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.