Autoimmune Inner Ear Disease among Patients with Selective IgA Deficiency.

OBJECTIVES: Autoimmune inner ear disease (AIED) is a distinct clinical entity from sudden sensorineural hearing loss. The purpose of this study was to investigate the clinical characteristics of AIED in patients with selective IgA deficiency (sIgAD). MATERIALS AND METHODS: This retrospective observational study was based on data from the Leumit Healthcare Services database in Israel. We searched all subjects aged ≥12 years who had undergone serum total IgA measurements during 2004-2014 for any reason. The sIgAD patients included all subjects with serum IgA of ≤7 mg/dL (0.07 g/L). A control group was randomly sampled from the full study population (n ≈ 730,000) with a case-control ratio of 10 controls for each case (1:10). RESULTS: Among 347 subjects with sIgAD, we identified 9 patients with concomitant AIED (sIgAD + AIED group). This group was characterized by a higher prevalence of allergic diseases (8 patients; 88.9%) than sIgAD patients without AEID (sIgAD + AIED group; 153 patients; 45.2%; p = 0.014). Both systemic diseases (3 patients; 33.3%) and organ-specific autoimmune diseases (7 patients; 77.8%) were more prevalent in the sIgAD + AIED group (sIgAD + AIED group: 19 patients 5.5%, p = 0.015; sIgAD - AEID group: 76 patients, 21.9%, p < 0.001), with an OR of 8.39 (1.94-36.19; p = 0.004). sIgAD patients with and without AIED were characterized by a higher prevalence of documented episodes of acute otitis media, allergic diseases, and autoimmune diseases than the control group. CONCLUSION: The study exposes a significant association between AIED and sIgAD. We believe that sIgAD has to be excluded in AIED patients.

Immune-mediated conditions affecting the brain, eye and ear (BEE syndromes).

The triad of central nervous system symptoms, visual disturbance and hearing impairment is an oft-encountered clinical scenario. A number of immune-mediated diseases should be considered among the differential diagnoses including: Susac syndrome, Cogan syndrome or Vogt-Koyanagi-Harada disease; demyelinating conditions such as multiple sclerosis or neuromyelitis optica spectrum disorder; systemic diseases such as systemic lupus erythematosus, Sjögren syndrome or Behcet disease and granulomatous diseases such as sarcoidosis. In this article, we coin the term 'BEE syndromes' to draw attention to the various immune-mediated diseases that affect the brain, eye and ear. We present common disease manifestations and identify key clinical and investigation features.

Preliminary Study on Antinuclear Antibodies in Patients With Chronic Dilatory Eustachian Tube Dysfunction.

BACKGROUND AND HYPOTHESIS: There are some known reasons for chronic dilatory Eustachian tube dysfunction (chronic D-ETD, also known as chronic obstructive tube dysfunction), for example infections, hyperplastic adenoids, or tumors. In many cases though, none of these reasons apply. The question arises whether there might be an autoimmune pathogenesis in patients with idiopathic chronic D-ETD. METHODS: The study includes 31 consecutive patients with chronic D-ETD and 92 consecutive blood donors (BD, comparative cohort). The production of antinuclear antibodies (ANA), as an indicator for autoimmune pathologies, was measured in the serum of patients and BD. RESULTS: ANA titers were significantly higher in patients with chronic D-ETD, compared with BD (p = 0.0027). The results weighted clearly toward higher ANA titers in younger patients. A comparison of ANA titers in patients and BD aged less than 40 years showed a significant difference (p = 0.0062), whereas it was not significant between patients and BD aged ≥ 40 years (p = 0.19). CONCLUSION: The significant results of elevated ANA titers in chronic D-ETD make an autoimmune pathogenesis highly probable, at least in some of the patients concerned. Further research with higher numbers of patients is needed to confirm the hypothesis of an autoimmune chronic D-ETD. A better understanding of etiology and pathogenesis of chronic D-ETD might open up new and perhaps even causal therapeutic strategies.

Ear, nose and throat involvement in granulomatosis with polyangiitis: how it presents and how it determines disease severity and long-term outcomes.

Ear, nose and throat (ENT) manifestations in granulomatosis with polyangiitis (GPA) represent the most frequent symptoms at disease onset. The aim of the study was to analyse ENT involvement at diagnosis, as well as how it could influence relapse rate, mortality and disease severity. A retrospective non-controlled cohort study was performed including all consecutive diagnosed GPA from 1996 to 2016 in two rheumatology centres of Northern Italy, focusing particularly on ENT presenting signs and symptoms at baseline. Eighty-nine patients (48.3% females) with new onset GPA were evaluated. They were mostly Caucasian (97.7%), middle aged (mean 54.5 years) and more frequently anti-neutrophil cytoplasmic antibodies (ANCA) positive (78.6%) with PR3 specificity (81.4%). At diagnosis, ENT involvement was reported in 71.9% patients, second only to systemic symptoms. These patients were significantly younger at disease onset (0.013), with less frequent renal involvement (0.014) irrespectively to ANCA status, but with significantly higher Vasculitis Damage Index (VDI) (0.001). The most frequent ENT manifestation was sinonasal involvement (58.4%, 73% of which with nasal inflammation/chronic sinusitis and 48% with nasal crusting), while otologic involvement (mainly otitis media/otomastoiditis) was observed in 34.8%. ENT-GPA patients presented a higher survival rate at 5 years (98.1 vs 77.7%, 0.049), and ENT involvement resulted to be an independent predictor of better outcome (OR 0.37, 95% CI 0.2-0.8, 0.019). Our data confirms that ENT involvement is not only one of the key clinical features of GPA, but also could point out a milder GPA subset with lower renal involvement and lower mortality rate, irrespectively to ANCA status.

Adoptive Cellular Gene Therapy for the Treatment of Experimental Autoimmune Polychondritis Ear Disease.

In the past, the clinical therapy for autoimmune diseases, such as autoimmune polychondritis ear disease, was mostly limited to nonspecific immunosuppressive agents, which could lead to variable responses. Currently, gene therapy aims at achieving higher specificity and less adverse effects. This concept utilizes the adoptive transfer of autologous T cells that have been retrovirally transduced ex vivo to express and deliver immunoregulatory gene products to sites of autoimmune inflammation. In the animal model of collagen-induced autoimmune polychondritis ear disease (CIAPED), the adoptive transfer of IL-12p40-expressing collagen type II (CII)-specific CD4+ T-cell hybridomas resulted in a significantly lower disease incidence and severity compared with untreated or vector-only-treated animals. In vivo cell detection using bioluminescent labels showed that transferred CII-reactive T-cell hybridomas accumulated in the inflamed earlobes of the mice with CIAPED. In vitro analysis demonstrated that IL-12p40-transduced T cells did not affect antigen-specific T-cell activation or systemic anti-CII Ab responses. However, IL-12p40-transduced T cells suppressed IFN-γ and augmented IL-4 production, indicating their potential to act therapeutically by interrupting Th1-mediated inflammatory responses via augmenting Th2 responses. These results indicate that the local delivery of IL-12p40 by T cells could inhibit CIAPED by suppressing autoimmune responses at the site of inflammation.

Vasculopathy related to cocaine adulterated with levamisole: A review of the literature.

BACKGROUND: Recently, there have been numerous case reports and series describing patients presenting with cutaneous vasculopathy that has been linked to the levamisole frequently found in cocaine. OBJECTIVE: The purpose of this study was to review all published case reports and series of patients reported with cutaneous vasculopathic findings of lemavisole induced vasculopathy (LIV) associated with cocaine use. METHODS: A review of PubMed was performed searching the keywords: levamisole, cocaine, in combination with vasculitis, and vasculopathy. Twenty-two case reports and series were available with sufficient data on reported patients to be included. Four patients from the authors' clinical experience are included as well. RESULTS: A number of common clinical and pathological findings are reviewed, including lower extremity (46/55 patients, 84%) and ear involvement (40/55 patients, 73%), and positive anti-neutrophil cytoplasmic antibodies (ANCA) findings (p-ANCA 42/48 patients, 88%; anti human neutrophil elastase 11/11 patients, 100%). Similar numbers of patients were treated with systemic corticosteroids as were treated conservatively; there was comparable improvement on follow up. CONCLUSIONS: There are a number of clinical and laboratory findings that are commonly found in patients with LIV. There is currently insufficient data to recommend treatment with systemic corticosteroids in patients with this condition.

Cross-reactivity among some metals in a murine metal allergy model.

BACKGROUND: Information concerning cross-reactivity among metal allergens is scarce. We previously devised a murine metal allergy model using lipopolysaccharide (LPS) as an adjuvant. LPS reduces the minimum allergy-inducing concentration (MAIC) of metals at both the sensitization and the elicitation steps. OBJECTIVES: Here, we examined allergic cross-reactivity among some metals in this murine model, and compared the effects of ultrapure (99·99% or more) and low purity (93-99%) metal salts. METHODS: A mixture of a metal salt and Escherichia coli LPS was injected intraperitoneally into BALB/c mice (0·25 mL per mouse). Ten days later, metal salts (with or without LPS) were challenged to ear pinnas (20 µL per ear), and ear swelling was measured. RESULTS: Among the ultrapure metals tested (Ni, Pd, Co, Cr, Cu and Au), only Ni and Pd cross-reacted. In this cross-reaction, their MAICs were at the same level. Combined challenge with Ni and Pd at sub-MAICs (but not at higher concentrations) produced an additive effect. Surprisingly, mice sensitized with low purity Ni reacted to all the tested low purity metals (Ni, Pd, Co and Cr), and the low purity metals were shown to contain contaminant metals. CONCLUSIONS: In our model: (i) Ni and Pd (members of the same group in the periodic table of elements) cross-react with each other, (ii) this cross-reaction may depend on true and false antigens forming metal-protein complexes with similar spatial geometries, (iii) Co, Cr, Cu and Au do not cross-react with each other, (iv) in low purity materials, trace contaminant metals may be sufficient to evoke allergy, and thus (v) high purity metal salts should be considered for use in clinical patch testing.

Recovery of Mycoplasma agalactiae from the ears of goats experimentally infected by the intramammary route.

The role of inapparent carriers of Mycoplasma agalactiae and the strategies used to colonise the external ear canal in goats remain unclear. This study examined the ability of M. agalactiae to colonise the ears of goats infected experimentally by the intramammary route. The right mammary glands of 15 lactating goats were inoculated with 10(10) colony forming units (cfu) of M. agalactiae. The goats were randomly assigned to three groups of five animals each and sampled at slaughter at 5, 15 or 45 days post-infection (dpi). A further four goats served as uninfected controls. Right and left ear swabs were collected for detection of M. agalactiae by culture before and after sacrifice. M. agalactiae was detected in 19/20 (95%) ear swabs from goats sampled at 15 and 45dpi, whereas all ear swabs collected before inoculation, ear swabs collected from the group sampled at 5dpi and ear swabs from control goats at the time of sacrifice were negative for M. agalactiae. Blood samples collected at 6, 12, 24, 48 and 72h post-infection for detection of M. agalactiae by culture were also negative. There were differences in the antigenic profiles of isolates recovered from the ears compared to the 7MAG strain used to inoculate the animals and most isolates from the mammary gland, milk and supramammary lymph nodes.

Novel CC chemokine receptor 4 antagonist RS-1154 inhibits ovalbumin-induced ear swelling in mice.

CC chemokine ligand 17 (CCL17/thymus and activation-regulated chemokine: TARC) and CCL22 (macrophage-derived chemokine: MDC) selectively bind to CC chemokine receptor 4 (CCR4). The CCR4 system is considered to be responsible for the pathology of allergic diseases such as atopic dermatitis. To find and develop potential medicines against allergic diseases, we screened an in-house library to search for compounds having a profile as a CCR4 antagonist. From among the screening hits, we focused on 3-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}quinazoline-2,4(1H,3H)-dione (named RS-1154), which had been newly synthesized in our laboratory. This compound inhibited the binding of [(125)I]CCL17 to human CCR4-expressing CHO cells with an IC(50) value of 27.7 nM and moreover inhibited CCL17-induced migration of DO11.10 mice-derived T helper 2 cells with an IC(50) value of 1.5 nM in vitro. We then examined the effect of RS-1154 in an ovalbumin-induced ear swelling assay. The ear thickness was decreased by intravenous administration of anti-CCL17 or anti-CCL22 antibodies, suggesting that the CCR4 system is involved in the ear swelling. Though partially, the oral administration of RS-1154 also significantly ameliorated the ear swelling at the doses of 30 and 100 mg/kg. Furthermore, the serum level of interleukin-4 decreased after the administration of RS-1154. In this study, we succeeded in obtaining a newly-synthesized compound, RS-1154, which has a potential to inhibit the chemotaxis of T helper 2 cells in vitro and to ameliorate ovalbumin-induced ear swelling in vivo. These results raise the possibility that RS-1154 or one of derivatives might become a therapeutic agent for atopic dermatitis patients.

Enhanced Leishmania braziliensis infection following pre-exposure to sandfly saliva.

BACKGROUND: Sand fly saliva has an array of pharmacological and immunomodulatory components, and immunity to saliva protects against Leishmania infection. In the present study, we have studied the immune response against Lutzomyia intermedia saliva, the main vector of Leishmania braziliensis in Brazil, and the effects of saliva pre-exposure on L. braziliensis infection employing an intradermal experimental model. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice immunized with L. intermedia salivary gland sonicate (SGS) developed a saliva-specific antibody response and a cellular immune response with presence of both IFN-gamma and IL-4. The inflammatory infiltrate observed in SGS-immunized mice was comprised of numerous polymorphonuclear and few mononuclear cells. Mice challenged with live L. braziliensis in the presence of saliva were not protected although lesion development was delayed. The inoculation site and draining lymph node showed continuous parasite replication and low IFN-gamma to IL-4 ratio, indicating that pre-exposure to L. intermedia saliva leads to modulation of the immune response. Furthermore, in an endemic area of cutaneous leishmaniasis, patients with active lesions displayed higher levels of anti-L. intermedia saliva antibodies when compared to individuals with a positive skin test result for Leishmania. CONCLUSION: These results show that pre-exposure to sand fly saliva plays an important role in the outcome of cutaneous leishmaniasis, in both mice and humans. They emphasize possible hurdles in the development of vaccines based on sand fly saliva and the need to identify and select the individual salivary candidates instead of using whole salivary mixture that may favor a non-protective response.

Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma?

The authors report 4 cases of cutaneous lymphoproliferation unusual by their histology and their clinical presentation. Each presented with a history of a slow growing nodule on the ear. Despite the indolent clinical evolution, the histology suggested a high-grade lymphoma. All lesions consisted of a dense, diffuse proliferation of monomorphous medium-sized T cells throughout the dermis and subcutis. There was no epidermotropism and a grenz zone was clearly present in each case. The tumor cells displayed irregular blastlike nuclei, with small nucleoli and clear chromatin and had a CD3+, CD8+, CD4+, TIA1+, granzyme B(-)immunophenotype with a loss of other T-cell antigens. The 3 cases with available material for polymerase chain reaction studies displayed a monoclonal T-cell rearrangement of the T-cell receptor-gamma chain. These cases do not correspond to a recognized cutaneous T-cell lymphoma as described in the recent WHO/EORTC classification. The apparent striking propensity for the ear suggests that they might represent a specific entity. Further cases are needed to confirm this hypothesis. It is important for such indolent lesions to be known to avoid over treatment.

[Immunomediated inner ear disease: diagnostic validation by means of a systematic analysis of the scientific literature]. / Enfermedad inmunomediada del oído interno: validación diagnóstica mediante un análisis sistemático de la literatura científica.

INTRODUCTION: Numerous tests have been developed to help in the diagnosis of the immunomediated inner ear disease (IMIED), although their usefulness is still the subject of some dispute. MATERIAL AND METHOD: Studies of cohorts of patients with suspected IMIED have been reviewed. A number of different serological tests were carried out and their response to immunosuppressive therapy was noted. RESULTS: After reviewing 790 articles, the studies analyzed present great heterogeneity in the clinical characteristics of the patients recruited (sudden deafness, fluctuating and rapidly progressive hearing loss, Menière's disease), the inclusion and exclusion criteria, the delay between the diagnosis and the start of medical treatment or the response criteria. CONCLUSIONS: The diagnosis of IMIED is based on clinical presentation and response to corticosteroids. At present no test represents the gold standard in the diagnosis of IMIED. Serologic tests can support the diagnosis, but a methodologically more rigorous approach is needed to identify the true clinical importance of these tests for daily practice.

Antibodies to myelin protein zero (P0) protein as markers of auto-immune inner ear diseases.

BACKGROUND/AIMS: The inner ear can be the target of autoimmune disorders. Recognition of autoimmune inner ear disease is important, as it is one of the very few forms of sensorineural hearing loss (HL) that can be successfully treated by medical therapy. The aim of this study was to evaluate whether the detection of antibodies to myelin protein P0 (MPZ) could be a diagnostic test for inner ear disease of autoimmune cause. METHODS: This multicentric prospective study included 129 patients: patients with progressive sensorineural HL or with Menière's disease, together with their control group corresponding to patients with similar symptoms, but of presumably known origin. Detection of antibodies to myelin P0 protein was performed by using western blots. NORMAL: The prevalence of antibodies to myelin P0 protein in patients with rapidly progressive HL was not statistically different from that of the control group corresponding to genetic HL patients (30 versus 28%). In patients with Menière's disease, the prevalence was lower than that of the control group corresponding to patients with benign paroxysmal positional vertigo (5.4 versus 18.7%). No patient with auto-immune disease had antibodies to myelin P0 protein. CONCLUSIONS: The sole presence of antibodies to myelin P0 may not be used as a marker of inner ear disease of autoimmune origin.

Otosyphilis mimics immune disorders of the inner ear.

Syphilis is a well established cause of hearing loss. Sensorineural hearing loss may develop in the congenital or acquired form. The clinical course of the early acquired and late congenital forms are similar: sudden or rapidly progressive bilateral sensorineural hearing loss with mild vestibular symptoms. Cochleovestibular involvement in early acquired syphilis has been related to a basilar meningitis with lymphocytic infiltration of the labyrinth and VIIIth nerve. However, neurosyphilis and inner ear syphilis are not the same disease. Prompt diagnosis and treatment with corticosteroids and penicillin are mandatory to reduce the immune response and fibrosis of the labyrinth and the endolymphatic sac. Unfortunately, early acquired syphilis is frequently overlooked in the differential diagnosis of other forms of sensorineural hearing loss, particularly autoimmune inner ear disease. Given the increasing number of luetic infection cases, especially in immunocompromised patients, this condition should be considered in any sexually active patients affected by sudden hearing loss. Cases of inner ear syphilis are presented. Immunopathology of luetic inner ear infection is discussed and compared with immune disorders of the inner ear.

Endolymphatic hydrops as a cause of audio-vestibular manifestations in relapsing polychondritis.

Relapsing polychondritis (RP) is characterized by inflammation and subsequent degeneration of cartilage. We report a 61-year-old woman who had RP with audio-vestibular manifestations. She was also diagnosed as having a myelofibrosis with myeloid metaplasia (MMM). Bilateral endolymphatic hydrops (EH) was confirmed by dominant -SP/AP of the electrocochleogram (ECochG). When thalidomide and prednisolone were prescribed for the treatment of MMM, symptoms of RP -- including the inner ear dysfunction -- were ameliorated. Isosorbide, one of the osmotic diuretics commonly used for the treatment of Meniere's disease (MD) in Japan, was also effective in keeping her free from inner ear dysfunction. This is the first report to confirm the existence of EH in a patient with RP with audio-vestibular manifestations. We suppose that an immunological imbalance due to MMM, in conjunction with a specific immunogenetic background, may have played a role in the pathogenesis of RP and the formation of EH in this patient.

Characteristics of Chinese patients with Wegener's granulomatosis with anti-myeloperoxidase autoantibodies.

BACKGROUND: Cytoplasmic antineutrophil cytoplasmic autoantibodies (cANCA)/proteinase-3(PR3)-ANCA was considered the serologic diagnostic marker for Wegener's granulomatosis (WG). However, Chinese patients with MPO-ANCA positive WG were frequently diagnosed. We now analyze the characteristics of patients with MPO-ANCA positive WG and investigate the difference between patients with MPO-ANCA and PR3-ANCA. METHODS: Patients with WG were selected according to both Chapel Hill Consensus Conference definition and American College of Rheumatology (ACR) classification criteria in 500 Chinese patients with ANCA-associated systemic vasculitides. The clinical manifestions were compared between patients with MPO-ANCA and with PR3-ANCA. RESULTS: Eight-nine patients fulfilled the diagnostic criteria of WG: 54/89(60.7%) were MPO-ANCA positive, 34/89(38.2%) were PR3-ANCA positive. Patients with MPO-ANCA were predominantly female compared with patients with PR3-ANCA. Patients with MPO-ANCA also had multisystem involvement. However, the prevalences of arthagia, skin rash, ophthalmic and ear involvement were significantly lower in patients with MPO-ANCA than those in patients with PR3-ANCA (46.3% vs. 70.6%, P < 0.05; 20.4% vs. 44.1%, P < 0.05; 27.8% vs. 58.8%, P < 0.01; 40.7% vs. 67.6%, P < 0.05, respectively). The prevalence of elevated initial serum creatinine was significantly higher in patients with MPO-ANCA than that in patients with PR3-ANCA (81.5% vs. 61.8%, chi(2) = 4.20, P < 0.05). CONCLUSION: Patients with MPO-ANCA positive WG were not rare in Chinese.

Sordera súbita bilateral simultánea. Presentación de un caso / Simultaneous bilateral sudden deafness. Report of a clinical case

La sordera súbita bilateral es poco frecuente y se caracteriza por una pérdida auditiva neurosensorial brusca en ambos oídos de al menos 30 dB en 3 frecuencias consecutivas. Presentamos el caso de una mujer de 57 años con este diagnóstico que presentaba cofosis derecha e hipoacusia profunda de oído izquierdo sin patología vestibular asociada. Fue ingresada y sometida al protocolo de tratamiento médico establecido por nuestro Servicio (4 días IV y 10 más vía oral) con mejoría de su audición 25-30 dB de media. Ante una hipoacusia brusca neurosensorial bilateral rápidamente progresiva se debe pensar en la enfermedad del oído interno inmunomediada (EOIIM)

Bilateral sudden deafness is uncommon and characterized by an acute sensorineural hearing loss in both ears of 30 dB or more in 3 consecutive frequencies. We report the case of a 57 years old female with this diagnosis who presented a right anacusia and a severe audiometric loss on left ear without vestibular pathology associated. She was admitted and treated by the protocol of medical therapy that we have performed in our E.N.T. Department (4 days EV and then 10 ones oral medication) with improvement in her audition 25-30 dB average. If sudden bilateral sensorineural deafnes is founded, we must consider an immune-mediated inner ear disease (IMIED)

Keratinocyte-derived, CD80-mediated costimulation is associated with hapten-specific IgE production during contact hypersensitivity to TH1 haptens.

Background B7-1 transgenic mice exhibit exaggerated and persistent contact hypersensitivity responses compared with normal mice. Objective Because B7-1 and B7-2 deliver different costimulatory signals to T cells during antigen presentation, the purpose of this study was to compare B7-1 and B7-2 on keratinocytes and to compare their effects on contact hypersensitivity. Methods Contact hypersensitivity was studied in transgenic mice whose keratinocytes constitutively expressed B7-1, B7-2, or no costimulatory molecules (nontransgenic mice). Results B7-1 transgenic mice, and to a lesser extent B7-2 transgenic mice, developed exaggerated ear swelling responses after sensitization and challenge with haptens such as trinitrochlorobenzene or dinitrofluorobenzene. Ear swelling responses in B7-1 transgenic mice were characterized by the presence of markedly elevated inflammatory cytokine transcripts (IL-6, TNF-alpha, and lymphotoxin beta) as well as IL-10 compared with either B7-2 or nontransgenic mice. Hapten-specific IgE was detected by ELISA in B7-1 transgenic mice but not B7-2 transgenic or nontransgenic mice. Only B7-1 transgenic mice exhibited significant immediate type ear swelling responses to the hapten trinitrochlorobenzene. In addition, their sera can passively transfer cutaneous anaphylaxis to naive C57BL/6 mice, indicating that the hapten-specific IgE was relevant to the immediate ear swelling responses. Conclusion These data suggest that keratinocyte-derived costimulation mediated by B7-1 but not B7-2 results in the emergence of T H 2-lymphocyte immune responses to T H 1 haptens. Because human keratinocytes have been noted to express B7-1-like molecules in certain inflammatory skin diseases, this model may be important in understanding the pathophysiology of T H 2-lymphocyte-mediated skin diseases such as atopic dermatitis.