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Tuesday, August 5, 2014

Risks for infection in patients with asthma (or other atopic conditions): is asthma more than a chronic airway disease?

There is evidence that the presence of asthma can influence patients’ susceptibility to infections, yet research in this aspect of asthma has been limited. Additionally, there is a debate in the field with current literature tending to suggest an increased risk of infection among atopic patients as due to opportunistic infections secondary to airway inflammation, especially in severe atopic diseases. Other evidence suggests that such risk and its underlying immune dysfunction may be a phenotypic or clinical feature of atopic conditions. In his review, Young J. Juhn argues that improved understanding of the effects of atopic conditions on the risk of microbial infections will bring important new perspectives to clinical practice, research, and public health concerning atopic conditions [J Allergy Clin Immunol 2014; 134(2): 247-57].
The review focuses on the effect of atopic conditions on the risk of infections, termed reverse causality. For example, asthma is associated with a broad range of common and serious viral and bacterial respiratory tract infections controlled by different types of immunity (e.g. Th1 or Th2). However, given the association of atopic dermatitis and allergic rhinitis with risks of such infections, the results may imply that immunologic dysfunctions might have a role, while the structural alterations of airways observed in asthma may also need to be taken into account. Furthermore, research suggests that the effects of asthma on risk of infection may not be limited to the airways but go beyond the airways, for example, patients with asthma have an increased risk of contracting various types of herpes viruses.

 As effects of atopic conditions on the risks of various infectious diseases emerge, it will be increasingly necessary to address a broader range of patient care issues in the current guidelines. Also, the roles of allergists, immunologists, and pulmonologists may be broader in the future. This review provides insight into the foreseeable needs and challenges of the effects of atopic conditions.

Gene hunting in the genomic era: approaches to diagnostic dilemmas in primary immunodeficiencies

Over the past four decades, over 180 molecular defects causing primary immunodeficiencies (PIDs) have been discovered through advances in immunology and genetics. Recent studies have identified ways to solve difficult cases such as diseases with autosomal dominant inheritance, incomplete penetrance, or mutations in non-coding regions. In their review, Platt et al focus on selected causes to illustrate a spectrum of approaches for identifying causative mutations [J Allergy Clin Immunol 2014; 134(2): 262-68].  They broadly classified these approaches into 3 different strategies: 1) educated guesses based on known signaling pathways essential for immune cell development and function, 2) similarity of clinical phenotypes to mouse models, and 3) unbiased genetic approaches. They also address methods of overcoming challenges in identifying molecular causes of PIDS.
Since the majority of PIDs are monogenic, whole exome/genome sequencing has expedited the discovery of pathogenic mutations, particularly when combined with classical methods of identifying genetic defects. Recently, an unbiased approach to sequencing called next generation sequencing (NGS) has revolutionized genetics by making it possible to sequence entire human genomes within days. Although this technology offers comprehensive sequencing data, it is challenging to distinguish pathogenic variants within the 3.2 billion bases present in the human genome. NGS and other methods have greatly expedited the discovery of pathogenic mutations; however, there are still limitations.

Advances in immunology and genetics have facilitated the discovery of novel defects underlying PIDs. However, the authors explain that there is still much progress to be made despite what is already known. Epigenetic modifications regulating gene expression, such as DNA methylation, histone modifications, and non-coding RNAs, modulate the immune system and defects in these mechanisms may contribute to PIDs. Furthermore, the use of NGS can be used to investigate the transcriptome to detect disease-causing splice variants leading to exon skipping, alternative splicing, and alternative start and polyadenylation sites. These advances can benefit patients in that the identification of the defects underlying PID enables genetic counseling and pre-implantation diagnosis. The authors conclude that pinpointing these genetic defects is the foundation for the development of gene therapy as a cure.