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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


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


Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. As symptoms of CVID are usually heterogeneous and unspecific, diagnosis and follow-up of CVID can be challenging. In light of this, a broad review of advances in management and treatment of CVID is performed here in order to reach a distinct protocol. However, it should be noted that owing to the nature of the disease, it can only be treated symptomatically but not cured. There is little evidence to guide appropriate or universal guidelines to improve the current status of management of the disease. The most satisfactory treatments of CVID could be achieved by the use of immunoglobulin replacement, antibiotics, immunosuppressants and hematopoietic stem cell transplantation. This review is written based on the importance of clinical surveillance of asymptomatic CVID cases and early recognition of different clinical complications. Moreover, for each complication, appropriate interventions for improving outcomes are mentioned.

Concepts: Immune system, Medicine, Epidemiology, Medical terms, Hematopoietic stem cell, Immunodeficiency, Primary immunodeficiency, Common variable immunodeficiency


For successful switching of bio-originators to biosimilars, confidence in the switch is an important criterion. To promote confidence, scientific evidence is critical, but still there are insufficient data for the majority of approved biosimilars. Areas covered: Scientific evidence for switching from bio-originator DMARDs to biosimilars is derived from randomized controlled trials (RCTs) for switching, extension studies of RCTs for the approval process, and real-world observational studies. To identify candidate studies, PubMed was searched to collect appropriate studies in all approved biosimilars for the treatment of rheumatic diseases. In addition, abstracts for scientific meetings were reviewed to discover abstracts focused on switching. To date, we have identified 17 extension studies of RCTs, one RCT, and 17 real-world observational studies. Most real-world studies have originated from CT-P13 and SB4. Switching was definitively safe and effective in most of studies, but some nocebo effects were observed. Expert Commentary: Clear guidelines for switching and data from post-marketing surveillance and registries will be required to confirm existing results on the safety and efficacy of switching from bio-originators to biosimilars. To lessen the nocebo effect against biosimilars, effective educational programs should be provided for all stakeholders, including patients and physicians.


Giant cell arteritis (GCA) is the most common large-vessel vasculitis in individuals older than 50 years from Western countries. The goal of the treatment is to achieve improvement of symptoms and clinical remission as well as decrease the risk of severe vascular complications. Areas covered: The review summarizes the main epidemiological and clinical features of GCA and discusses in depth both the classic and the new therapies used in the management of GCA. Expert commentary: Prednisone/prednisolone of 40-60 mg/day is the mainstay in GCA therapy. It yields improvement of clinical features and reduces the risk of permanent visual loss in patients with GCA. Other drugs are used in patients who experience relapses (flares of the disease) or side effects related to glucocorticoids. Methotrexate is the most common conventional immunosuppressive drug used as a glucocorticoid sparing agent. Among the new biologic agents, the most frequently used is the recombinant humanized anti-IL-6 receptor antibody, which is effective to improve clinical symptoms, decrease the cumulative prednisone dose and reduce the frequency of relapses in these patients. Anti-tumor necrosis factor-α therapy is not useful in GCA. Experience with other biologic agents, such as abatacept or ustekinumab, looks promising but it is still scarce.


The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept. Expert commentary: The development of belatacept is a major advance in clinical transplantation. However, in spite of promising results in preclinical and clinical trials, clinical use remains limited at present, in part due to increased rates of acute rejection. Recent efforts showing encouraging progress in refining such protocols might be a step towards harnessing the full potential of costimulation blockade-based immunosuppression.