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Monday, November 28, 2016

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity

Over the past 25 years, the rates of both obesity and asthma have increased dramatically.  These are related to one another, with a 92% increased risk of asthma in people whose body mass index (BMI) exceeds 30 kg/m2. People who do lose weight through bariatric surgery or dietary restriction, tend to show improvement in their bronchial hyperresponsiveness, the major feature of asthma.  The reason for this correlation is not well understood.  IL-33, a intercellular messenger that skews helper T cells towards allergies, is produced by fat cells.  IL33 also induces type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), two more recently identified sets of immune cells in fat and the lungs. 

In this month’s issue of the Journal of Allergy and Clinical Immunology, Everaere and colleagues use mouse models to investigate the roles of innate lymphoid cells in the correlation between asthma and obesity (J Allergy Clin Immunol 2016; 138(5): 1309-1318).  The mice were given a high-fat diet to induce obesity and were then sensitized to dust mites.  Their lung secretions were isolated by bronchoaveolar lavage (BAL) and checked for various proteins, RNA, and cell types by histology and flow cytometry. 

They found that nonsensitized obese mice had increased ILC counts and tissue eosinophils, cells that mediate damage in asthma, compared to lean mice.  These mice also had high IL33 and IL-1-Beta levels.  When ILCs were depleted using an anti-CD90 antibody, there was decreased infiltration by cells that prompt allergic inflammation, such as TH2 and TH17 cells.

Altogether, these results suggest that ILC2s and ILC3s mediate and exacerbate airway inflammation in obese mice.  This opens the possibility of using anti-IL5 antibodies in treating asthma for obese patients.

Wednesday, November 23, 2016

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice

Eosinophilic esophagitis (EoE) is an allergic disorder seen in approximately 1 out of 2000 people in the United States.  Young children often present with vomiting and failure to thrive, while older children and adults may have difficulties swallowing, food impaction, or strictures in their esophagus.  Despite increasing awareness and diagnosis, the etiology remains unclear.  Past studies support the role of a subset of Helper T-cells, called TH2 cells, which are also present in many other allergic diseases, including atopic dermatitis (AD).  In fact, approximately half of patients with EoE have AD.  But why is that so?

In this month’s issue of the Journal of Allergy and Clinical Immunology, Venturelli and colleagues investigate the role of abnormal skin barriers in the development of EoE, and, in particular, the role of IL-33, a chemical messenger whose levels are elevated in both EoE and AD (J Allergy Clin Immunol 2016; 138(5): 1367-1380).  They also investigated the role of ST2, an IL-33 receptor found on basophils using a mouse model. They applied ovalbumin to the mechanically injured skin of wild-type mice, and then to the skin of mice lacking filaggrin (ft/ft), which tend to develop AD-like skin lesions.  They then challenged both strains of mice with intra-nasal ovalbumin.  The esophagi of these mice were then examined microscopically and through advanced genetic analytic techniques. 

They found that a disrupted skin barrier (by tape stripping or a Filaggrin gene mutation) promotes the development of EoE, and that this is mediated by IL-33, ST2, and basophils.  They also reported that patients with EoE have increased ST2 in their esophagus. Their findings suggest that IL-33 could be a potential link between AD and EoE.  This is an important step in understanding how patients with AD and filaggrin deficiency tend to develop EoE.  Just as importantly, it may prompt development of new medications that block IL-33 or ST2, which could be effective targets for EoE.

Tuesday, November 22, 2016

Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania

Chronic Rhinosinusitis is a chronic disease of the sinuses that’s seen in up to 27% of adults in Europe and 14% in the United States.  Grouped in two categories, chronic rhinosinusitis with nasal polyposis (CRwNP) and chronic rhinosinusitis without nasal polyposis (CRsNP), chronic rhinosinusitis appears to be mediated by very distinct immune mechanisms.  Interestingly, there are differences in the clinical presentations between ethnic groups as well as in the types and levels of cytokines produced by immune cells. 

Wang and colleagues expand upon this prior knowledge by looking at 435 patients with chronic rhinosinusitis, and comparing them to 138 control subjects (J Allergy Clin Immunol 2016; 138(5): 1344-1353).  They were recruited from six regions covering Europe, Australia, and Asia.  They checked the levels of cytokines, inflammatory mediators and IgE, the antibody mediating allergies, from the mucosa of subjects.  The levels of these parameters were then compared among the different subjects.

They found that there was a large variety of expression of these cytokines among the different subjects in various regions.  This suggests that chronic rhinosinusitis is more of an umbrella term and that there are actually many different endotypes of patients with chronic rhinosinusitis.  

Thursday, October 13, 2016

Asthma in the inner city: Three Analyses of the APIC Study

Asthma is an incredibly variable disease with its impact on people and molecular and cellular mechanisms what it does to the lungs and rest of the body.  This month’s issue of JACI features three articles by Zoratti et al (J Allergy Clin Immunol 2016; 138(4): 1016-1029), Pongracic et al (J Allergy Clin Immunol 2016; 138(4): 1030-1041), and Liu et al (J Allergy Clin Immunol 2016; 138(4): 1042-1050), covering asthma among inner city children.  They examine factors that determine the phenotype, severity and disease control, based on data they obtained from the Asthma Phenotypes in the Inner City (APIC) study, which looked at children aged 6 to 17 years and examined them every 2 months for one year.  Even though their techniques are all slightly different, all three analyses determined that allergic inflammation was a very significant contributor to disease.  In addition to rhinitis, pulmonary physiology also influenced severity and ability to control asthma despite guideline-based therapy.  Body mass index and environmental tobacco exposure were also quite significant in explaining severity of and ability to control disease activity, respectively.  Interestingly, Vitamin D did not have a significant effect on the control of asthma.  Altogether, the results of the APIC study provide insights into what strategies can be implemented to bring asthma under better control in inner cities.  Identifying those who are most at risk through the results of these studies, and targeting allergic inflammation, both in the upper or the lower respiratory passages, may help to reduce the burden of asthma.

Wednesday, October 12, 2016

Early-life gut microbiome composition and milk allergy resolution

Allergy to cow’s milk affects roughly one in fifty children, rendering them at risk for potentially deadly allergic reactions as well as for poor nutrition that comes with avoiding cow’s milk. In this month’s issue of JACI, Bunyavanich and colleagues relay the results of their research on how gut bacteria might influence the course of this disease (J Allergy Clin Immunol 2016; 138(4): 1122-1130).  They looked at the stools of 234 milk allergic children ranging in age from 3 to 16 months. They used 16s rRNA sequencing to profile the different types of gut bacteria and followed the children up to age 8 years.

They found that among children age 3 to 6 months, bacteria in the Firmicutes phylum and Clostridia class were associated with resolution of milk allergy by age 8 years.  This is consistent with preliminary findings from mouse models that also show that Clostridia have a role in regulating sensitization to food allergens.  However, these bacteria appear to have a very short time window to exert their effect, because there was no association in children beyond 6 months of age.  It is possible that the immune systems of infants up to six months of age are easier to tolerize, or that the introduction of solid foods at around age 6 months obscures this association.

It is possible that the fatty acids produced by bacteria may have potent roles in reestablishing tolerance, but the study was not structured to answer that question.  Other questions left to answer include whether supplementation with probiotics can help reestablish tolerance and whether introducing these bacteria would be safe.

Monday, September 12, 2016

Regulation of the host immune system by helminth parasites

They may be called parasites, but we may owe helminth worms a great deal of appreciation.  At least, that’s what Dr Maizels and McSorley write in this month’s issue of the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 138(3): 666-675).  To those who are unaware, there are only about a dozen or so species of helminths that commonly infect human beings, but they affect more than 2 billion people worldwide.  Their wide prevalence is a testament to the fact that they can evade host defenses and establish niches from themselves within our bodies.  Learning about how they do this can provide valuable insights about how our immune system works.

They do this through many different ways.  T-cells from helminth-infected asymptomatic humans show an increase in IL-4, IL-10, and TGF-beta over IL-17 and Interferon-gamma, suggesting that parasites skew our T-cells in a way that reduces the immune system’s ability to clear helminths.  In particular, the production of IL-10 correlates with the proliferation of regulatory T-cells, which in turn drive the body to produce IgG4 instead of pro-allergic IgE antibodies.  Interestingly, when helminths are cleared away by drug treatment, IgG4 levels decrease, which suggests that it is the helminths that are driving this movement.  Very broadly, this affects a host of other cells within the body, including macrophages, dendritic cells, and B-cells, which also seem to become more tolerating of these helminths.

The end-result of these changes is a mixed bag.  Helminths prevent the body from creating polyclonal responses, leading to decreased defense against pathogens like mycobacterium tuberculosis, and compromising the effect of childhood vaccines.  They also increase the risk of developing cancer, change metabolic processes (and maybe even protect against diseases like diabetes mellitus), and alter the bacteria that make up our gut microbiome.  Not surprisingly, at least in mice, helminth infection attenuates allergic responses as well. 

These insights are incredibly important, not only because they allow us to understand the immune system in a clearer manner, but also because research in this area holds the promise of creating new therapies that mimic the parasite molecules to treat a number of inflammatory diseases.

Friday, September 9, 2016

Creation and implementation of SAMPRO™: A school-based asthma management program

Childhood asthma affects over 6 million children in the United States.  In addition to its effects on physical health, asthma has an impact on academic and personal development.  Asthma related absences lead to decreased reading proficiency and increased learning disabilities.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Lemanske and colleagues describe the creation of a central resource, termed SAMPRO (School-based Asthma Management Program). (J Allergy Clin Immunol 2016; 138(3): 711-723).

The SAMPRO workforce identified four components for development and implementation: (1) a circle of support facilitating communication, (2) asthma management plans, (3) comprehensive education plan, and (4) assessment of school environment. 

The circle of support is comprised of persons involved in taking care of children, including family, school personnel, clinicians, and community members.  School nurses in particular are pivotal in helping to ensure that children with asthma receive proper treatment.  In fact, the SAMPRO workforce strongly endorses full-time licensed registered nurses in schools (REF).

Secondly, the SAMPRO workforce strongly endorses the dissemination of asthma action plans among members of the circle of support.  Because asthma action plans have been shown to reduce deaths and emergency room visits, this is a high priority.  Electronic health information exchanges, web portals and continuity of care documents are methods that can help with this.

Thirdly, education of members within the circle of support has been highlighted, especially for school nurses.  The SAMPRO toolbox provides resources that can support nurses and others in managing chronic diseases in children.

Lastly, environmental triggers like pests, and poor indoor air quality have to be addressed.  55% of school districts require monthly campus-wide pest inspections but there remains a lot to be done.  The SAMPRO workforce recommends development of an Indoor Air Quality (IAQ) management program to help promote a healthy school environment. School staff needs to be educated in order to help empower them to make changes to the environment.

Altogether, these recommendations can help keep asthma from getting out of control enusring that children can continue to be at school, learning and growing rather than struggling with their breathing problems.