Altered immunoglobulin E diversity and regulation of allergic inflammation in asthma

The clinical efficacy of anti-immunoglobulin E (IgE) therapy indicates a central role for IgE in perpetuation of allergic inflammatory diseases. Omalizumab is now uti- lized in treatment of a wide variety of allergic conditions including severe asthma, allergic rhinitis, atopic dermati- tis, food allergy and urticaria either alone or adjunct with other therapies such as steroid administration or allergen- specific immunotherapy [1, 2]. Current research activity is focused on the cellular and molecular mechanisms by which IgE influences the immunopathogenesis of allergic disease [3]. Increased knowledge of how IgE exerts its effects will underpin effective clinical use of anti-IgE treatment. In this issue Kerzel et al. [4] investigate the effects of altered antibo dy repertoire on the outcomes of an experimental model of allergic asthma.

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven

Background: IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses. Objectives: To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy. Methods: Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced. Results: The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts. Conclusion: In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p= 2·4×10-8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10-8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10-4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix. © 2011 Elsevier Ltd.

Condition-specific associations of symptoms of depression and anxiety in adolescents and young adults with asthma and food allergy

Objective: This study examined associations of asthma and food allergy with symptoms of depression and anxiety at 14 and 21 years of age to determine whether condition-specific associations exist. Methods: Data come from 4972 adolescents in the Mater University Study of Pregnancy. Symptoms of depression and anxiety were assessed using the Youth Self-Report and Young Adult Self-Report. Results: Condition-specific associations between asthma and depression, OR=1.37 [1.12, 1.67] and between food allergy and anxiety, OR=1.26 [1.04, 1.76] were found during adolescence, but not in young adulthood. Whereas asthma was associated with resolved depression, OR=1.70 [1.13, 2.55], food allergy was associated with persistent anxiety, OR=1.26 [1.01, 1.59]. Conclusions: In adolescents, asthma is associated with an increased risk of clinically relevant symptoms of depression and food allergy with and increased risk of clinically relevant symptoms of anxiety. Future research is needed to clarify directionality and mechanisms explaining these relationships. Health professionals should be aware of the increased risk of mental health problems in adolescents with asthma or food allergy.

The skin safety model: Reconceptualizing skin vulnerability in older patients

Purpose: To develop a unique skin safety model (SSM) that offers a new and unified perspective on the diverse yet interconnected antecedents that contribute to a spectrum of potential iatrogenic skin injuries in older hospitalized adults. Organizing Construct: Discussion paper. Methods: A literature search of electronic databases was conducted for published articles written in English addressing skin integrity and iatrogenic skin injury in elderly hospital patients between 1960 and 2014. Findings: There is a multiplicity of literature outlining the etiology, prevention, and management of specific iatrogenic skin injuries. Complex and interrelated factors contribute to iatrogenic skin injury in the older adult, including multiple comorbidities, factors influencing healthcare delivery, and acute situational stressors. A range of injuries can result when these factors are com- plicated by skin irritants, pressure, shear, or friction; however, despite skin injuries sharing multiple ntecedents, no unified overarching skin safety conceptual model has been published. Conclusions: The SSM presented in this article offers a new, unified framework that encompasses the spectrum of antecedents to skin vulnerability as well as the spectrum of iatrogenic skin injuries that may be sustained by older acute care patients. Current skin integrity frameworks address prevention and management of specific skin injuries. In contrast, the SSM recognizes the complex interplay of patient and system factors that may result in a range of iatrogenic skin injuries. Skin safety is reconceptualized into a single model that has the potential for application at the individual patient level, as well as health-care systems and governance levels. Clinical Relevance: Skin safety is concerned with keeping skin safe from any iatrogenic skin injury, and remains an ongoing challenge for healthcare providers. A conceptual framework that encompasses all of the factors that may contribute to a range of iatrogenic skin injuries is essential, and guides the clinician in maintaining skin integrity in the vulnerable older patient.