Applying Systems Immunology to the Search for Personalized Biomarkers of Clinical Efficacy: Predicting the T Cell Activation Potential in Vivo From Resting T Cells of Patients

Summary of the study: Applying systems immunology to the search for personalized biomarkers of clinical efficacy: Predicting the T cell activation potential in vivo from resting T cells of patients.

Introduction Allergy affects more than 20% of the populations of most developed countries. The major allergic diseases, allergic rhinitis, asthma, food allergies and urticaria, are chronic, cause major disability, and are costly both to the individual and to the society (World Allergy Organisation (WAO) white book 2013). Besides occupational allergies, the most common allergies are caused by food, pollen, dust, mold, animal dander, insect sting, medications...Allergic phenomena are due to an exacerbated response of the immune system to antigens that are tolerated by non-allergic patients.

After exposure to antigens, naive CD4+ (cluster of differentiation 4) T cells can be differentiated in different subsets of T helper (Th) cells (Th1, Th2, Th9, Th17, Th22, Tfh) and induced suppressive regulatory T cells characterized by different cytokine expression patterns, transcription factors and other surface markers, which will orchestrate adaptive and innate immune responses to these stimuli. Th2 cells are central players in all the various forms of Immunoglobulin E (IgE)-associated allergic diseases and are thus regarded as the most dominant T cell subset sustaining the allergic response. Upon antigen uptake and processing by antigen-presenting cells, CD4+ T cells are polarized towards a Th2 phenotype, leading to the expression of Th2 cell-associated cytokines such as Interleukin (IL)-4, -5, -9, -13, switching B cell response toward IgE production (sensitization or early phase). Allergen-specific IgE bind to a high-affinity receptor (FcεRI) of innate immune cells including basophils and mast cells, triggering the release of anaphylactogenic mediators (cytokines, chemokines, histamine, heparin, serotonin and proteases) responsible for inflammatory cell recruitment and allergic symptoms (effector or late phase). Identifying networks of genes expressed in resting and activated Th2 cells from allergic patients would help distinguish gene candidates predicting immune tolerance to allergens.

Allergies are diseases involving many cell subsets. The specific reactivities and contributions to the clinical picture are closely interdependent and not fully deciphered yet. The interplay between the different actors of the cellular immune system is further complexified by the existence of the commensal intestinal flora, also called the microbiota. Gut microbiota is partially under supervision of the immune system, and dysregulations or changes in the composition of the microbiota, for example due to antibiotics uptake during childhood and /or different eating habits, may impact adaptative and innate immune functions. Characterization of the gut microbiota of human hosts undergoing immunotherapy might be of high interest to delineate interactions between microbiota and adaptive immune system.

Despite substantial improvements in medications relieving daily allergy symptoms, a percentage of patients still experience uncontrolled severe symptoms. For these patients, strictly avoiding the allergen and keeping emergency medications within reach are the best recommendations so far, and the burden of living with allergy ultimately results in psychosocial, health, occupational and economic problems by impacting public health costs. In these cases, the best and feasible solution to improve quality of life is to apply an immunotherapeutic approach to induce allergen tolerance.