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.
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.
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.
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.
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.
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.
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.
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.
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by the presence of psoriasis, arthritis and enthesitis, with the association of other musculoskeletal and extra-articular manifestations. Current treatment of PsA is mainly based on the use of conventional, biological and targeted synthetic DMARDs; however, patients may not respond or have a loss of response to these agents. Recently, a deeper understanding of the pathogenetic mechanisms has made possible the development of new drugs that actively interact with the activation of immune system, inhibiting the co-stimulation between antigen presenting cells and lymphocytes. Areas Covered: The aim of this paper is to review the role of the activation of the immune system in the pathogenesis and treatment of PsA, with a discussion on the emerging CTLA4Ig drugs (abatacept) for PsA. A search in PubMed and EMBASE was performed with the keywords: “abatacept”, “CTLA4” and “Psoriatic Arthritis”. We considered preclinical studies, phase I, II and III clinical trials. Expert Commentary: The inhibitors of co-stimulation may represent an effective treatment strategy by acting on the very early phase of the immunological process that brought about the development of inflammation and activation of the immune system, mainly for patients with peripheral joint involvement and mild psoriasis.
Functional dyspepsia (FD) is widespread with 20% prevalence worldwide and a significant economic burden due to health care cost and constraints on daily activities of patients. Despite extensive investigation, the underlying causes of dyspepsia in a majority of patients remain unknown. Common complaints include abdominal discomfort, pain, burning, nausea, early satiety, and bloating. Motor dysfunction of the gut was long considered a major cause, but recent investigations suggest immune-based pathophysiological and molecular events in the duodenum are more probable contributing factors. Areas Covered: Inflammatory mediators and immune cells including duodenal eosinophils, intraepithelial lymphocytes, and T-cells have been implicated in the underlying cause of disease process, as have genetic factors. In this article, we critically reviewed findings, identified gaps in knowledge and suggested future directions for further investigation to identify targets and develop better therapeutic approaches. Expert Commentary: Impaired gastric accommodation, slow gastric emptying, and increased visceral sensitivity have long been thought of as main causal factors of FD. However, more recent identification of eosinophilic degranulation and recruitment of T cells that induce mild duodenal inflammation are giving rise to new insights into immune-mediated pathophysiology. These insights offer promising avenues to explore for immune-mediated therapy in the future.