Treatment of peanut allergy with omalizumab

Peanut allergy is a well known food allergy estimated to include 3-4% of the US population and accounts for a disproportionate number of severe allergic reactions. The vast majority of food allergy death is related to peanut allergy and is often ingested accidentally despite strict food avoidance. Peanut allergy sensitivity often fails to diminish over time compared to other food allergens causing a lifetime of anxiety and food avoidance for patients and families. The only effective treatment option for this epidemic other than food avoidance is ready access to injectable epinephrine. 

Recent clinical trials using double blind, placebo controlled food challenges (DBPCFC) have reported success with allergen immunotherapy and desensitization with common food allergens including peanut. Although long term tolerance can be achieved with daily intake, most patients experienced mild to severe symptoms including anaphylaxis which occurred in up to 25% of patients with a high peanut specific IgE. Nevertheless, these trials demonstrate that oral food challenge is a useful method for treating food allergies by increasing the threshold for tolerance with possible resolution.

Schneider et al hypothesized that treatment with an anti-IgE monoclonal antibody (mAb) such as omalizumab may contribute to a more rapid desensitization with greater success (Journal of Allergy and Clinical Immunology 2013; 132(6): 1368-1374). Omalizumab binds free IgE which inhibits allergic reactions and is currently approved for older children and adults with moderate to severe asthma. 

The authors administered the drug prior to and during oral peanut desensitization to 13 children who failed initial DBPCFC at low doses (< 100 mg of peanut flour). After pretreatment, all subjects tolerated initial desensitization doses given on the first day, including the maximum dose of 500 mg of peanut flour and 12 subjects reached the maximum daily dose of 4000mg/day within a median time of 8 weeks, at which point omalizumab was discontinued.  The 12 subjects continued the 4000mg/day of peanut flour and subsequently tolerated a challenge of 8000 mg which is up to 400 times the dose that was tolerated before desensitization.  Of the 13 subjects, 6 experienced mild or no allergic symptoms, 6 had a grade 2 reaction, and 2 had a grade 3 reaction which all responded rapidly to treatment. 

These results suggest that omalizumab can facilitate a more rapid oral desensitization in high risk patients with high peanut specific IgE. Schneider’s results provide strong evidence that omalizumab can effectively reduce allergic reactions and expedite rapid oral desensitization.  Larger studies are currently under way to confirm the beneficial role of omalizumab in facilitating oral peanut desensitization.

Questions for the authors:

Could this treatment be used for other severe allergic diseases not yet indicated?  Could longer treatment with omalizumab prevent or reduce other side effects such as eosinophil esophagitis?

Further studies would be needed to determine whether this approach can be applied to other severe allergic diseases.  We don't know if  longer treatment with omalizumab would reduce reactions during desensitization since this was not part of the study.

Atopic disease and the herpes microbiome

Unlike bacteria or fungi, herpes viruses establish life-long infection in the human host through latent genomic persistence within the host cells nuclei and are thus considered part of the human microbiome. The ability of the virus to interact with the human genome influences allergic and atopic disease due to the bias these patients have towards a Th2 profile. Dr. David Dreyfus examined the role of common human herpes viruses on the microbiome of atopic patients, who have more severe and atypical disease when infected (J Allergy Clin Immunol 2013; 132(6): 1278-1286).

The herpes virus Epstein Barr (EBV or mononucleosis) expresses latency in lymphocytes and has co-evolved with humans long enough to encode for a protein that resembles the cytokine IL-10, as well as other cytokines by activating host transcription factors. The author explains that EBV and other herpes viruses encode for microRNAs that cause immunomodulation of distant cells. This lead to studies suggesting that EBV infection early in life is protective against atopic disease compared to infection later in life, where there is a predisposition to atopic disease. Atopic patients that have a primary infection of EBV can have a more severe non-specific rash that can be mistaken for allergic diseases or other infectious diseases and can be misdiagnosed.

Another ubiquitous herpes virus, VZV or shingles, becomes latent in neuronal cells and reactivation risk increases with age as the natural antibodies decline over time. The current VZV vaccine has been successful for a decade, reducing the VZV associated morbidity and mortality especially in the elderly. However, studies suggest that children who receive the vaccine have an increased incidence for atopic disease compared to children that are infected naturally with the virus, suggesting there could be a protective benefit to natural infection. Like VZV, Human Simplex Virus 1 and 2 (HSV1 and HSV 2) become latent in the neuron after primary infection of subcutaneous and pulmonary epithelial cells. The author explains that infants and others that are immunodeficient are at high risk of pulmonary syndromes such as bronchitis and pneumonia, and neurologic syndromes such as encephalitis. The most common atypical presentation of the virus is a severe skin rash called eczema herpeticum among atopic patients. This is similar to the severe drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) seen with the reactivation of HSV6, also referred to as roseola, which is present in both atopic and non-atopic patients. Furthermore, another related herpes virus, cytomegalovirus (CMV) can cause cutaneous symptoms similar to EBV, as well as chronic inflammation and cardiovascular disease due to its latency in macrophages that are associated with vascular inflammation by directly inducing Th2 cytokines.

Molecular evidence suggests that herpes viruses have been co-evolving with the human immune system since before the origin of the adaptive immune system. The herpes microbiome along with environmental factors such as improved global hygiene that prevents the exposure to a variety of components interact with each other to create the atopic phenotype. Dr. Dreyfus emphasizes that this information can positively impact the care for the allergic and atopic patient populations. Clinicians must have a heightened awareness of the various presentations of herpes viruses to avoid unnecessary testing and treatments for drug allergy or autoimmune disease. 

Questions for the author:

What are the effects of the herpes microbiome on other allergic diseases?  Is there an increase in Th2 dependent disease in patients who express viral lesions and reactivation of herpes viruses? 

Regarding the question of effects of herpes on atopic disease, in addition to the references cited in my article particularly regarding an increase in atopic disease in pediatric patients who receive the varicella vaccine vs wild type virus there is a more recent article just published with some more experimental observations on this question:

Sohlberg, E. et al (2013) Cytomegalovirus-Seropositive Children Show Inhibition of an In Vitro EBV infection That Is Associated with CD8+ CD57+ T-cell Enrichment and IFN-gamma. Journal of Immunology 191:5669

Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor кB and c-Jun N-terminal kinase activation

Inhaled glucocorticoids are often highly effective in treating symptoms of asthma exacerbations, however they are ineffective at treating and preventing exacerbations brought on by rhinovirus infection, especially in children.  Glucocorticoids act by binding to glucocorticoid receptors (GR) α which become activated and translocate to the nucleus, leading to the activation of down-stream anti-inflammatory pathways.  Papi et al sought to determine the mechanistic actions of glucocorticoids during rhinovirus infection by studying factors in these anti-inflammatory pathways (J Allergy Clin Immunol 2013; 132(5): 1075-1085).

Using a variety of assays and human bronchial epithelial cells, the authors determined that the rhinovirus RV-16 reduces the ability of dexamethasone to inhibit the pro-inflammatory cytokine IL-1β induction of the chemokine CXCL8.  They went on to show that there is an RV-16 dependent impairment of dexamethasone-induced GRα nuclear translocation that is mediated by the transcription factor NFкB p65 as well as the c-JUN N-terminal Kinase, JNK-1, both pro-inflammatory pathways.  To solidify this finding, Papi attempted to reverse the RV-16 induced attenuation of GR nuclear translocation by dexamethasone with inhibitors of NFкB and JNK. Their results indicate that independently, both inhibitors partially rescued the impairment and the combination of both inhibitors totally restored dexamethasone sensitivity. The authors show that rhinovirus infection inhibits glucocorticoid mechanisms of action and impair both the transactivation and transrepression activities of dexamethasone, implying that rhinovirus infection targets an upstream aspect of GR activation. 

These finding suggest a novel molecular mechanism for rhinoviruses, the biggest trigger of asthma exacerbations, to impair the ability of glucocorticoids to control airway inflammation.  These data indicate a strategy through which rhinovirus infection can overcome the anti-inflammatory defense but also indicate approaches that might reverse this process.  The discovery of completely inhibiting both NFкB and JNK pathways reverses glucocorticoid resistance identifies new therapeutic approaches for asthma and rhinoviruses in general for which there is no effective treatment available.

Questions for the authors:

Are there other markers or pathways that are involved that could be considered therapeutic approaches for treatment?

Yes, it is possible that the mechanisms by which rhinovirus inhibit corticosteroid activity involves the activation of other pro-inflammatory pathways, as 1) rhinovirus induces the production of multiple inflammatory mediators; 2) rhinovirus inhibits an upstream step of the mechanism of action of corticosteroids. We analyzed the keys/main mediators, but many other could be affected.

Could there be other pro-inflammatory cytokines that are up-regulated that amplify the effect of rhinoviruses?

Several pro-inflammatory mediators are induced by rhinovirus infection (Hansell TT. Lancet. 2013). They are likely affected by the mechanisms we described in the study as they are upstream steps of the mechanism of action of corticosteroids.

Predictors of response to tiotropium versus salmeterol in asthmatic adults

The severity of asthma symptoms is well known to be attenuated by inhaled corticosteroid (ICS) due to their anti-inflammatory effect.  Long-acting β-agonists (LABA) and long acting muscarinic antagonists (LAMA) are current treatment options for patients that do not respond well to low dose ICSs.  Using data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network’s Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid, Peters et al sought to determine individual and differential responses of asthmatic patients to salmeterol (LABA) and tiotropium (LAMA) when added to an inhaled corticosteroid, as well as predictors of a positive clinical response to the end points FEV₁, morning peak expiratory flow (PEF), and asthma control days (ACDs) (J Allergy Clin Immunol 2013; 132(5):1068-1074).

In the attempt to personalize the best treatment options for patients, investigators have used a variety of strategies, including the use of biomarkers, patient-specific and physiologic “predictors” and genetic/genomic approaches.  Predictors of response that have been investigated by researchers include short-acting bronchodilators and leukotriene modifiers, but more recently, predicting the response to glucocorticoids, namely ICSs have contributed valuable insight into this framework.  The author’s interest in long-acting bronchodilators, such as LABAs and LAMAs stems from the lack of information that has been published concerning these predictors of response, including intra-subject response of asthmatic patients treated with both a LABA and a LAMA.

Utilizing information from 210 asthmatic adults, the authors discovered that the use of tiotropium with a low dose of ICS resulted in a superior primary outcome compared to doubling the ICS alone, as assessed by improvement of morning PEF, evening PEF, a decrease in ACDs, and an increase in FEV₁.  Salmeterol had a similar but less robust response, and subjects showed a differential response to tiotropium for FEV₁, but not for salmeterol.  Furthermore, younger patients responded better to tiotropium in terms of ACDs.  Peters also reports that large numbers of patients responded to either salmeterol or tiotropium, but not to both agents.  This suggests that at the time of administration, different mechanisms were operating to produce airway constriction and symptoms in these 2 groups of patients.  Finally, although the use of a short-acting bronchodilator did predict a positive response to a long-acting bronchodilator controller of the same class, albuterol response better predicted a response to tiotropium than did ipratropium. 

While these findings need to be replicated in an independent study, the data suggest that asthmatics that have suboptimal asthma control using ICSs alone, with airway obstruction as demonstrated by a reduced FEV₁/FVC ratio, a positive response to albuterol, or both, should be good candidates for treatment with tiotropium as an add-on therapy.  This could be used for patients where combination ICS-LABA therapy fails or when ICS monotherapy in inadequate for symptom control.  

Exhaled NO levels and blood eosinophil counts independently associate with wheeze and asthma events

Eosinophils and exhaled Nitric Oxide (NO) levels are prominent features of asthma.  It is known that both exhaled NO and blood eosinophil counts (B-Eos) are markers of local and systemic eosinophil inflammation respectively, and are elevated in patients with the disease. However, little is known about the association of these markers with wheeze and asthma events.  Malinovschi et al [J Allergy Clin Immunol 2013; 132(4):821-827] examined subjects from National Health and Nutrition Examination Survey 2007-2008 and 2009-2010 to determine individual and independent B-Eos and Fraction of Exhaled Nitric Oxide (FENO) levels in relation to wheeze, asthma diagnosis, and asthma events.

From the cross sectional study, 12,408 subjects ranging from 6-80 years old were selected who had FENO measurements and blood differential counts.  The authors report that the prevalence of current asthma and wheeze increased progressively with FENO values and B-Eos values.  Furthermore, there was an increase in asthma attacks and asthma related ED visits which associated with an increase in both FENO and B-Eos respectively. While intermediate or high FENO and B-Eos levels were independently associated with having asthma, wheeze, and asthma attacks, only the B-Eos values were independently associated with asthma-related ED visits. 

Malinovschi explains that these 2 markers cannot be used interchangeably but rather in combination due to the finding that the correlation between the markers is weak. This indicates that they represent 2 different inflammatory pathways with separate trigger mechanisms, contrary to previous thought.  The B-Eos levels associated with asthma-related ED visits, which is in-line with recent findings that eosinophilic asthma patients receiving anti-IL-5 treatment have a reduction in severe asthma symptoms. Whereas FENO values appear to precede moderate but not severe asthma exacerbations and signal local IL-4/IL-13 mediated mechanisms in bronchial mucosa that are triggered by aeroallergen exposure. 

The authors conclude that both local and systemic Th2 cytokine-driven mechanisms, partly with different triggers, are involved in eosinophilic asthma, suggesting a double-hit mechanism for the development of respiratory symptoms and asthma.   The clinical significance of assessing both of these components for individualizing treatment warrants further study.

A major allergen of public health relevance in the inner city of Baltimore

The prevalence of asthma is ubiquitous across the United States, but the major allergens of public health relevance that contribute to the disease vary across geographical regions.  Within inner cities, the 2 most common allergens are mouse and cockroach. Ahluwalia et al [J Allergy Clin Immunol 2013; 132(4):830-835] sought to determine the relevant antigen(s) most highly associated with inner city asthma morbidity within Baltimore city. The motivation of their study was not only to aid in the management of asthma within the community but to assist in the reduction of levels of these antigens community wide. 

The authors selected 144 children between 7 and 10 years old that had been clinically identified with asthma at least one year before the start of the study.  At the start of the study, they underwent skin prick tests and had clinical data collected at baseline and again at 3, 6, 9, and 12 months.  At the same time points, settled house dust samples were collected to quantify indoor allergens.  The participants were grouped based on sensitization and exposure status of common allergens from the dust samples. 

Results indicated that mouse was the most relevant allergen with regard to asthma outcomes.  Both mouse and cockroach sensitization and exposure was significantly associated with an increased prevalence of heath care use for asthma, but only mouse sensitization and exposure was associated with higher levels of pulmonary inflammation.  Furthermore, the authors report that mouse IgE levels were also associated with poor asthma health whereas cockroach-specific IgE levels were not.   The authors went on to determine that the relationships between asthma outcomes and mouse antigen were independent of cockroach antigen. 

Ahluwalia points out that although cockroach antigen is prevalent and has some effect on outcomes, mouse antigen appears to be the strong driver of asthma morbidity among Baltimore City children.  Their data show that mouse allergen is strongly associated with a range of outcomes, including acute asthma visits, pulmonary inflammation, and lung function.  There is a profound clinical implication of these data by allowing for specific treatments for the patients and reduction of the mouse antigen at the community level.

Question for the authors: If individual urban communities used this type of study to determine the primary antigen(s) that cause community wide allergy and asthma exacerbation, what type of outcomes do you anticipate both clinically and financially both within the community and across the country? 

This question is terrific and gets to the heart of whether community-wide environmental interventions would be expected to have a broad public health benefit - by, for example, reducing asthma ED visits or hospitalizations - and what the associated costs would be.  The best means we have of estimating the potential public health impact is to calculate the proportion of asthma-related hospitalizations, for example, that can be attributed to sensitization and exposure to a particular allergen in a community.  We have done this using another Baltimore City population and estimated that between 20 and 25% of hospitalizations for asthma among Baltimore City children may be attributed to mouse allergen sensitization and exposure. In terms of costs, one multifaceted environmental intervention cost about $1500 per child [Morgan W et al NEJM 2004], which is currently the best estimate we have for the cost of an effective environmental intervention.  Whether the reduction in hospitalizations expected with, for example a mouse-targeted public health intervention in Baltimore, would be worth the cost remains to be seen.  However, a year's supply of controller medication typically costs more than $1500, so that if a mouse-targeted environmental intervention was at least as effective as controller medication, a strong case could be made to allocate more public health resources to target mouse infestation and for insurance to cover such an intervention.  Thus, the data accumulated to date suggest that a public health approach to environmental control has the potential to make a meaningful dent in asthma morbidity and asthma-related costs, not just in Baltimore City, but also in other communities with high asthma prevalence and morbidity.

Primary NK immunodeficiencies

Keeping on the topic of natural killer cells, Jordan Orange, MD, PhD contributes a review on immunodeficiencies associated with NK cell dysfunction [J Allergy Clin Immunol 2013; 132(3):515-525].  The author provides a concise review of NK cell biology, covering their intrinsic activities of cytotoxicity, tumor surveillance, and co-stimulation and signaling.  Orange points out that NK cell deficiency [NKD] is a subset of primary immunodeficiency diseases [PID] that is difficult to diagnose and treat because of the limited clinical information and testing available. 

Like other PID, the author notes that NKD patients are characterized by a susceptibility to chronic and/or severe viral infections, especially herpes viruses.  Accurate diagnosis hinges on determining that the seminal deficiency is associated with NK cells, and that NKD is not secondary to other causes. The author provides an algorithm for identifying primary NKD. 

Orange discusses the current classification of NKD into two types:  classical NKD and functional NKD.  Classical NKD [CNKD] is characterized by severe depletion or absence of NK cells in peripheral blood, while functional NKD [FNKD] is typified by the presence of peripheral NK cells with impaired or abrogated activity.  He points out that there is some overlap in these phenotypes in the reported cases.  Orange further discusses the subtypes of CKND and their associated genetic abnormalities.  In his discussion of FNKD, the author reports on the first identified subtype, FNKD1, which involves a defect in the IgG receptor. 

Orange continues describing the clinical cases that have been reported and the availability and applicability of diagnostics for NKD.  The author also reviews briefly other PID that effect NK cell immunity, but that affect other components of the immune system in the majority.  Addressing the clinical treatment of NKD, he notes that intervention is focused on the herpetic infection susceptibility and employs approved antivirals such as gancyclovir.  Additionally, the author reports that severe presentations of NKD have been treated successfully with stem cell transplantation.  

Natural killer cell interactions in adaptive immunity

This month, Deniz et al. give an overview of current knowledge about natural killer cells [NK cells] and their interface with pathways and mechanisms of adaptive immunity, with attention to allergic disease processes [J Allergy Clin Immunol 2013; 132(3):527-535]. 

The authors cover fundamentals of NK biology, such as their surface marker characterization, IFN-γ secretion, MHC class I interactions, phenotypes, tissue prevalence, cytokine profiles, and cytotoxicity to target cells.  NK cells are characterized by their cytotoxic activity through release of perforin and granzymes that are targeted at tumor cells, virally infected cells, and IgG antibody expressing cells, cytokine and chemokine secretion and signaling of adaptive immune cells, and co-stimulatory interaction with antigen presenting cells [APC] via IL-10 and TGF-β.   Deniz et al. note that NK chemokine secretion is particularly important in the co-localization and mutual maturation of dendritic cells [DC] and NK cells in areas of inflammation. 

The authors discuss the interesting parallels between NK cell subsets and T cells, noting the overlaps in surface markers and cytokine expression.  NK cells subsets consist of NK1 and NK2 cells, analogous to Th1 and Th2 cells, NK regulatory cells, NK-17 cells and NK-22.  They point out that peripheral blood mononuclear cells [PBMC] from patients with asthma showed decreased NK1 and increased NK2 levels, suggesting a NK2 bias that shadows the Th2 bias.  Also discussed was the protective effect that has been associated with NK-17 cells in rheumatoid arthritis and NK-22 cells on epithelial cell response to contact sensitivity. 

The authors discuss the limited evidence that has been reported to date on NK cell interactions in allergic diseases.  They discuss skin NK cells are known orchestration of keratinocyte apoptosis through type I cytokine signaling.  Also covered is the critical role of DCs in the evolution of NK cells.  Deniz et al report that NK cell expression and cytotoxicity is increased in patients with allergic rhinitis.  NK1 cells, but not NK2 cells, are also known to have anti-IgE activity. 

The authors conclude commenting that, while findings are limited, there is growing evidence that NK cells, like many innate immune cells, have important interactions with adaptive immune cells.  The research should now be focused to understand the characteristics of these cells in different endotypes and phenotypes of asthma, atopic dermatitis and other chronic inflammatory diseases.

Is the human gut microbiota the critical mediator of health?

In a review this month, Greer and co-authors present interesting information on just how much our health depends on the well-being and communal balance of the microscopic symbionts in our gastrointestinal tract [Journal of Allergy and Clinical Immunology 2013; 132(2): 253-262].  They begin their review noting that, until fairly recently, immunity, metabolic functions and gut physiology had been studied as separate biological systems.  In light of growing evidence that the delineation between these is arbitrary, the authors point out that systems biology has developed new methods for investigating the interactions between the intestinal microbiota and immune and metabolic outcomes.

Greer et al covers two broad categories, small intestine enteropathies and obesity with metabolic syndrome.  They describe current animal models used to study immunodeficiency enteropathies, celiac disease, inflammatory bowel disease, obesity and lipid metabolism dysregulation.

The authors discuss notable findings from mouse models that have been employed to study enteropathies.  For example, B lymphocyte deficient mice are known have fat absorption issues, which correlate to IgA deficiency.  B cell secreted IgA is required for maintaining a proper balance between immunity, fat metabolism and gut microbes.  They note that B cell deficient mice have intestinal gene expression profiles that are very similar to those seen in HIV/CVID patients.

They note that gut microbiota contribute to dyslipidemia and insulin resistance in obese mice and induce intestinal inflammation in response to increased fat intake.  Greer et al discuss also the physical changes in the ileum that cause increased uptake of fats in the diet-induced obese mice.  Interesting, they comment that TLR5 knock-out mice have increased weight gain, pointing to innate immune interactions in fat metabolism.

Greer et al discuss evidence on short chain fatty acid balance and metabolism as critical to maintenance of a “core” microbiota.  Transplantation of microbes from diet-induced obese mice to control mice results in obesity in the control mice without increase in food intake.  The authors suggest that this points to persisting changes in gut microbiota that may be causally related to obesity and altered fat metabolism.  Concluding, Greer et al suggest that the gut microbiota is a cardinal mediator between the immune system and gastrointestinal epithelium. 

In answer to the question, "In your opinion, does manipulation of the gut microbiota present a therapeutic intervention for obesity and/or lipid metabolism disorders?", the authors responded, "Yes, we believe that manipulation of gut microbiota presents great potential for therapeutic interventions in a range of diseases, including obesity and metabolic syndrome, but we need first to understand which taxa or which microbial genes might be most beneficial and in each case."

A novel mode of cell death in active versus resting eosinophils: a potential pathway for treatment of asthma and allergic disease

Apoptosis was previously thought to be the only mode of regulated or programmed cell death in eosinophils, as necrosis was regarded as unregulated cell death.  However, Kano et al., have discovered that the activated eosinophils, found in abundance in asthma and allergic disease, can die by means of a type of regulated necrosis in response to Siglec-8 ligation [J Allergy Clin Immunol 2013; 132(2): 437-445]. Siglec-8 is a cell-surface receptor protein that is highly and selectively expressed by human eosinophils, as well as mast cells and basophils. The authors show that Siglec-8 ligation in the presence of IL-5 triggers necrosis in activated eosinophils in a reactive oxygen species (ROS)–dependent manner. Further, they explain why IL-5 promotes cell death in this system even though it is typically a pro-survival signal.  They demonstrate that ROS switch IL-5’s function from pro-survival to cell death enhancement by augmenting ERK phosphorylation and this serves as a decisive trigger of necrotic cell death. These discoveries indicate that necrotic eosinophil cell death can be regulated by signal transduction, suggesting that potential therapeutics targeting regulation of the mode of cell death could be beneficial in various eosinophilic diseases.

Pattern recognition receptors in obesity and metabolic disturbances

Highlighting the role of innate immunity in the evolution of obesity and associated metabolic disorders, Jin and Flavell deliver a concise review of mechanisms involving pattern recognition receptors that produce pathology in liver, pancreas, brain and intestinal microbiota [J Allergy Clin Immunol 2013; 132(2):287-294]. 

The authors provide a summary of the biology of the major types of pattern recognition receptors [PRR], with emphasis on toll-like receptors [TLR] and NOD-like receptors [NLR].  They discuss briefly their activity in response to pathogen infection and endogenous injury.  Several NLRs can coalesce into multiprotein complexes called inflammasomes which have proven to be importantly involved in the development of insulin resistance. 

Jin and Flavell review PRR mechanisms in five critical physiologic areas: brain, pancreatic islet, and vascular inflammation, induction of peripheral insulin resistance, and disruption of intestinal microbiota homeostasis.  They note that PRRs can directly mediate and sustain inflammation in response to excessive nutrient resulting in abnormal lipid metabolism and insulin resistance in multiple tissues, which accounts for comorbidities such as type 2 diabetes and atherosclerosis.

In the gut, the authors point out that PRRs are critical to sensing and regulating the microbiota as well as responding to pathogenic insult.  TLR/NLR deficiency-associated microbial imbalance has been associated with obesity risk, insulin resistance, and fatty liver.  Interestingly, transplantation of abnormal microbiota from obese mice into wild-type mice results in reproduction of the obese metabolic phenotype that can be corrected by antibiotic treatment.  This points to a causal relationship between disrupted intestinal microbiota and the development of metabolic syndrome. 

Regarding the recent AMA announcement that obesity is a disease as opposed to lifestyle that results in a disease state, I think this is supported by findings from basic research that the development of obesity is not simply due to a lifestyle exemplified by overeating and inactivity, but also profoundly impacted by intrinsic genetic factors in metabolic system, immune system and intestinal microbial ecosystem. Recognizing obesity as a disease will help the community pay more attention to this emerging health issue and also hopefully stimulate research to understand the complex pathophysiology of obesity.

SLIT immunotherapy in South Africa

In a new series for the Journal, “Allergy and clinical immunology around the world,” Paul Potter, MD, describes sublingual immunotherapy practice in South Africa, which is based on recommendations put forth by the Allergy Society of South Africa [J Allergy Clin Immunol 2013; 132(1): 99-100].  Because of the long grass pollen season, approximately 8 months, seasonal rhinitis in the region is reclassified as persistent rhinitis, for which SLIT is indicated. 

Potter notes that SLIT has been available for 15 years in South Africa.  European vaccines are employed for Bermuda/rye grass pollens and D. pteronyssinus/farinae for mite allergies.  Patients eligible for SLIT must be sensitive to only one allergen per the recommendations, though 80% of the patient population is allergic to multiple allergens. 

The author reports that clinical trials for SLIT in South Africa have had variable outcome agreement, in spite of significant efficacy results.  A retrospective review is discussed by Potter who notes that the drop-out rate is highest in the first year of a 3-year intervention.  Reasons for discontinuing study participation were most commonly financial and logistic.  He discusses additional findings that implementing 6-month follow-up contact with subjects and administering a quality of life questionnaire increases compliance with therapy and completion of the full course of treatment. 

MicroRNAs – the hot new thing in allergic inflammation regulation

While investigations of microRNAs [miRNA] and their role in transcription in disease have been growing for the last decade, more recently they have come under the scrutiny of immunologists searching for signs of miRNA dysregulation in allergic inflammation.  This month, Lu and Rothenberg review the evidence to-date and give us some very interesting news on miRNA in several atopic diseases [J Allergy Clin Immunol 2013; 132(1): 3-13].

Lu and Rothenberg start with a review of the general pathophysiology of miRNAs, which effect gene transcription networks by silencing posttranscriptional gene expression of mRNA.  One miRNA can modulate multiple genes and one gene may be targeted by many miRNAs.  miRNAs are also known to modify DNA methylation and histone acetylation, as well as interact with transcription factors.  The authors comment that miRNAs have been found in exosomes in cell-free body fluids, raising the intriguing possibility of their usefulness as peripheral biomarkers.  

The authors present the current knowledge of miRNA profiles that have been identified in allergic asthma, eosinophilic esophagitis, atopic dermatitis, and allergic rhinitis.  By far the most abundant information is available for allergic asthma.  One particular miRNA – miR-21 – has been well characterized in experimental models of asthma.  Lu and Rothenberg discuss findings that point to miR-21 involvement in T_H1-T_H2 polarization.  In these models, miR-21 is over-expressed in experimental asthma and strongly suppresses expression of IL-12p35 mRNA, permitting T_H2 bias in the immune response.  They note that studies of MiR-21 deficiency in asthma mice report increases in IL-12p35 and IFN-g production and concomitant decreases in eosinophilia and IL-4 in bronchoaveolar fluid.  Lu and Rothenberg discuss other miRNAs that have been identified in allergic inflammatory processes such as miR-126 and the Let miRNA family. Critical miRNAs associated with airway smooth muscle function are also discussed along with the early results of miRNA profiling in human asthma. 

Important findings on critical miRNAs identified in eosinophilic esophagitis are reviewed.  The authors discuss miR-21 mechanisms in eosinophilic esophagitis that are consistent with those reported for allergic asthma.  One miRNA, miR-146a, has been characterized in eosinophilic esophagitis as a repressor of T_H1 responses through dysregulation of T_reg suppression in a STAT1 dependent manner. Peripherally circulating miR-146a and miR-223 in patients with eosinophilic esophagitis are discussed as promising non-invasive biomarkers for diagnosis and therapy response. 

Lu and Rothenberg further review miRNA profiles that have been characterized in atopic dermatitis and allergic rhinitis, noting that miRNA data in AR is currently sparse.  Also discussed is the role of miRNA in eosinophil development in light of the collaborative interaction between miR-21 and miR-223 in eosinophil viability, proliferation, and maturation. 

The authors provide an excellent table that summarizes miRNAs common to allergic asthma, eosinophilic esophagitis, and atopic dermatitis.  Concluding, Lu and Rothenberg offer a number of topics for future research focus.  

Restoring health

The rise in non-communicable, inflammatory diseases (NCD), and in particular allergic and atopic illnesses, has begun to redirect the efforts of the clinical research community toward early prevention in addition to supportive intervention.   This is in light of the significant burden on healthcare created by NCD as well as the realization of the limitations of pharmacotherapies to affect underlying causes. 

This month’s review article by Pfefferle, Prescott and Kopp (J Allergy Clin Immunol 2013; 131(6): 1453-1463) assesses the practical application of findings that commensal gut microbes are critical partners in the evolution of environmental tolerance.   They focus on the accumulating evidence supporting a disrupted human microbiome that has led researchers to propose the use of pro- and pre-biotic therapies as means to prevent inflammatory immune processes that create chronic allergic and atopic diseases.

Pfefferle et al. review briefly the current knowledge on the collaboration of the gut and the immune system in developing tolerance, pointing out the importance of maternal exposure to both pathogenic and non-pathogenic microbes in directing fetal immunity.  They note that high prenatal exposure has been shown to have an independent protective effect on allergic outcomes and that these effects are epigenetic.  Citing a study that compared the immune status and responsiveness of urban Australian children with native Papua New Guinea children, Pfefferle discuss the higher immune activation but lower reactivity of the Papua New Guinea children compared to their urban counterparts, an observation that points to highly divergent microbial exposure of the mothers and their children.

The authors go on to cover the research on maternal pro- and prebiotic interventions for eczema and food allergies.  At least half of the maternal probiotic intervention studies for eczema and food allergy showed positive results, but conflicting results were presented in the remainder.  Maternal prebiotic studies also showed positive effects in both animal models and human subjects, with offspring having greatly diminished expression of eczema.  The observed variability of trial results is analyzed with respect to study design, dosing, population and environmental region. 

Mechanically prepared bacterial lysates (BL) for protection against respiratory illness is also discussed in Pfefferle et al.  Observations that BL push upper airway responses toward Th1 maturation were the basis for studies that examined the effect of BL in reducing the incidence of acute respiratory tract infections (ARTI).  Results showed a protective effect of BL, especially in high risk children.  The authors comment that ARTI and recurrent wheeze in childhood is associated with the development of asthma and suggest that BL may be a future focus of asthma prevention research. 

Pfefferle et al. concludes noting that both the intrinsic and extrinsic microbial environment are implicated in almost all inflammatory NCD and suggest that methods of microbial manipulation are an important focus of future research aimed at prevention strategies. 

Early life BMI progression and asthma incidence

Results from an interesting epidemiological investigation based on data from eight birth cohorts collected under the Global Allergy and Asthma European Network [GA²LEN] research initiatives are presented this month in Rzehak et al (J Allergy Clin Immunol 2013; 131(6): 1528-1536).  Risk of “incident asthma,” defined as first reported physician diagnosis, for 3 age brackets up to 6 years old is analyzed.

Using a novel growth curve analysis method to identify classes of BMI trajectories normalized according to WHO standards [BMI-SDS], the authors identify three classes, a normative class [Class 1], an early rapid growth only up to 2 years class [Class 2], and a persistent rapid growth to 6 years class [Class 3].  Survival analysis of the three BMI-SDS trajectories assessed the hazard ratio [HR] for incident asthma in each. 

Rzehak et al. report that children in the Class 2 trajectory had a significant increased risk of incident asthma within their first 6 years.  Class 3 children had similar risk that did not achieve significance.  Hazard ratios were similar between Class 2 and 3, the latter class having a greater prevalence of excess weight and obesity, suggesting that there is an association of early rapid weight gain with incident asthma, independent of overweight or obesity.

Rzehak et al. conclude that rapid weight gain during the first two years of life increases the risk of incident asthma by the age of 6 years.

Mechanisms of T cell plasticity

Continuing with the topic of T helper cell “shapeshifting,” Hirahara et al. report on the complexity of environmental determinants and epigenetic factors that orchestrate T helper cell plastic responses (Journal of Allergy and Clinical Immunology 2013; 131(5):1276-1287). 

The authors discuss the regulatory and metabolic factors that affect the plastic capabilities of helper T cells.  Beginning with an excellent overview of the current taxonomy of Th cells, Hirahara et al. reviews the current understanding of CD4 T cell fate and their homeostatic interactions within T helper cell lineages. 

Further discussion addresses the idea of “signature” transcription factors and cytokine production in T cell lineages.  The authors question the accuracy and usefulness of this static characterization in light of the accumulating knowledge of T helper cell capacity for expression of multiple transcription factors and cross-family cytokines under the influence of different pathological contexts.   The complexity and variable expression of “master” transcription regulators is covered, in particular the STAT family of binding proteins. 

Hirahara et al. go on to discuss the transcription factor “orchestra” that permits the observed plasticity in response to different environmental conditions.  Transcription, epigenetic, and metabolic systems are discussed, with particular elaboration on those elements that are responsible for the accessibility of genes that can be transcribed.  Discussion includes active and silent histone modifiers, methylation, and “enhancers” found in junk DNA that are now being discovered as critical to gene expression. 

The authors conclude noting that future therapeutic approaches could possibly manipulate “good” CD4 T cell phenotypes to persist, while diminishing “bad” phenotypes.  Importantly, they point out that existing technologies may provide the tools necessary to accomplish this, but must be re-evaluated for their impact on factors that promote helper T cell plasticity. 

Chameleon T cells

Lloyd and Saglani present us with a new perspective on T cells as major players in asthma genesis this month (Journal of Allergy and Clinical Immunology 2013; 131(5):1267-1274). They discuss the classic Th2 model of asthma, and then begin to probe the inconsistencies that have arisen around this paradigm in light of current research and new therapeutics.

Lloyd and Saglani focus on current knowledge of the heterogeneity of asthma phenotypes, the lung epithelium interface, and the less than expected efficacy of new, Th2-targeted therapies to frame their discussions about the various types of effector T cell subsets including classic Th2 cells, Th17 and -22 cells, T regulatory cells, and the novel Th9 subset. The authors emphasize, where relevant, that T cell cytokines are now known to be associated with non-immune cell sources, such as the lung epithelium, and that is an important predicator of effector response. In fact, many T cell-related cytokines have both positive and negative modulating effects that are dependent on the cell type that produced them.

The authors review T cell plasticity as demonstrated in current mechanistic findings. For example, a novel T cell that expresses both GATA 3 and RORgt and secretes both Th2 and Th17 cytokines has recently been reported. This cell line elicited an augmented and more diverse inflammatory response in the lung. They also note that T cells can express more than one transcription factor and that it may be related to the environment within which the response is generated.

The critical role of the lung epithelium and its interactions with allergens and pathogens is highlighted, noting its primary role in initiating and orchestrating the sensitivity response. Further, Lloyd and Saglani comment that the characteristics of a response are variable and are determined by genetic environment and the cell that are the source of the cytokines. They point out that exogenous environmental conditions, such as smoke and pollution, also impact the characterization of the response.

Lloyd and Saglani conclude urging the development of more sophisticated methods for characterizing asthma response phenotypes in order to design more effective interventions. They point out that simple categorization of cell function and cytokine profile is misleading with regard to appropriate therapies, citing the mepolizumab clinical trial as an example. The authors suggest that manipulation of T cell fate and function, rather than blockade of their downstream cytokine products, should be explored as therapeutic alternatives.

The B cell encyclopedia of lung disease

Lung disease researchers could be accused of an excessive focus on aberrant T cell mechanisms in studies of most airway diseases.  In this month’s issue, Kato and co-authors have elegantly restored some balance to this T cell biology-centric perspective [p933-957#].  In what can only be described as an encyclopedic version of a B cell immunology textbook, complete with impressive tables and illustrated figures, Kato et al. deliver the sum of current thinking and knowledge on B cell and plasma cell biology in the respiratory system. [Journal of Allergy and Clinical Immunology 2013;131(4):933-957]

The authors begin with a comprehensive review of adaptive immunity including B lymphocyte development, lineage differentiation and commitment in secondary lymphoid organs [SLO] under the influence of cytokines, class switch recombination, and chemokine-induced trafficking and recirculation.  Kato et al. discusses B cell and plasma cell localization and activation in the airway parenchyma, draining lymph nodes and mucosa.

In particular, Kato et al. cover B cell-associated diseases that manifest in the respiratory system, such as systemic lupus erythematosus [SLE], and the targeted therapies that are currently approved for treatment or undergoing clinical trials.  A few highlights:

•    Anti-IL-9, a Th cytokine that acts on B-cells and mast cells, is in clinical trials as a therapy for asthma.
•    Anti-IL-6 receptor, approved for use in the treatment of rheumatoid arthritis, has been proposed as therapy for asthma and COPD, and is in clinical trials for cancer treatment.
•    Anti-IFNα is in clinical trials for SLE.
•    Anti-BAFF has been approved for the treatment of SLE.

The authors review B lymphocyte organization in the airway, critical airway immunoglobulins and associated lung diseases, such as the hyper-Ig syndromes, and the commonality of excessive B cell expansion with subsequent loss of self-tolerance that characterizes certain lung diseases such as hypersensitivity pneumonitis, rheumatoid arthritis, and Sjogren’s disease.  They conclude posing important questions that remain, which are stalling the development of therapies. 

A clinical picture of recalcitrant chronic rhinosinusitis

Dr. Daniel Hamilos [p1263-1264] discusses  the importance of microbes (viruses, bacteria and fungi) in chronic rhinosinusitis [CRS] in this month’s issue [Journal of Allergy and Clinical Immunology 2013; 131(4):1263-1264] Starting with a case report, the author reviews the current state of knowledge of CRS with [CRSwNP] and without [CRSsNP] nasal polyposis and further discusses the definitions of refractory and recalcitrant CRS.  CME questions are included at the end of the article.

Dr. Hamilos notes that eosinophilic inflammation is present to some degree in both CRSwNP and CRSsNP patients, whereas neutrophilia is more common in CRSsNP.  While there is little evidence for persistent viral infection in CRS, there is evidence for persistent infection with Staphylococcus aureus and/or Pseudomonas aeruginosa in sinus tissue  in roughly 80% of refractory CRS cases.  The presence of these bacteria is often found in association with “biofilm” formation.  The author discusses biofilm and studies showing that its presence is associated with more severe disease and poorer outcomes.  The fungus Alternaria is also more frequently detected in CRS tissues than in tissues from healthy patients. 

The author discusses the various components of innate and adaptive immunity that function in response to microbial colonization or infection in CRS patients.  Examples of key observations include the presence of  a Th2 inflammatory bias in CRSwNP that negatively impacts TLR-9 function.  Dr. Hamilos wraps up commenting that more precise clinical characterization of CRS patients based on their  microbial and immunological phenotype is needed to assist clinicians in designing more effective treatment strategies. 

Phenotypic heterogeneity in COPD and asthma

It has come as small comfort for pulmonary clinicians that the two most prevalent obstructive lung diseases, COPD and asthma, are being characterized as phenotypically heterogeneous.  While it sheds light on the challenging clinical management of patients with these diagnoses, it dredges up more concerns about how exactly this variability in presentation should and could be addressed to mitigate the disease-related impairment.

This month’s Clinical Review from Carolan and Sutherland [Journal of Allergy & Clinical Immunology 2013; 131(3): 627-634] compiles important advances in understanding COPD phenotypes, current knowledge of asthma phenotypes, where they overlap and the focus of therapies.  The authors cover guidelines, clinical phenotypes, exacerbations and morbidity in both diseases.  They also discuss radiologic phenotypes in COPD and the promising predictive tool, the BODE index, which applies BMI, obstruction, dypsnea, and exercise capacity to predict disease progression with greater accuracy than decline in FEV₁. 

Carolan and Sutherland note that COPD, unlike asthma, has not yet been sensitively correlated to any inflammatory biomarker, which has impaired programs for targeted drug development in COPD.  Phenotypic cluster analyses for both diseases are also covered in the authors’ review.  They comment that these efforts are creating alternative perspectives that may be useful for improving management of the variable clinical presentations.  Improved characterization of phenotype variability would permit development of personalized treatment regimens for both COPD and asthma. 

Dietary intervention for EoE remission

An article by Lucendo et al in this month’s issue [Journal of Allergy & Clinical Immunology 2013; 131(3): 797-804] provides convincing evidence supporting a drug-free therapy for eosinophilic esophagitis [EoE].  Noting that food elimination diets in children with EoE are being reported as successful for a majority of patients, the authors designed a six-food elimination diet [SFED] study involving adult EoE patients.  The six foods selected – cow’s milk, soy, cereals, eggs, nuts and legumes, and fish – were selected based on previous reports of their common association with EoE. 

Endoscopy, IgE and skin prick testing were performed to confirm diagnosis, determine EoE remission, and upon food rechallenge.  Lucendo et al report that 73% of subjects had clinical improvement and statistically significant reduction in esophageal mucosal eosinophilia.  Food challenge results showed that 1 food was the offender in approximately a third of the subjects, 2 foods in another third and 3 or more foods in the last third.  Cow’s milk was the most common food trigger affecting 62% of subjects, followed by wheat and eggs.  The authors report that among those who maintained the food avoidance at the 2 and 3 year follow up EoE remained in remission clinically and pathologically and that the subjects had not required medications for EoE during that period. 

Of particular interest, Lucendo et al report very low concordance and predictive power of IgE and skin prick testing with regard to food triggers.  They suggest that this may point to EoE as a delayed hypersensitivity response rather than an IgE-associated one. 

EoE may constitute a new, different type of food allergy, pathophysiologically closer to celiac disease than to food-triggered anaphylaxis. In fact, common IgE-based allergy tests are not sensitive in celiac patients for diagnosing the disease, even when this is also an immunologically mediated disorder. As a result, small bowel biopsies remain essential for diagnosing most patients. As in celiac disease, the mechanisms leading to EoE may be predominantly cell-mediated, but we lack specific peripheral markers that may help us in diagnosing and monitoring the disease in such as way as celiac serology does. Looking for new non-invasive markers of EoE that allow us to predict those exact food triggers and avoiding repeated endoscopies and biopsies are new challenges for EoE researchers.

The microbiota in induced sputum

Recent research has shown that the bacterial constituents of lungs from patients with asthma differ markedly from their non-asthma comparators.  Specifically, asthma lungs have increased predominance of Proteobacteria as well as higher bacterial load.  These findings came from subjects on chronic ICS therapy, which is known to be immunosuppressive.  Marri et al. in this month’s issue present important results from their investigation on lung bacteria from asthma patients not on ICS therapy (J Allergy Clin Immunol 2013; 131(2): 346-352).

The authors analyzed induced sputum from 10 asthma subjects and 10 non-asthma subjects.  Bacterial 16s rRNA was sequenced and compared to data from the Ribosomal Database Project.  All samples contained 5 phyla of bacteria, Firmicutes, Proteobacteria, Actinobacteria, Fusobacteria, and Bacteroides.  Sputum from asthma subjects had significantly higher percentages of Proteobacteria with a concordant drop in Firmicutes prevalence as compared to sputum from non-asthma subjects.  They also found increased bacterial load in the asthma subjects as well as increased bacterial diversity.   Marri et al. report a higher relative abundance of bacterial families that contain Moraxella catarrhalis and  Haemophilus influenza in asthma subjects, potentially implicating these pathogens in asthma pathogenesis.  They also note that atopic status did not influence the results.

 The authors conclude that an altered lung bacterial community in asthma patients is not attributable to ICS therapy or atopy, though further investigations are required to determine if the differential bacterial components are causal or consequential.  Antibacterial therapeutics aimed at Proteobacteria might be one of the ways to reduce the bacterial load in asthmatics.

 

Recent advancement in understanding primary immunodeficiencies

The International Union of Immunological Societies [IUIS] published an updated classification in 2011 of primary immunodeficiency diseases [PID] as part of their on-going work to collate and disseminate PID research findings reported worldwide.  This month, Parvaneh et al. provide a compendium of reports that have been published since the 2011 update (J Allergy Clin Immunol 2013; 131(2):314-323). 

Following the 2011 IUIS classification, newly published reports are summarized under combined immunodeficiences, syndromes with associated immunodeficiencies, predominant antibody defects, immune dysregulation, congenital phagocytic defects, defects of innate immunity, and autoinflammatory disorders.  Some highlights are provided below.

TCRα gene mutation/TCRαβ T cell depletion: Two patients from unrelated Pakistani families were identified after presenting with infection susceptibility, autoimmunity, T cell proliferation dysfunction, but normal antibody responses.  Both patients’ T cells were missing surface expression of TCRαβ, though CD3+ cells expressed TCRgd.  A homozygous mutation in the T cell receptor alpha constant [TRAC] gene was found in both patients.  Both patients were treated successfully with sibling bone marrow transplants. 

WIP deficiency/Wiskott-Aldrich Syndrome-like phenotype:Wiskott-Aldrich protein [WASP] binds with WASP-interacting protein [WIP] to form a stable complex.  A Morrocan infant presented with symptoms suggesting WAS, such as recurrent infections, eczema, and T cell lymphopenia.  Sequencing demonstrated normal WASP sequence and expression, though WASP was undetectable in the patient’s cells.  Additional analyses determined that WIP was absent as well and that a homozygous nonsense mutation was present in the WIPF1 gene, coding for WIP.  The patient was treated with unrelated cord blood transplantation at 4½ months and was reported to be thriving at 21 months. 

Parvaneh et al. conclude noting that reports of novel primary immunodeficiencies are increasing. There is no formal evidence that the incidence of PID has increased; however, improved treatment, allowing long-term survival may have increased the pool of mutant alleles in the general population.  The growing number of reportsofnew PIDs probably reflects several factors including:1) the increasing awareness of practicing physicians regarding the clinical and laboratory manifestations of PID; 2) improved networking (or collaboration) within the international PID community; 3) new immunological techniques to analyze leukocyte subsets and function; and finally 4) usage of next generation sequencing (whole exome sequencing) which has had a major impact on the field.  The authors emphasize the importance of this expansion in knowledge, not only to improve the patients’ outcomes, but also to contribute to the general understanding of these immune diseases.