Intrinsic Atopic Dermatitis Patients Research Articles

Intrinsic Atopic Dermatitis: Titration of Precipitins in the Screening of Food Allergens for Prescription of Elimination Diets and Desensitization Strategies

Background: The diagnosis of non-IgE mediated food allergies may be a complex puzzle when there is no start point to establish an elimination diet to allow a clear clinical field to initiate diagnostic Oral Food Challenges tests.
 Objective: To evaluate the opportunity of the tube titration of precipitins to select food allergens to proceed with elimination diets to assist the diagnosis and management of adult patients with Food Allergy manifested as Intrinsic Atopic Dermatitis (IAD).
 Methods: The tube titration of specific precipitins against anamnesis-chosen food allergens were performed in 64 IAD patients and their titers were associated with an Improvement Verbal Scale Rate (IVSR) of the patient’s perception of the benefits of the Precipitins-based Elimination Diet (PED) performed with these specific food allergens, as well correlated with their positive or negative perception of the impairment of symptoms after the reintroduction of the Symptom-Related Food Allergen (SRFA).
 Results: In most cases, the PED contributed to a significant clinical improvement that allowed the patients to evaluate the individual effect of the reintroduction of each food allergen on their diets. There was a significant positive correlation coefficient between the titers of the food-specific titration of precipitins and the percentage of positive SRFA (Pearson r = 0.91; p-value = 0.0004). 
 Conclusion: The semiquantitative titration of specific precipitins against food allergens is a promising triage test to select food allergens to proceed with elimination diets to support the diagnosis and management of non-IgE mediated Food Allergy in patients with Intrinsic Atopic Dermatitis.

Immunoinflammatory Biomarkers in Serum Are Associated with Disease Severity in Atopic Dermatitis

Background: A growing body of evidence links various biomarkers to atopic dermatitis (AD). Still, little is known about the association of specific biomarkers to disease characteristics and severity in AD. Objective: To explore the relationship between various immunological markers in the serum and disease severity in a hospital cohort of AD patients. Methods: Outpatients with AD referred to the Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark, were divided into groups based on disease severity (SCORAD). Serum levels of a preselected panel of immunoinflammatory biomarkers were tested for association with disease characteristics. Two machine learning models were developed to predict SCORAD from the measured biomarkers. Results: A total of 160 patients with AD were included; 53 (33.1%) with mild, 73 (45.6%) with moderate, and 34 (21.3%) with severe disease. Mean age was 29.2 years (range 6–70 years) and 84 (52.5%) were females. Numerous biomarkers showed a statistically significant correlation with SCORAD, with the strongest correlations seen for CCL17/thymus and activation-regulated chemokine (chemokine ligand-17/TARC) and CCL27/cutaneous T cell-attracting-chemokine (CTACK; Spearman R of 0.50 and 0.43, respectively, p < 0.001). Extrinsic AD patients were more likely to have higher mean SCORAD (p < 0.001), CCL17 (p < 0.001), CCL26/eotaxin-3 (p < 0.001), and eosinophil count (p < 0.001) than intrinsic AD patients. Predictive models for SCORAD identified CCL17, CCL27, serum total IgE, IL-33, and IL-5 as the most important predictors for SCORAD, but with weaker associations than single cytokines. Conclusions: Specific immunoinflammatory biomarkers in the serum, mainly of the Th2 pathway, are correlated with disease severity in patients with AD. Predictive models identified biomarkers associated with disease severity but this finding warrants further investigation.

Immunological Properties of Atopic Dermatitis-Associated Alopecia Areata.

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.

Food-Related Contact Dermatitis, Contact Urticaria, and Atopy Patch Test with Food

A wide variety of foods may cause or aggravate skin diseases such as contact dermatitis, contact urticaria, or atopic dermatitis (AD), both in occupational and private settings. The mechanism of action underlying allergic disease to food, food additives, and spices may be immunologic and non-immunologic. The classification and understanding of these reactions is a complex field, and knowledge of the possible reaction patterns and appropriate diagnostic test methods is essential. In addition, certain foods may cause worsening of atopic dermatitis lesions in children. The atopy patch test (APT) is a well-established, clinically useful tool for assessing delayed type reactions to protein allergens in patients and may be useful to detect protein allergens relevant for certain skin diseases. The APT may even detect sensitization against allergens in intrinsic atopic dermatitis patients, who show negative skin prick test and negative in vitro IgE test results against these allergens. Native foods, SPT solutions on filter paper, and purified allergens in petrolatum have been used for APT. The European Task Force on Atopic Dermatitis (ETFAD) has worked on standardizing this test in the context of AD patients, who are allergic to aeroallergens and food. This recommended, standardized technique involves test application at the upper back of children and adults; use of large, 12-mm Finn chambers; avoidance of any pre-treatment such as tape stripping or delipidation; standardized amounts of purified allergens in petrolatum; and use of the standardized ETFAD reading key. The APT may not be the best working or best standardized of all possible skin tests, but it is the best test that we currently have available in this niche.

Serum Leptin Level among School Children with Atopic Dermatitis

Background: Atopic dermatitis (AD) is a chronic inflammatory skin condition. The pathogenesis of AD is still not fully understood. The association between obesity and AD suggests a potential role for adipocytes hormones, mainly leptin, which had variable immunological functions. Objective: The aim of the present study was to assess serum leptin concentrations in children with AD and to evaluate the relationship between serum leptin levels and various demographic and clinical parameters. Material and Methods: A case control study included 90 school age children (54 cases and 36 controls) conducted at Al-Azhar University Hospital (New Damietta), from January 2016 to April 2017. The diagnosis of AD was based on ISAAC questionnaire. Enrolled children completed scoring of severity of AD (SCORAD), blood tests for total IgE, eosinophil counts. Serum leptin was measured by ELIZA. Results: There was no significant difference between cases and controls as regard age, sex and BMI. Serum leptin was significantly (P=0.015) higher among patients than healthy control. This difference was apparent between both boys (P=0.043) and girls (P=0.026). In addition, serum leptin was significantly higher among atopic girls (P=0.017) than boys. Regarding type of AD, there was no significant difference between patients with intrinsic AD and patients with extrinsic AD considering variable clinical parameters. Serum leptin was higher among intrinsic AD patients but it was not significant (P=0.062). Correlation analysis revealed significant negative correlation between leptin and total IgE (P=0.004). Also, non-significant negative correlation between serum leptin level and SCORAD value (P=0.062). Conclusion: There was significant association between serum leptin levels and atopic dermatitis, which was apparent among both atopic boys and girls. However, serum leptin was significantly higher among atopic girls than boys. Thus, leptin might play a role in the pathogenesis of AD. The tendency of leptin to increase among girls and with intrinsic AD suggests complex pathological mechanisms.

Extrinsic and intrinsic types of atopic dermatitis

Atopic dermatitis (AD) can be categorized into the extrinsic and intrinsic types. Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens, whereas intrinsic or non-allergic AD exhibits normal total IgE values and the absence of specific IgE. While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20% with female predominance. The clinical features of intrinsic AD include relative late onset, milder severity, and Dennie-Morgan folds, but no ichthyosis vulgris or palmar hyperlinearity. The skin barrier is perturbed in the extrinsic, but not intrinsic type. Filaggrin gene mutations are not a feature of intrinsic AD. The intrinsic type is immunologically characterized by the lower expression of interleukin (IL) -4, IL-5, and IL-13, and the higher expression of interferon-gamma. It is suggested that intrinsic AD patients are not sensitized with protein allergens, which induce Th2 responses, but with other antigens, and metals might be one of the candidates of such antigens.

Increased expression of CC chemokine ligand 18 in extrinsic atopic dermatitis patients

Background: Although most patients with atopic dermatitis (AD) show high total and allergen‐specific serum immunoglobulin E (IgE) levels, a small subgroup of AD patients have normal total IgE levels and negative serum allergen‐specific IgE. This subgroup has been termed ‘intrinsic’ AD (IAD) as a counterpart to ‘extrinsic’ AD (EAD). However, the difference of chemokines between IAD and EAD has not yet been evaluated.Objective: We investigated the expression of CC chemokine ligand (CCL) 17, CCL22, and CCL18 in patients with IAD and EAD, which are known to be highly expressed in AD patients.Methods: We assessed the protein levels of these chemokines in peripheral blood mononuclear cells (PBMCs), sera and lesional skins. We also evaluated CCL18 mRNA levels in monocytes, Langerhans cell (LC)‐like dendritic cells (DCs) and inflammatory dendritic epidermal cell (IDEC)‐like DCs from both types of AD patients.Results: There were no significant differences in CCL17 and CCL22 expression in PBMCs, sera and lesional skins of patients with IAD and EAD. CCL18 expression did not differ in PBMCs, sera and LC‐like DCs from the two subgroups, but strong CCL18 expression was observed in lesional skins and IDEC‐like DCs in patients with EAD. Lastly, serum CCL18 levels significantly decreased after immunotherapy.Conclusion: This study suggests that the chemokine micromilieu, especially the level of CCL18, is different between EAD and IAD patients. High FcεRI surface‐expressing DCs, such as IDEC, were the major source of CCL18, and produced a prominent CCL18 microenvironment in EAD patients compared with IAD patients.

Mechanism of HBD-3 deficiency in atopic dermatitis

Extrinsic atopic dermatitis (EAD) and intrinsic atopic dermatitis (IAD) patients suffer from recurrent bacterial and viral infections. In this study, we demonstrate significantly decreased expression of human beta defensin (HBD)-3, a potent antimicrobial peptide (AMP), in lesional skin of both IAD ( p < 0.01) and EAD patients ( p < 0.01), as compared to psoriasis patients. Using primary keratinocytes from EAD and IAD patients, we determined that the deficiency in HBD-3 expression is an acquired rather than a constitutive defect. Furthermore, we demonstrate the down-regulatory effect of IL-4, IL-10, and IL-13 – which are over-expressed in the skin of AD patients – on HBD-3 expression in keratinocytes. Additionally, treatment of EAD skin explants with antibodies against IL-4, IL-10, and IL-13 augmented the expression of HBD-3. These studies suggest that neutralizing the Th2 cytokine milieu in AD skin may augment the innate immune response against bacterial and viral pathogens.

IgE‐independent atopic dermatitis is associated with a β‐2 adrenergic receptor gene polymorphism

IgE levels are not elevated in about 20% of patients with atopic dermatitis (AD). In this intrinsic AD (IAD), allergic mechanisms are not very important and pathogeny could be mainly neurogenic. β2‐adrenergic receptors are localized on cells involved in AD: Langerhans' cells, keratinocytes and lymphocytes. We wondered whether IAD could be associated with gene polymorphisms 16 and 27 of this receptor. We studied 98 healthy subjects and 83 subjects suffering from DA (UKWP criteria). IgE levels were normal in 12 of them and elevated in 71 (EAD). After DNA extraction, the genotyping was done by PCR and Direct Sequencing of candidate gene. Statistical analysis was performed with EPI‐INFO 6.04 for χ2 test. We found a significant association of Gln27Glu polymorphism with IAD (P = 0.00071 and χ2 = 14.51). There was no difference between healthy subjects and EAD patients. Adrenergic receptor agonists are known to attenuate the proliferative response of human lymphocytes after activation, through the inhibition of interleukin‐2 release. It is known that catecholamines inhibit the antigen‐presenting capability of epidermal Langerhans' cells. Long‐term agonist‐promoted downregulation of receptor number is absent when glu is at position 27. We suggest that the suppression of inhibiting effects of catecholamines could be involved in IAD pathogeny. Dichotomic nature of AD (EAD and IAD) is also associated with polymorphisms (SNP) of the interleukin‐4/interleukin‐13 receptor gene and the differences of cutaneous variables (transepidermal water loss, capacitance and pH). Altogether, these findings indicate that IAD patients exhibit phenotypic and also genotypic features which differ from those patients with EAD. Otherwise, the presence of this polymorphism could provide an explication of rarity of hypertension with AD, because Glu27Gln has been identified as a susceptibility polymorphism for HTA.

The Interleukin-13 Production by Peripheral Blood T Cells from Atopic Dermatitis Patients Does Not Require CD2 Costimulation

Background: Although allergic mechanisms appear to be important, the pathogenesis of both extrinsic and intrinsic forms of atopic dermatitis (AD) is unknown. Methods: We compared the cytokine production of peripheral blood mononuclear cells of extrinsic AD (EAD) and intrinsic AD (IAD) patients and normal control individuals after stimulation with anti-CD3 and/or anti-CD28 monoclonal antibodies (mAbs) in the presence or absence of anti-CD2-blocking mAb. The cytokine production was measured by immunoassays in supernatants of 24-hour cultures. Results: EAD patients showed a decreased capacity to synthesize interferon gamma and granulocyte-macrophage colony-stimulating factor upon anti-CD3 mAb stimulation as compared with IAD patients. Both EAD and IAD patients demonstrated an increased production of interleukin (IL)-5 and IL-13. As expected, interferon gamma, granulocyte-macrophage colony-stimulating factor, and IL-5 levels were reduced in the presence of anti-CD2-blocking mAbs. CD28 costimulation restored the release in cultures with anti-CD2 mAbs added, suggesting that CD2 and CD28 have redundant functions in T cell activation and subsequent cytokine production. Strikingly, the IL-13 production was not blocked by anti-CD2 mAbs and also not increased by agonistic anti-CD28 mAb, in particular within the EAD patient group. Conclusion: The signalling pathway initiated by the T cell receptor complex leading to increased IL-13 production in AD patients appears to be highly sensitive and is largely independent on CD2 costimulatory signals.

Peripheral blood mononuclear cells from extrinsic and intrinsic atopic dermatitis patients demonstrate increased capacity of generating interleukin-13 but differ in their potential of synthesising interforon-γ

Peripheral blood mononuclear cells from extrinsic and intrinsic atopic dermatitis patients demonstrate increased capacity of generating interleukin-13 but differ in their potential of synthesising interforon-γ