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.