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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.

Thursday, July 3, 2014

Progress in HIV-1 Vaccine Development

Advances in HIV vaccine development have been hampered by roadblocks associated with failure to prevent infection. In recent years, a number of basic and translational science advances have shown promise in the development for an effective vaccine. In their review, Haynes and colleagues summarize these advances along with the roadblocks that still remain, as well as the most promising approaches to successful vaccine design (J Allergy Clin Immunol 2014, 134(1): 3-10). 

This year, the field of HIV-vaccine research had a major disappointment in the announcement of the lack of a vaccine efficacy seen in a DNA prime, recombinant adenovirus type 5 (rAd5) boost HIV-1 vaccine trial developed by the NIH Vaccine Research Center. The vaccine was designed to test the hypothesis that high levels of CD8+ cytotoxic T cells (CTLs) could either protect against transmission or lead to control of plasma HIV-1 viral load. The second failed trial, the Merck recombinant adenovirus type 5 trail, not only lacked vaccine efficacy, but also appeared to enhance infection in those vaccines seropositive for Ad5. Although these 2 trials were of great disappointment, they provided valuable information on the types of immune responses that are unlikely to be protective.

New advances have demonstrated a variety of promising results such as the discovery of new envelope (Env) targets of potentially protective antibodies. A recent study shows promise with the finding that CD8+ T cells are associated with control and eradication of early retrovirus infections in rhesus macaques. Another recent study shows that the development of immunogens to overcome HIV-1 T cell epitope diversity while another study identifies correlates of transmission risk in an HIV-1 efficacy trail. And finally, a recent advancement has mapped the co-evolution of HIV-1 founder Env mutants in infected individuals who develop broad neutralizing antibodies (bnAbs), thereby defining bnAb developmental pathways.

Despite these advances, the field is still years away from deployment of an effective vaccine. Moving forward in HIV-1 vaccine research requires the conversion of subdominant immune responses into dominant ones, which has yet to be accomplished by an infectious disease vaccine. HIV-1 vaccine research is breaking promising new ground in vaccinology, and success in its development will herald success for other difficult vaccines such as influenza and hepatitis C. 

Prenatal exposure to diesel exhaust induces asthma susceptibility through NK cell priming

Asthma often begins early in life and is attributed to more than just genetic factors, because the prevalence continues to rise. Epidemiological studies have indicated roles for prenatal and early childhood exposures, including exposure to diesel exhaust, however, little is known about the mechanisms involved. To elucidate this, Manners et al developed a mouse model of asthma susceptibility through prenatal exposure to diesel exhaust (J Allergy Clin Immunol 2014; 134(1): 63-72).

In this model, pregnant mice were repeatedly exposed to diesel exhaust particles (DEPs). Offspring were immunized and challenged with ovalbumin (OVA) or exposed to PBS (control) then examined for features of asthma. Compared to controls, offspring that were exposed to DEP were hypersensitive to OVA, indicated by airway hyperresponsiveness, elevated serum levels of OVA-specific IgE, and elevated levels of pulmonary and systemic T-helper type 2 (Th2) and Th17 cytokines. The authors determined that natural killer (NK) cells were the primary source of cytokine production and airway inflammation was diminished by antibody-mediated depletion of NK cells. Furthermore, asthma susceptibility was associated with increased transcription of genes known to be specifically regulated by the aryl hydrocarbon receptor (AhR) and oxidative stress.

These results coincide with previous data that suggests NK cells initiate allergic inflammation. AhR is expressed in NK cells which may provide a link between maternal exposure to diesel exhaust and asthma in offspring. Taken together, this data provides mechanistic insight into the process of prenatally-induced asthma susceptibility. 

Monday, June 2, 2014

The effects of calcitriol treatment in glucocorticoid resistant asthma

The current and most effective treatment for asthma therapy is the use of glucocorticoids by improving the clinical features and airway inflammation associated with asthma. However, a cohort of well-defined asthma patients exists in whom high-dose glucocorticoid treatment is not only clinically ineffective, but potentially detrimental.  Several mechanisms have been proposed to contribute to glucocorticoid resistance, including vitamin D insufficiency. Nanzer et al recently published data that glucocorticoid resistant patients fail to synthesize the anti-inflammatory cytokine interleukin-10 (IL-10) in response to glucocorticoid in vitro compared to glucocorticoid sensitive patients (J Allergy Clin Immunol 2014; 133(6): 1755-1757). When resistant patients ingested a form of vitamin D called calcitriol (1,25-dihydroxyvitamin D3) in combination with glucocorticoid, levels of IL-10 were restored in vivo and ex-vivo. Taken together, these data along with epidemiological evidence linking vitamin D insufficiency/deficiency with poor clinical response to asthma treatment provided the rationale for the authors to perform a proof-of-concept clinical trial.

A small group of glucocorticoid resistant severe asthmatics were chosen and placed on a 2-week course of oral prednisolone and then randomly assigned placebo or 0.25ug calcitriol twice daily for 4 weeks. During the last 2 weeks patients repeated a course of oral prednisolone. The authors hypothesized that the concomitant calcitriol therapy would improve clinical glucocorticoid responsiveness in these patients. They did not expect the short course of calcitriol to restore Vitamin D sufficiency, but to address the short-term effects of calcitriol itself.

A within group comparison showing the change in lung function during the initial screening in response to 2-weeks oral prednisolone versus the response to an identical course of prednisolone plus either placebo or calcitriol, revealed a modest but significant improvement in absolute and predicted FEV₁ within the calcitriol but not the placebo arm. Furthermore, a trend for a positive correlation between baseline serum Vitamin D concentrations and change in predicted lung function following prednisolone was observed in placebo patients. This data suggests that treatment with a short course of calcitriol may improve the clinical glucocorticoid responsiveness in asthma, including patients classified as clinically glucocorticoid resistant. While larger studies with clinically well-defined cohorts are warranted, these results are very encouraging for the treatment of glucocorticoid resistant asthma. 

Mechanisms underlying the neuronal based symptoms of allergy

People with allergies often present with symptoms that are the result of alterations in the nervous system in the organ in which the reaction occurs. Common neuronal symptoms include itchy eyes, sneezing, nasal congestion, rhinorrhea, cough, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. Mediators released during an allergic reaction interact with sensory nerves, altering the transmission of signals in the sympathetic and parasympathetic autonomic nerves. Undem and Taylor-Clark describe how the nervous system itself is altered in allergic disease either due to events occurring during critical periods of neuronal development or to persistent nerve stimulation (J Allergy Clin Immunol 2014; 133(6): 1521-1534).

Those that suffer from allergic rhinitis for example, more often react strongly by sneezing when stimulants are applied to the nasal mucosa compared to healthy controls. Considering sneezing is a parasympathetic reflex, it is not surprising that these allergic individuals are often more likely to have nasal allergic symptoms when exposed to smoke, irritants, and cold air.  Similarly, in response to food allergy, immunological activation of mast cells in the gut is associated with alterations in neurotransmission. The authors detail the basic mechanisms of allergen-induced neuromodulation, highlighting the molecular interactions and phenotypic changes that occur. 

The authors emphasize that not only those with allergy produce neuroactive mediators at sites of allergic inflammation, but that the nervous system itself is altered in allergic diseases. Whether this is due to events occurring during critical periods of neuronal development or to persistent nerve activation, the nervous system is rendered hyperactive. As the understanding of basic mechanisms continue to evolve, new therapeutic strategies that target the nervous system will continue to emerge that work synergistically with anti-inflammatory treatments that allow for new, more powerful therapeutic options for allergy sufferers.

Potential food allergens in medications

Excipients are all of the substances found in pharmaceuticals that are added to the active ingredient to provide a benefit in manufacturing, stability, bioavailability, or patient acceptability.  Some excipients are foods or substances derived from foods.  Food allergic patients may rarely have reactions to these products. In his review, John M. Kelso, MD details which food-derived substances are used as pharmaceutical excipients and in which medications. Furthermore, the safety of administration of these medications in food allergic patients is also discussed (J Allergy Clin Immunol 2014; 133(6): 1509-1518). 

Food allergens are proteins that can generate IgE-mediated responses in food-allergic individuals. Since some food-derived excipients in medications are proteins, there is potential for an allergic response.  However, in most cases there is not enough of the food protein present to cause a reaction even in an allergic individual.  For example, most influenza vaccines are grown in eggs,  however there are only trace amounts of the protein in the vaccines and they are considered safe in egg-allergic recipients.  Other vaccines, however, contain substantial quantities of gelatin and do pose a risk of an allergic reaction in those with gelatin allergy.  Other excipients are derived from foods but do not contain protein, thus fish-allergic patients need not avoid fish oil for example.  In some cases, a food-derived excipient such as lactose may be contaminated with milk protein accidentally.

Although food-derived excipients may contain food proteins, reactions are generally quite rare likely because protein amounts are too low to elicit a reaction. If there is a reaction to a medication, it may be from a specific lot that was accidentally contaminated with food protein. However, if a reaction occurs, allergy to the food component should be investigated as a possible cause.