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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.

Clinical trial data access: Opening doors with TrialShare

The issue of “Data Sharing” has received considerable coverage in the medical literature and in the lay press recently.  There is a push to increase data transparency and to open such data for secondary use and analysis.  There have been different approaches to this issue with varying degrees of access. .  In this month’s issue of the Journal of Allergy and Clinical Immunology, Asare and colleagues describe their experiences with TrialShare, an online research resource providing data from the Immune Tolerance Network (ITN) of the National Institute for Allergy and Infectious Diseases (NIAID) (J Allergy Clin Immunol 2016; 138(3): 724-726).

Users of TrialShare have access to clinical trial protocols, case report forms, complete trial results, extensive de-identified participant level data, downloadable datasets for offline use, the ability to create alternate analyses, and a searchable database of ITN bio-specimen repository, among other features. 

The only requirement for registration is an e-mail address and password to establish an account.  In the 24 months since its introduction, a variety of different academic, government, nonprofit, and corporate individuals have used it to view and analyze data.

There are still many barriers preventing widespread use of data sharing software, but TrialShare is working towards breaking these down.  Unlike other data sharing projects, like the Yale Open Data Access Project and the Clinical Studies Data Access Project, there are no negotiation of data-use agreements and provisions to protect the competitive advantage of primary data generators.  Although there have been concerns that by sharing information more freely, there may be potential improper use of data, the experience of TrialShare has not demonstrated this.  And there is a vast infrastructure in the background to ensure that costs do not become burdensome for those carrying out clinical trials (about 0.5 to 2% of total costs of a clinical trial).

TrialShare is open to the biomedical community. Asare and colleagues invite us all to utilize this vital tool in order to ensure that the data being generated from immunology-related clinical trials is being analyzed in a free and open manner.

Wednesday, August 17, 2016

Cellular and molecular immunologic mechanisms in patients with atopic dermatitis

Atopic dermatitis is one of the most common chronic skin diseases among both adults and children.  Although it is often thought of as a skin disease, it also affects many organ systems. There remain a lot of gaps in our knowledge of atopic dermatitis, but researchers are developing a greater appreciation for its complexity of atopic dermatitis and introducing new treatments for this frustrating disease.

From an immunologic point of view, atopic dermatitis appears to be a collection of many different variants.  These endotypes are just recently beginning to be described, but involve the various arms of the immune system.  Defects in the innate immune system skew the skin towards inflammation; polarization of T-cells (Th2, Th17, and Th22) lead to further inflammation.  Other cell types, like dendritic cells, eosinophils, and mast cells, play important roles in the development of atopic dermatitis.  The interplay between immune cells and skin barrier proteins, like filaggrin, is also being explored.  Filaggrin influences cell differentiation, prevents water loss, and maintains the integrity of the skin barrier.  With defects in filaggrin, allergens penetrate deeper into the skin and bacteria like staphylococcus aureus are more likely to colonize the skin.

To make things even more complicated, as time progresses, so too does the disease, and patients can have an “atopic march” towards asthma, allergic rhinitis, and other allergic diseases.  Additionally, patients with atopic dermatitis have changes in the bacteria that colonize their skin and gut.  They have less microbial diversity, particularly when there is greater inflammation.  The role of these bacteria are being increasingly fleshed out with basic science and clinical research.

These insights are helping to guide new therapies.  In particular, dupilumab, an antagonist of the IL-4 receptor alpha chain, is showing promise in the treatment of atopic dermatitis.  And in those that don’t respond to dupilumab, there’s interest in other therapies like the IL-6 receptor antagonist tocilizumab.  As Werfel and colleagues note, it is difficult to find the best treatment for atopic dermatitis without knowing the pathophysiology behind the disease and its various endotypes (J Allergy Clin Immunol 2016; 138(2): 336-349).  In the future, with better knowledge, it may be possible to personalize appropriate treatment by identifying the correct endotype for each patient.

Tuesday, August 9, 2016

Multidisciplinary interventions in the management of atopic dermatitis

Atopic dermatitis is the most common skin disease in children, affecting up to 1 in 5 children in the United States.  But it doesn’t do it justice to call it just a skin disease.  The itching and scratching leads to a breakdown of the skin, disruptions in sleep, conflicts with parents, and an inability to concentrate at school.  Studies have shown that children with atopic dermatitis have a higher risk of developing mental health disorders like attention-deficit hypersensitivity disorder, anxiety, depression, conduct disorder, and autism.

Because atopic dermatitis does not have a single cause and has such far-ranging effects, management can be a challenge.  As LeBovidge and colleagues describe, multidisciplinary interventions are being investigated as a way to help these children (J Allergy Clin Immunol 2016; 138(2): 325-334).  Evaluation by an allergist or dermatologist can help to determine triggers, and education by nurses can help improve adherence and technique of applying emollients.  Psychologists can help redirect unhelpful compulsive behaviors like scratching into more helpful activities, such as re-application of moisturizers.  And nutritionists can ensure that children, especially those that have food allergies that require restriction of certain foods, receive enough Vitamin D and other nutrients.

Several institutions have embraced this multidisciplinary approach, but randomized controlled trials are limited.  Some group-based models have shown an improvement in control but others found no difference in disease severity, quality of life, or medical therapy use.  New models of collaboration between specialists and primary care providers are being developed in order to improve the quality of care.  It is hoped that improving the quality of care will decrease the economic burden of the disease.

Atopic dermatitis may be a skin disease, but its effects are felt in more than just the skin.  In order to get the disease under better control, new ways of delivering care will have to be developed.  Professionals in various fields, including allergists, dermatologists, nurses, nutritionists, and psychologists, are aligning with parents to break the itch-scratch cycle that causes such misery to the millions to have atopic dermatitis.

Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march

Some things are so evident that we take them for granted.  Take our skin for example.  We live in our skin and, for the most part, don’t give a second thought about it.  But skin is more than meets the eye.  It is vital for immunity, not only because it protects us from the outside but also because it fine tunes how our immune system responds to the various stimuli it encounters.  For those who have atopic dermatitis, a type of allergic disease that affects the skin leading it to become dry, irritated, and thickened, we see one result of a poor skin function.  In this month’s issue of JACI, Egawa and Kabashima discuss the role of skin barrier dysfunction in atopic dermatitis (J Allergy Clin Immunol 2016; 138(2): 350-358).

To understand the skin, we have to think about it in layers.  The topmost layer, called the stratum corneum, is a little like a wall, with flattened cells called corneocytes working like bricks and intercellular lipids functioning as mortar.  Together, they maintain the integrity of the skin.  But in atopic dermatitis, the wall is weakened.  Mutations in filaggrin, a protein important in making the corneocytes, have been associated with an increased risk of developing atopic dermatitis.
With the growing knowledge of genetics and immunology, there are beginning to be great insights into how atopic dermatitis starts to take hold.  In addition to filaggrin mutations, there’s a host of newer mutations that lead to the irritation, peeling, and thickening of the skin.  Mutations in genes encoding some proteins, like LEKTI and KLKs, have to do with the way that skin desquamates, or sheds, whereas others, like CLDN1, influence the tight junctions that maintain the integrity of the skin barrier.  And, in addition to these structural proteins, the immunologic messengers, particularly type 2 cytokines like IL-4, IL-13, IL-31, and IL-33, are found to be key in the development of atopic dermatitis.

As Egawa and Kabashima note, the skin is a very complex organ, and one that we are just starting to understand from an immunologic perspective.  Its importance cannot be overstated, not only because it brings us closer to figuring out what causes diseases like atopic dermatitis, but also because it opens the door towards finding new, effective medications and therapies that can target proteins like filaggrin.  In turn, this can improve the lives of the millions who live with atopic dermatitis, and the diseases that are associated with it.

Monday, July 11, 2016

Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation

You are more than just one human being.  That may sound like an inspirational quote, but it’s actually a scientific fact: there are literally millions of bacteria living on, in, and around you that play crucial roles in the ways that your body and your mind work.  And now, thanks to newer technology, we have the ability to see how these ‘old friends’ – bacteria have likely been around since the emergence of humans – interact with our own cells to change how our immune system works.
In this month’s issue of the Journal of Allergy and Clinical Immunology, Garn and colleagues provide an overview of how these microbes influence our metabolism and can lead to inflammation, based on the insights from the International von-Behring-Röntgen-Symposium (J Allergy Clin Immunol 2016; 138(1): 47-56).  While our knowledge of the microbiome keeps on growing, the fact is that there remains so much to be researched.  For example, how does our modern age of hygiene, where we have eliminated so many of the old infectious agents with which we have co-evolved, impact chronic inflammation?  How do resident microbes interact with food to cause inflammation, or resolve it?  What role does biodiversity (which plummets while on antibiotics) play in maintaining the balance between promotion and resolution of inflammation?  And how do these microbes educate our immune systems during infancy and childhood?  Unfortunately, these questions remain mostly unanswered but there are some promising leads.  For example, a study involving 560 babies of families from Baltimore, New York City, and St. Louis demonstrated that exposure to allergens in the first few months of life may be associated with a reduced risk of recurrent wheeze, while exposure to microbes may reduce both the risk of atopy and atopy plus wheeze.

Extracellular RNA, DNA, and proteins that may come from microbes have been shown to mediate inflammation.  These molecules alter the cytokines released by our own cells, and can lead to upregulation of inflammatory responses.  While research is extremely preliminary, the influence of the microbiome on allergic, autoimmune, gastrointestinal, and neuropsychiatric disease is becoming more and more appreciated, possibly opening doors to new management strategies.  So embrace your inner germs and realize that you’re more than just one, sole human being.