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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


In systemic lupus erythematosus (SLE), flares can be caused by infections. In particular, Streptococcus pneumoniae infection can be severe or even potentially lethal in absence of previous immunization or in case of “aggressive” systemic antibiotic therapy. Immunization efficacy, however, can be reduced in such patients with the use of the various immunosuppressive therapeutic regimens. In particular, the use of novel monoclonal antibodies against B lymphocytes raises concerns over the potential interference with antipneumococcal vaccination. Previous studies demonstrated that belimumab therapy did not significantly reduce the efficacy of antipneumococcal vaccination, when received after the initiation of belimumab therapy. The study being evaluated in this article investigated the efficacy of vaccination in relationship to initiation of belimumab therapy in SLE patients.

Concepts: Immune system, Rheumatoid arthritis, Systemic lupus erythematosus, Lupus erythematosus, Immunosuppressive drug


Remission or low disease activity should be the target of therapy in spondyloarthritis (SpA). Due to the complexity of the disease, several composite indices that assess all disease domains were proposed to define a status of low disease activity/remission in both axial and peripheral SpA. With the introduction, in the past years, of effective biologic and targeted synthetic treatments aimed at inhibiting key cytokines and intracellular pathways, the goal of clinical remission has become an achievable target in these conditions. However, residual disease activity may occur in some domains and the management of patients that achieve the target of remission is still an unmet need. Areas covered: This manuscript aimed to review the current evidence on clinical remission and residual disease activity in SpA (both axial SpA and psoriatic arthritis), and its potential treatment implications. Expert commentary: Progress in our understanding of the pathogenesis of SpA will lead to a rapid increase in the number of available treatments, with the possibility for patients to achieve a status of remission. However, the topic of residual disease activity should be taken into consideration.

Concepts: Arthritis, The Target, Spondyloarthropathy, Psoriatic arthritis, Psoriasis, Reactive arthritis


B cells mediate allograft rejection through antigen presentation, and production of cytokines and antibodies. More and more immunosuppressive agents specifically targeting B cells and plasma cells have been applied in clinical transplantation. However, recent studies have indicated the regulatory roles of B cells. Therefore, it is vital to clarify the different effects of B cell subsets in organ transplantation so that we can completely understand the diverse functions of B cells in transplantation. Areas covered: This review focuses on the regulatory roles of B cells in transplantation. B cell subsets with immune modulation and factors mediating immunosuppressive functions of regulatory B (Breg) cells were analyzed. Therapies targeting B cells and the application of B cells for transplant tolerance induction were discussed. Expert commentary: Besides involving rejection, B cells could also play regulatory roles in transplantation. Breg cells and the related markers may be used to predict the immune tolerant state in transplant recipients. New therapeutic strategies targeting B cells should be explored to promote tolerance induction with less impact on the host’s protective immunity in organ transplanted patients.

Concepts: Immune system, Antibody, Protein, Immunology, Humoral immunity, Adaptive immune system, Organ transplant, Epitope