Asthma and atopy are complex phenotypes that are influenced by both genetic and environmental factors. A review of nearly 500 papers on disease association studies identified 25 genes that have been associated with an asthma or atopy phenotype in six or more populations. An additional 54 genes have been associated in 2-5 populations. Here, we discuss the methods that have been used to identify susceptibility genes for common diseases and overview the status of asthma genetic research. Finally, current challenges and future directions are discussed.

Asthma genetics 2006: the long and winding road to gene discovery.

Asthma and asthma-related traits are complex diseases with strong genetic and environmental components. Rapid progress in asthma genetics has led to the identification of several candidate genes that are associated with asthma-related traits. Typically the phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context. Despite the achievements made in asthma genetics formidable challenges remain. The development of novel, powerful tools for gene discovery, and a closer integration of genetics and biology, should help to overcome these challenges.

Discovering susceptibility genes for asthma and allergy

Asthma is a common, disabling inflammatory respiratory disease that has increased in frequency and severity in developed nations. We review studies of murine allergic airway disease (MAAD) and human asthma that evaluate the importance of Th2 cytokines, Th2 response-promoting cytokines, IL-17, and proinflammatory and anti-inflammatory cytokines in MAAD and human asthma. We discuss murine studies that directly stimulate airways with specific cytokines or delete, inactivate, neutralize, or block specific cytokines or their receptors, as well as controversial issues including the roles of IL-5, IL-17, and IL-13Rα2 in MAAD and IL-4Rα expression by specific cell types. Studies of human asthmatic cytokine gene and protein expression, linkage of cytokine polymorphisms to asthma, cytokine responses to allergen stimulation, and clinical responses to cytokine antagonists are discussed as well. Results of these analyses establish the importance of specific cytokines in MAAD and human asthma and have therapeutic implications.

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Importance of cytokines in murine allergic airway disease and human asthma.

Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use.

https://err.ersjournals.com/content/errev/19/115/46.full.pdf

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma.

The B cell inhibitory receptor FcgammaRIIB plays crucial roles in the maintenance of self-tolerance. We have identified a polymorphism FCGR2B c.695T>C that results in the non-conservative replacement of 232Ile at the transmembrane helix to Thr and demonstrated the association of the polymorphism with susceptibility to systemic lupus erythematosus (SLE) in Asians. In this study, we examined the impact of FCGR2B c.695T>C on the functional properties of FcgammaRIIB by expressing each allele product in a human B cell line ST486 lacking endogenous FcgammaRIIB. FcgammaRIIB 232Thr was found to be significantly less potent than wild-type 232Ile in inhibiting B cell receptor (BCR)-mediated phosphatidylinositol-3,4,5-trisphosphate accumulation, Akt and PLCgamma2 activation and calcium mobilization, and to display decreased levels of tyrosine phosphorylation and SH2-containing 5'-inositolphosphate phosphatase recruitment compared with 232Ile after IgG Fc-mediated coligation with BCR. Notably, a quantitative analysis of the subcellular distribution of FcgammaRIIB using 125I-labeled anti-FcgammaRIIB revealed that FcgammaRIIB 232Thr is less effectively distributed to detergent-insoluble lipid rafts than 232Ile, findings in accordance with the importance of the transmembrane amino acid residues, in particular large hydrophobic amino acids including Ile, in the association of membrane proteins with lipid rafts. Given the crucial roles of lipid rafts in integrating BCR signaling, decreased association of FcgammaRIIB 232Thr could contribute to its impaired inhibitory potential. Collectively, the present findings indicate that the Ile232Thr substitution affects the localization and function of FcgammaRIIB and that the molecular mechanism may link the polymorphism and susceptibility to SLE.

/pdf/fcgriib-ile232thr-transmembrane-polymorphism-associated-with-4xc9gc67vu.pdf

FcγRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling

Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044G→A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044G→A on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13Rα2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13–mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.

/pdf/il-13-r130q-a-common-variant-associated-with-allergy-and-15da7t2ssa.pdf

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation.

Microsporidia are obligate intracellular parasites. Microsporidian spores infect a wide variety of hosts, including humans. The spores may be found in infected hosts' urine and feces, thus waterborne transmission is possible. This study details method development for the detection of microsporidia in tap water. In this study, filtration, centrifugation, purification, and detection parameters were optimized for the detection of microsporidia. The Pall-Gelman Envirocheck sampling capsule (Pall Gelman, Ann Arbor, MI) was chosen as the filter element. Optimal centrifugal force for spore recovery was 1500 x g. Additionally, it was determined that eluting microsporidia spores in a detergent elution buffer solution had a detrimental effect on spore recovery. A direct examination of the concentrate resulted in a greater recovery with less variability than subjecting the sample concentrate to a Percoll-sucrose density gradient purification step. The staining method employed for the detection spores was Calcofluor white (Sigma, St. Louis, MO). Percent recoveries for 10 L tap water samples (n = 5) using the Envirocheck sampling capsule without a density gradient purification step were 26.1+/-13.4 compared to 25+/-13.8 for samples subjected to a density gradient purification step.

Frank D. Vladich

Papers

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation.

Development of a Method for the Concentration and Recovery of Microsporidia from Tap Water