Peanut, milk and wheat intake during pregnancy is associated with reduced allergy and asthma in children

The relationship between maternal diet and childhood allergy and asthma is controversial.  Not long ago, the American Academy of Pediatrics advised that maternal dietary restrictions are not necessary with the possible exception of excluding peanuts.  Subsequent systematic reviews concluded that the evidence was inadequate to support any dietary restrictions during pregnancy. In fact, recent research suggests that fetal exposure to common food allergens may be beneficial. Bunyavanich et al examined the associations between maternal intake of common childhood food allergens during pregnancy and childhood asthma and allergies (J Allergy Clin Immunol 2014; 133(5): 1373-1382).

 

The authors studied a healthy pre-birth cohort of 1277 mother-child pairs from the United States and used food frequency questionnaires administered during pregnancy. Children were assessed for food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum specific IgE levels at a mean age of 7.9 years. They discovered that higher maternal peanut intake during the first trimester was associated with 47% reduced odds of peanut allergic reaction. Higher milk intake during the first trimester was associated with reduced asthma and allergic rhinitis, while higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis. The authors discuss that the first trimester is a formative period of fetal immune development and the mother’s diet may influence helper T cell differentiation as well as fetal airway differentiation. 

The results of this study do not support avoidance of specific foods during pregnancy to prevent allergy and asthma in children.  The authors conclude that the inclusion of peanut, milk, and wheat during pregnancy could be beneficial for the prevention of allergic diseases.

Exposure to food allergens through inflamed skin promotes intestinal food allergy via the TSLP-basophil axis

Along with all allergic diseases, the prevalence of food allergies has increased markedly in recent decades in industrialized nations. An estimated 5% of children and up to 4% of adults are living with food allergy and the fear of having a life threatening allergic reaction. Incidentally, atopic dermatitis (AD) is a known risk factor for developing food allergies later in life. However, the mechanisms through which antigen sensitization in the skin can predispose to allergic inflammation in the intestine remain unclear. Considering AD skin lesions are associated with elevated thymic stromal lymphopoietin (TSLP) expression and basophil infiltration, Noti et al determined that TSLP-elicited basophils promote antigen-induced intestinal food allergy (J Allergy Clin Immunol 2014; 133(5): 1390-99).

 The authors employed a new model of food allergy by sensitizing mice to food antigens on an AD-like skin lesion that predisposed to allergic inflammation in the intestine upon oral antigen feeding. Oral antigen exposure of skin-sensitized mice resulted in antigen specific IgE responses, type-2 inflammation and the accumulation of mast cells in the intestine. In addition to intestinal food allergy, mice also developed eosinophilic esophagitis (EoE)-like disease, a food allergy related disorder. They determined that antigen-induced food allergy is dependent on TSLP that elicits basophils to promote antigen-specific Th2 cytokine responses. Furthermore, the authors demonstrate that TSLP-elicited basophils are both necessary and sufficient to promote IgE-mediated intestinal food allergy in their model.

Despite the challenges associated with mouse models, Noti and colleagues have provided significant insight into mechanisms that mediate food allergy by using  a novel animal model that mimics some characteristics of human disease.  Targeting the TSLP-basophil axis may offer a novel therapeutic approach to treatment and prevention of food allergy.  

Innate lymphoid cells and asthma

The recent discovery of innate lymphoid cells (ILCs) has changed our understanding of immune regulation and uncovers the importance of innate immunity in the development of asthma. Historically, asthma was thought to be a Th2 mediated disease of the adaptive immune system but it has recently become clear that there are several different phenotypes of asthma some of which are non-allergic. In their review, Yu et al discuss the various roles of ILCs in the immune system specific to different asthma phenotypes and other allergic diseases (J Allergy Clin Immunol 2014; 133(4): 943-950).

ILCs are lymphocytes that produce a variety of cytokines similar to CD4+ T cells, but are antigen non-specific, which allows them to function independently of adaptive immunity.  The authors explain that ILC1s are similar to Th1 cells and have been shown to inhibit eosinophilic airway inflammation by promoting eosinophil apoptosis. Several studies show the likeness of ILC2s to Th2 cells in that they produce Th2 cytokines IL-4, IL-5, and IL-13.  ILC2s are found in the lungs of mice and humans with airway hyper responsiveness (AHR) and in the skin of atopic dermatitis patients. Similar to Th17 cells, ILC3s producing IL-17 have been found in the lung of some asthma patients and in the gut of colitis patients, and have been proposed to be implicated in obesity induced asthma, based on studies in mice. 

The authors conclude that at least two of the three types of ILCs are likely to be involved in human asthma, and in regulating both inflammation and homeostasis. The discovery of ILCs also suggests that innate immunity profoundly shapes allergic disease, in the presence or absence of adaptive immunity. For example, while the markers of ILC2s are not fully understood, the ability of ILC2s to interact with other Th2 associated cell types involved in allergy shows promise for asthma research that may lead to improved therapies.

Question for the authors:

Could you elaborate further on how ILCs managed to elude scientists for so long?  

ILCs eluded scientists in the past because they do not express cell surface markers associated with adaptive lymphocytes (e.g., T cells and B cells).  In our zeal to understand adaptive lymphocytes, we gated out other lymphocytes (including ILCs) during flow cytometric analyses.  In effect, we “threw out the baby with the bath water.”

Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts

Live vaccines and the growing neglect of adherence to routine immunizations can be life-threatening to immunodeficient patients.  This prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on the literature and the collective experience of the committee members. Shearer et al describe the relative risk for a child with severe immunodeficiency from close-contact spread of infectious diseases that are vaccine-preventable or from the shedding of live virus or bacteria from individuals who have received a live vaccine (J Allergy Clin Immunol 2014; 133(4): 961-966).  

The risk of acquiring an infection is well known to immediate family members of an immunodeficient child. However, relatives and non-family members who have not been vaccinated or have been vaccinated with live virus or bacteria pose a serious threat to these patients. Complacency is prevalent in society regarding pertussis, measles, mumps, and rubella vaccines. For example, the threat of pertussis to the pediatric population is alarming, especially for immunodeficient patients. This rise of preventable disease is associated with loss of the herd immunity in the general population along with parents avoiding vaccines out of fear of autism despite overwhelming evidence to the contrary. The immunosuppressed subject is at most risk of contracting these infections in crowded living conditions due to the ease of spread of disease by aerosol or oral-fecal route.  While avoidance of these diseases is ideal, the parent of an immunodeficient child must maintain a balance with the needs of a child to develop socially and educationally.

Vaccination for common infections represents a major advancement in the battle of communicable disease that threatens the welfare of humankind, especially the pediatric population. However, the alarming rise of non-immunized individuals could lead to a return of avoidable global epidemics.  Close contact with individuals recently vaccinated with live vaccines may cause the spread of infection to an immunodeficient child.  Shearer et al stress the importance of herd immunity, avoidance of live vaccines, and balancing the needs of this fragile population.

Questions for the authors:

What are the political implications of these findings?

There is no political agenda for those who have vaccine immunizations, only evidence-based science.

Could federal law mandate that all children and adults receive appropriate vaccinations?

That is most unlikely to happen.

Host-microbial interactions in patients with chronic rhinosinusitis

The initiation and perpetuation of chronic rhinosinusitis (CRS) is known to be associated with host-microbial interactions.  Many studies have investigated these interactions with CRS in order to understand the mechanisms of the disease and provide better treatment options.  Dr. Hamilos summarizes the knowledge of host-microbial interactions in regards to normal sinus physiology and pathology, patients with CRS with and without polyps, and allergic fungal rhinosinusitis (AFRS) (J Allergy Clin Immunol 2014; 133(3): 640-653).

 

Much of the research on the subject of CRS has been on bacterial infection and potential defects in innate immunity that might predispose patients to sinus infections.  Of CRS patients undergoing surgical intervention, more than 50% have bacterial biofilm in their diseased sinus tissues.   Biofilm is an important survival mechanism of bacteria allowing for attachment to surfaces.  The biofilm has been described to have an enhanced resistance to antibiotics and is associated with more severe disease and worse surgical outcomes.  Dr. Hamilos explains that less is known about viral or fungal infection in CRS; in fact it remains unclear if upper respiratory tract viruses contribute causally to CRS analogous to their possible role in asthma.  Other research has ruled out defects, such as defects in mucociliary clearance or toll like receptor function as primary defects in CRS.  A decreased level of the antimicrobial protein lactoferrin has been found in sinus secretions, however other antimicrobial protein levels have been found  to be normal. 

CRS research has focused on patients that have either “refractory” disease which can be defined as no improvement following  surgery  and medical management or “recalcitrant” disease which is defined as the recurrence of nasal polyps after polyp surgery.  Studies suggest that patients with recalcitrant nasal polyps have down regulated innate immunity associated with T helper type 2 (Th2) inflammation, potentially causing persistent infection.   While surgical treatment and use of culture-directed antibiotics remain the best treatment options, Dr. Hamilos is hopeful that further understanding of the underlying genetics of CRS and host-microbial interactions will allow for greater insight and more effective treatment options.

Genetic analysis of asthma distinguishes subphenotypes

About 50% of asthmatics that are genetically screened have T helper type 2 (Th2)-driven inflammation that is characterized by improved symptoms with inhaled corticosteroid response, higher IgE levels, and higher peripheral blood eosinophils.  While this genetic profiling is highly valuable by elucidating the pathogenesis of asthma and tailoring individual treatment regimens, bronchial airway epithelium brushings are invasive which limits its application to childhood asthma research.  This realization led Poole et al to determine if less invasive nasal airway epithelium brushings can proxy expression changes seen in the bronchial airway transcriptome in children with asthma (J Allergy Clin Immunol 2014, 133(3): 670-678). 

In a cohort of Puerto Rican children, the authors used whole transcriptome RNA sequencing (RNA-seq) on nasal airway brushings from 10 controls and 10 subjects with asthma and targeted RNA-seq on 50 asthmatics and 50 controls to profile 105 genes. The results were compared to established bronchial and small airway transcriptomes.  They found 90% overlap in expressed genes between the nasal and bronchial transcriptomes.  Clustering analysis identified Th2-high and Th2-low subjects differentiated by the expression of 70 genes including the Th2 cytokines IL-13 and IL-5 which were activated in Th2-high subjects. Furthermore, Th2-high subjects were more likely to have atopy, atopic asthma, high blood eosinophils, and rhinitis compared to Th2-low subjects.  

Their results indicate that nasal airway gene expression profiles largely recapitulate expression profiles in the lung and can be used to identify the Th2-high subphenotype of children with asthma.  The genetic information in nasal airway brushings can easily and effectively identify individuals with IL-13 driven asthma and a Th2-skewed systemic immune response.  Poole shows that this type of analysis identifies Th2 airway inflammation as part of the mechanistic basis of asthma in atopic individuals and it can be used to identify other genes that are dysregulated in asthma but independent of atopic status.  While larger and more diverse population studies are required, this data is valuable in both research and clinical settings. 

See below for an interview between Dr. Donald Leung, Editor-in-Chief of the Journal, and Dr. Max Seibold, one of the authors of the article:

Peanut oral immunotherapy increases Tregs and epigenetically modifies FOXP3

The mechanisms contributing to clinical immune tolerance are largely unknown. The objective of Syed et al was to study the changes associated with clinical immune tolerance in antigen induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy (J Allergy Clin Immunol 2014; 133(2): 500-510). The induction of regulatory T (Treg) cells has been a potential mechanism of maintaining immune tolerance, with Treg deficiencies implicated in the development of allergies.  Fork head box protein 3 (Foxp3) is a transcription factor that regulates Tregs, including natural regulatory Tregs (nTregs) and induced regulatory Tregs (iTregs). Epigenetic modifications to regions within the Foxp3 locus have been associated with stable Foxp3 expression and Treg cell-suppressive function.  

The authors investigated whether antigen-induced Tregs (aiTregs) and humoral and basophil immune markers are induced by OIT in clinically immune tolerant (IT) versus non-tolerant (NT) patients after OIT.  20 participants (with 20 peanut allergic controls undergoing standard avoidance therapy) successfully completed 24 months of OIT, tolerating up to 4g of peanut protein after maintenance therapy.   After 3 months of peanut avoidance, only 7 of 20 participants were defined as IT participants; these 7 avoided peanut for an additional 3 months and only 3 of 7 remained clinically nonreactive (IT).  The peanut induced basophil response was reduced in the OIT participants with a trend of more reduction in the IT group. The IT participants had higher numbers of ai-Treg cells with greater suppressive function and with higher levels of FOXP3 hypomethalation compared with NT and control participants.  The population of ai-Tregs the authors identified during OIT had a marked increase in Foxp3 expression and associated increases in both chemotaxis toward intestinal epithelial cells and suppressive function toward antigen-induced effector T cells (Teff).  Furthermore, dendritic cells (DCs) isolated after OIT therapy significantly decreased the methylation of Foxp3 in Teff cells.

These data suggest that ai-Treg cells are a key regulatory cell type modulating the immune response during OIT and that epigenetic regulation of these T cells might contribute to the induction of such immune tolerance. Although larger phase 2 clinical trials in OIT are justified and feasible, the results may be predictive of a state of operationally defined clinical immune tolerance during peanut OIT and contribute to providing safe and effective therapy for patients with peanut allergy.

Below are some questions posed to the authors regarding their article and the authors’ responses:

Why do there seem to be mixed results about the presence of Treg in food oral immunotherapy in humans?
The gating and definition of Treg is very important. Some labs report CD4+CD25+Foxp3+ cells as Treg but Treg should best be defined by suppression assays on the functional level if there is enough blood sample. In addition, the presence of Foxp3 can indicate an activated CD4+ T cell, not necessarily a Treg and Treg don't have to have Foxp3 to be a Treg.

Is there potential for Type 2 cytokines to be immune markers in IT vs NT participants?

We have examined some Th2 markers by flow cytometry and intracellular staining with no specific trends showing a difference between IT vs NT but further studies are underway.

What if any data is available about ILC2 activation during food allergy?

We are currently examining ILC2 cells in the periphery of food allergic patients.

What could be a potential outcome if patients did not avoid peanut after OIT therapy and included it in their diets?

There are several trials around the world examining this and we will be conducting mechanistic studies to try to understand differences in desensitization vs sustained unresponsiveness long term.