Nikolaus Ballenberger

Atopic dermatitis, STAT3‐ and DOCK8‐hyper‐IgE syndromes differ in IgE‐based sensitization pattern

BACKGROUND Increased serum IgE levels are characteristic but not specific for allergic diseases. Particularly, severe atopic dermatitis (AD) overlaps with hyper-IgE syndromes (HIES) regarding eczema, eosinophilia, and increased serum IgE levels. HIES are primary immunodeficiencies due to monogenetic defects such as in the genes DOCK8 and STAT3. As it is not known to date why allergic manifestations are not present in all HIES entities, we assessed the specificity of serum IgE of AD and HIES patients in the context of clinical and immunological findings. METHODS Clinical data, skin prick tests, specific IgE to aero- and food allergens, and T helper (Th) subpopulations were compared in AD and molecularly defined HIES patients. RESULTS Total serum IgE levels were similarly increased in STAT3-HIES, DOCK8-HIES, and AD patients. The ratio of aeroallergen-specific IgE to total IgE was highest in AD, whereas DOCK8-HIES patients showed the highest specific serum IgE against food allergens. Overall, clinical allergy and skin prick test results complied with the specific IgE results. Th2-cell numbers were significantly increased in DOCK8-HIES and AD patients compared to STAT3-HIES patients and controls. AD patients showed significantly higher nTreg-cell counts compared to STAT3-HIES and control individuals. High Th17-cell counts were associated with asthma. Specific IgE values, skin prick test, and T-cell subsets of STAT3-HIES patients were comparable with those of healthy individuals except decreased Th17-cell counts. CONCLUSION Hyper-IgE syndromes and atopic dermatitis patients showed different sensitization pattern of serum IgE corresponding to the allergic disease manifestations and Th-cell subset data, suggesting a key role of DOCK8 in the development of food allergy.

STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years.

The transcription factor STAT6 is crucial for activation of the interleukin (IL)‐4/IL‐13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown.

Novel Statistical Approaches for Non-Normal Censored Immunological Data: Analysis of Cytokine and Gene Expression Data

Background For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. Objective We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. Methods For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. Results If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. Conclusion Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets.

Influence of Different Upper Cervical Positions on Electromyography Activity of the Masticatory Muscles

OBJECTIVE The aim of this study was to determine the activity of the masseter and anterior temporalis muscles in relation to different positions of the upper cervical spine during maximal voluntary isometric clenching by surface electromyography (EMG). METHODS This was a cross-sectional study with a repeated-measures design performed using 25 asymptomatic subjects (13 female and 12 male; mean age, 31 years; SD, 8.51). The EMG activity of the masseter and anterior temporalis muscles was recorded bilaterally during maximal clenching at neutral position and during extension, flexion, ipsilateral lateral flexion, contralateral lateral flexion, and ipsilateral and contralateral rotations in maximal flexion. In addition, the upper cervical range of motion and mandibular excursions were assessed. The EMG activity data were analyzed using a 3-way analysis of variance in which the factors considered were upper cervical position, sex (male and female), and side (right and left), and the hypothesis of importance was the interaction side x position. RESULTS The 3-way analysis of variance detected statistically significant differences between the several upper cervical positions (F = 13.724; P < .001) but found no significant differences for sex (F = 0.202; P = .658) or side (F = 0.86; P = .53) regarding EMG activity of the masseter muscle. Significant differences were likewise observed for interaction side x position for the masseter muscle (F = 12.726; P < .001). The analysis of the EMG activity of anterior temporalis muscle did not produce statistically significant differences (P > .05). CONCLUSION This preliminary study suggests that the upper cervical movements influence the surface EMG activity of the masseter muscle. These findings support a model in which there are interaction between the craniocervical and the craniomandibular system.

Childhood allergic asthma is associated with increased IL-13 and FOXP3 histone acetylation

reactivity in the BAL of Der p 2.1–vaccinated mice, confirming previous reports demonstrating the lack of IgE reactivity toward this recombinant hypoallergenic derivative (Fig 2, E). However, contrary to recent results, we did not observe an increase in the inhibitory Der p 2–specific IgG1 (Fig 2, E). 8 Furthermore, we observed no influence of Der p 2.1 vaccination on the production of Der p 2–specific IgG2a. This result could be explained by the fact that B cells require IL-4 to produce both IgG1 and IgE. Consequently, by decreasing IL-4–producing T cells, vaccination with Der p 2.1 also reduced the production of TH2-related immunoglobulins. Given their structural homology, Der p and Der f antigens demonstrate an important IgE cross-reactivity. On the basis of this cross-reactivity, we investigated whether vaccination with Der p 2.1 peptide could control the development of Der f–induced airway hyperresponsiveness. Vaccination with Der p 2.1 inhibited bronchial hyperresponsiveness in Der f–induced asthma to the same extent as in the Der p–induced asthma model (Fig 2, F). Collectively, these data demonstrate the protective effect of Der p 2.1 vaccinations given before and duringHDM sensitization. By inhibiting T-cell–mediated IL-4 production, Der p 2.1 vaccination is believed to dampen IgE production, leading to a global attenuation on airway inflammation and hyperresponsiveness. Lower levels of IgE lead to fewer allergen-IgE pathogenic complexes and therefore to less activation of innate cells such as eosinophils, mastocytes, and basophils. The fact that IgG1 was also decreased is intriguing. The decrease in IgG1 may be explained by the fact that IL-4 is also involved in the production of IgG1 in mice. Der p 2.1 vaccination could also promote the expansion of immunosuppressive cells, such as regulatory T cells or induced-regulatory B cells. Indeed, many reports demonstrate that specific immunotherapy promotes the emergence of IL-10–producing T and B cells in allergic patients. Another interesting finding is the fact that vaccination also dampens the frequencyofTH17 cells in lungs.Given thepotent role of these cells in severe asthma, this therapeutic strategy could represent an interesting alternative in some cases of severe allergic asthma.Most interestingly, we demonstrated that vaccination with Der p 2.1 could be effective inDer f asthmaticmice. Consequently, this vaccine may reduce IgE-mediated as well as T-cell–mediated allergic inflammation irrespective of the HDM species. Finally, the protective role provided by vaccination with a hypoallergenic peptide could be of interest clinically, especially in sensitized children in whom allergic processes are sequential from sensitization to asthma. For these individuals, peptide immunotherapy may offer an alternative to block the allergic process and prevent its progression to allergic asthma.

Do subjects with acute/subacute temporomandibular disorder have associated cervical impairments: A cross-sectional study

BACKGROUND There is preliminary evidence of cervical musculoskeletal impairment in some temporomandibular disorder (TMD) pain states. OBJECTIVES To determine whether people with TMD, classified as either mild or moderate/severe TMD, have more cervical signs of dysfunction than healthy subjects. DESIGN Cross-sectional survey. METHOD Based on the Conti Amnestic Questionnaire and examination of the temporomandibular joint (Axis I classification of the Research Diagnostic Criteria for TMD), of 144 people examined 59 were classified to a mild TMD group, 40 to a moderate/severe TMD group and 45 to an asymptomatic control group without TMD. Subjects were evaluated for signs of cervical musculoskeletal impairment and disability including the Neck Disability Index, active cervical range of motion, the Flexion-Rotation Test, mechanical pain threshold of the upper trapezius and obliquus capitis inferior muscles, Cranio-Cervical Flexion test and passive accessory movements of the upper 3 cervical vertebrae. RESULTS According to cervical musculoskeletal dysfunction, the control group without TMD were consistently the least impaired and the group with moderate/severe TMD were the most impaired. These results suggest, that the more dysfunction and pain is identified in the temporomandibular region, the greater levels of dysfunction is observable on a number of cervical musculoskeletal function tests. The pattern of cervical musculoskeletal dysfunction is distinct to other cervical referred pain phenomenon such as cervicogenic headache. CONCLUSION These findings provide evidence that TMD in an acute/subacute pain state is strongly related with certain cervical spine musculoskeletal impairments which suggests the cervical spine should be examined in patients with TMD as a potential contributing factor.

Patterns of cervical and masticatory impairment in subgroups of people with temporomandibular disorders–an explorative approach based on factor analysis

Abstract Objectives: To identify clinical patterns of impairment affecting the cervical spine and masticatory systems in different subcategories of temporomandibular disorder (TMD) by an explorative data-driven approach. Methods: For this observational study, 144 subjects were subdivided according to Research Diagnostic Criteria for TMDs into: Healthy controls, temporomandibular joint (TMJ) signs without symptoms, TMJ affected, temporomandibular muscles affected, or TMJ and muscles affected. Factor analysis and linear regression were applied to cervical spine and masticatory data to identify and characterize clinical patterns in subgroups. Results: Factor analysis identified five clinical dimensions, which explained 59% of all variance: Mechanosensitivity, cervical movement, cervical and masticatory dysfunction, jaw movement, and upper cervical movement. Regression analysis identified different clinical dimensions in each TMD subgroup. Conclusion: Distinct clinical patterns of cervical spine and masticatory function were found among subgroups of TMD, which has clinical implications for therapeutic management.