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Journal: Expert review of clinical immunology


Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Central tolerance within the thymus and peripheral tolerance in peripheral lymphoid organs lead to immunologic nonresponsiveness against self-components. The central tolerance represents the mechanism by which T cells binding with high avidity to self-antigens are eliminated through the so-called negative selection. Thymic medullary epithelial cells and medullary dendritic cells play a key role in this process, through the expression of a large number of tissue-specific self-antigens involving the transcription factor autoimmune regulator (AIRE). Mutations of AIRE result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, a rare autosomal recessive disease (OMIM 240300), which is the paradigm of a genetically determined failure of central tolerance and autoimmunity. This review focuses on recent advances in the molecular mechanisms of central tolerance, their alterations and clinical implication.

Concepts: Immune system, DNA, Genetics, Gene expression, Lymph node, Immunology, Thymus, Central tolerance


Currently, imaging in asthma is confined to chest radiography and CT. The emergence of new imaging techniques and tremendous improvement of existing imaging methods, primarily due to technological advancement, has completely changed its research and clinical prospects. In research, imaging in asthma is now being employed to provide quantitative assessment of morphology, function and pathogenic processes at the molecular level. The unique ability of imaging for non-invasive, repeated, quantitative, and in vivo assessment of structure and function in asthma could lead to identification of ‘imaging biomarkers’ with potential as outcome measures in future clinical trials. Emerging imaging techniques and their utility in the research and clinical setting is discussed in this review.

Concepts: Scientific method, Psychology, Avicenna, Evaluation methods, Sociology, Research, Quantitative research, Social sciences


An adjuvant is a substance that enhances the antigen-specific immune response, induces the release of inflammatory cytokines, and interacts with Toll-like receptors and the NALP3 inflammasome. The immunological consequence of these actions is to stimulate the innate and adaptive immune response. The activation of the immune system by adjuvants, a desirable effect, could trigger manifestations of autoimmunity or autoimmune disease. Recently, a new syndrome was introduced, autoimmune/inflammatory syndrome induced by adjuvants (ASIA), that includes postvaccination phenomena, macrophagic myofasciitis, Gulf War syndrome and siliconosis. This syndrome is characterized by nonspecific and specific manifestations of autoimmune disease. The main substances associated with ASIA are squalene (Gulf War syndrome), aluminum hydroxide (postvaccination phenomena, macrophagic myofasciitis) and silicone with siliconosis. Mineral oil, guaiacol and iodine gadital are also associated with ASIA. The following review describes the wide clinical spectrum and pathogenesis of ASIA including defined autoimmune diseases and nonspecific autoimmune manifestations, as well as the outlook of future research in this field.

Concepts: Immune system, Antibody, Innate immune system, Immunology, Humoral immunity, Immunity, Autoimmunity, Immunologic adjuvant


Evaluation of: Waldmann TA, Conlon KC, Stewart DM et al. Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-β-1 mAb in patients with T-cell large granular lymphocytic leukemia. Blood 121(3), 476-484 (2013). IL-15 is a cytokine that stimulates the proliferation of NK and T cells. Previous studies have shown that IL-15 is critical to the induction of T-cell large granular lymphocyte (T-LGL) leukemia. A Phase I trial of a humanized antibody (Hu-Mikβ1) to the IL2/IL15Rβ receptor, expressed on T-LGL, is explored in this trial to evaluate the safety, pharmacokinetics, specificity and clinical efficacy of Hu-Mikβ1. The study demonstrated no toxicity and favorable saturation of IL2/IL15Rβ receptor, but no clinical efficacy in this Phase I study.

Concepts: Immune system, White blood cell, Lymphocyte, Antibody, Natural killer cell, B cell, Leukemia, Large granular lymphocytic leukemia


Our global hypothesis is that atopic conditions and asthma develop because an individual’s immune system is not able to appropriately resolve inflammation resulting from allergen exposures. We propose that the failure to appropriately down-regulate inflammation and produce a toleragenic state results primarily from less robust immune homeostatic processes rather than from a tendency to over-respond to allergenic stimuli. An individual with lower immune homeostatic capacity is unable to rapidly and completely terminate, on average over time, immune responses to innocuous allergens, increasing risk of allergic disease. A lack of robust homeostasis also increases the risk of other inflammatory conditions, such as prolonged respiratory viral infections and obesity, leading to the common co-occurrence of these conditions. Further, we posit that the development of vigorous immune homeostatic mechanisms is an evolutionary adaptation strongly influenced by both 1) exposure to a diverse maternal microbiota through the prenatal period, labor and delivery, and, 2) an orderly assemblage process of the infant’s gut microbiota ecosystem shaped by breastfeeding and early exposure to a wide variety of ingested foods and environmental microbes. This early succession of microbial communities together with early allergen exposures orchestrate the development of an immune system with a robust ability to optimally control inflammatory responses and a lowered risk for atopic disorders.

Concepts: Immune system, Inflammation, Bacteria, Asthma, Immunology, Allergy, Atopy, Allergen


Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with significant functional impairment and increased risk for cardiovascular disease. Along with pharmacological therapy, exercise seems to be a very promising intervention to improve disease-related outcomes, including functional ability and systemic manifestations, such as the increased cardiovascular risk. In this review, we discuss the physiological mechanisms by which exercise improves inflammation, cardiovascular risk and psychological health in patients with rheumatoid arthritis (RA) and describe in detail how exercise can be incorporated in the management of this disease using real examples from our clinical practice.

Concepts: Inflammation, Medicine, Atherosclerosis, Blood vessel, Cardiovascular disease, Rheumatoid arthritis, Rheumatology, C-reactive protein


The aim of this article was to review current evidence about cryotherapy in inflammatory rheumatic diseases (therapeutic and biological effects). For therapeutic effects, we performed a systematic review (PubMed, EMBASE, Cochrane Library, LILACS databases, unpublished data) and selected studies including non-operated and non-infected arthritic patients treated with local cryotherapy or whole-body cryotherapy. By pooling 6 studies including 257 rheumatoid arthritis (RA) patients, we showed a significant decrease in pain visual analogic scale (mm) and 28-joint disease activity score after chronic cryotherapy in RA patients. For molecular pathways, local cryotherapy induces an intrajoint temperature decrease, which might downregulate several mediators involved in joint inflammation and destruction (cytokines, cartilage-degrading enzymes, proangiogenic factors), but studies in RA are rare. Cryotherapy should be included in RA therapeutic strategies as an adjunct therapy, with potential corticosteroid and nonsteroidal anti-inflammatory drug dose-sparing effects. However, techniques and protocols should be more precisely defined in randomized controlled trials with stronger methodology.

Concepts: Rheumatoid arthritis, Rheumatology, Osteoarthritis, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Paracetamol, Ibuprofen, Gout


Prevalence of food allergy is rising in different regions of the world. Asia has not been spared from this epidemic, but epidemiological data have revealed a different pattern of food allergens in this continent. Allergen-specific immunotherapy (AIT) for food allergy (FA), which has been revolutionary as the main focus of research in recent years, needs to be adapted for the different populations in Asia. Areas covered: Recent evidence shows increasing popularity and superiority of AIT over strict food avoidance as the cornerstone of food allergy management. Asia is a distinctive continent with specific food allergy triggers, in particular seafood and wheat. Peanut, on the contrary, is not a common food allergen in most parts of Asia. The common Asian food allergens, as well as the rapidly developing food-specific AIT in this region will be covered in this article. Expert commentary: Evidence on oral immunotherapy for wheat allergy, and pre-clinical data on shellfish AIT are promising. Further work should be done on resolving cross-sensitization between environmental allergens with wheat and shellfish allergens, and a modified AIT approach to enhance the safety and effectiveness of food-specific immunotherapy.


Dysregulation of melanocyte function is associated with vitiligo, an idiopathic autoimmune hypopigmentary skin disorder, caused by the selective destruction of melanocytes. Cytokines, the key mediators of immune response, which are pivotal in maintaining immune homeostasis, are crucial in vitiligo pathogenesis. Several studies indicate that there is an imbalance between pro- and anti-inflammatory cytokines in the skin and serum of vitiligo patients. Areas covered: In this comprehensive review, we have summarized the correlation of cytokine imbalance and vitiligo pathogenesis, its role in melanocyte biology and its impact on vitiligo treatment. We have integrated various published reports on the levels of major cytokines from skin and serum samples of vitiligo patients. We have also discussed the role of endoplasmic reticulum (ER) and oxidative stress on cytokine imbalance and vice-versa leading to destruction of melanocytes. Expert commentary: The review reflects that dysregulation of cytokines is multi-factorial, ranging from genetic predisposition to altered protein expression relevant to vitiligo pathogenesis. We emphasize that cytokine imbalance in systemic and skin microenvironment plays a crucial role in vitiligo pathogenesis and has promising potential as therapeutic targets for vitiligo.


Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine involved in the pathogenesis of many inflammatory diseases. Several drugs blocking TNF-α are employed in clinical practice in pediatrics. Given their action on the immune system, TNF-α inhibitors have raised concerns on their safety profile since their introduction. A broad spectrum of side effects related to TNF inhibition has been reported: immunogenicity, infectious diseases, malignancies and others. Areas covered: In order to assess the risk related to the use of anti-TNF-α agents in children with rheumatic diseases we analyzed data obtained from retrospective and prospective safety studies, case reports and case series and controlled trials. Expert commentary: Anti-TNF-α agents have shown a remarkably good safety profile in the pediatric population so far. However, there are lots of questions to be answered and maintaining active surveillance on these drugs is necessary in order to not overlook any possible unexpected adverse effects.