch supports the notion that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves.

Interleukin-33 promotes the proliferation of mouse mast cells through ST2/MyD88 and p38 MAPK-dependent and Kit-independent pathways.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new modulator of immune and inflammatory responses. Although IL-33 and its associated receptor ST2 are reportedly expressed in mast cells (MCs), the precise role of IL-33 in modulating MC function has not been determined. In the present studies, we explored IL-33 effects on MCs in vivo and in vitro. IL-33 increased the number of peritoneal and skin MCs in vivo. IL-33 also resulted in increased proliferation of MCs in vitro, as explored by WST assay. Cell cycle analysis further confirmed this result by showing increased G2 cell populations in MCs stimulated with IL-33. We found that IL-33-mediated MC proliferation requires ST2 and MyD88, is independent of Kit, and is mediated through a p38 MAPK-dependent pathway. IL-33 did not induce degranulation and was not cytotoxic for MCs. This novel mechanism for increasing MC proliferation and numbers further defines the role of IL-33 in MC-dependent diseases including allergies and may help to develop novel approaches for the treatment of these disorders.