Allergy and clinical immunology are examples of areas of knowledge in which working hypotheses are dominant over mechanistic understanding. As such, sometimes scientific efforts follow major streams and overlook some epidemiologically prevalent conditions that thus become underestimated by the research community. For this reason, we welcome the present issue of Clinical Reviews in Allergy and Immunology that is dedicated to uncommon themes in clinical immunology and allergy. First, comprehensive discussions are provided for allergy phenomena of large potential impact in clinical practice such as reactions to cephalosporins or aspirin-induced asthma and in everyday life such as allergies to food additives or legumes. Further, the issue addresses other uncommon themes such as urticaria and angioedema, cercarial dermatitis, or late-onset inflammation to soft tissue fillers. Last, there will be discussion on transversal issues such as olfactory defects in autoimmunity, interleukin 1 beta pathway, and the search for new serological markers in chronic inflammation. As a result, we are convinced that this issue will be of help to clinicians involved in internal medicine as well as to allergists and clinical immunologists. More importantly, we are convinced that these discussions will be of interest also to basic scientists for the numerous translational implications.
Attempts to reproduce the features of human influenza in laboratory animals date from the early 1890s, when Richard Pfeiffer inoculated apes with bacteria recovered from influenza patients and produced a mild respiratory illness. Numerous studies employing nonhuman primates (NHPs) were performed during the 1918 pandemic and the following decade. Most used bacterial preparations to infect animals, but some sought a filterable agent for the disease. Since the viral etiology of influenza was established in the early 1930s, studies in NHPs have been supplemented by a much larger number of experiments in mice, ferrets and human volunteers. However, the emergence of a novel swine-origin H1N1 influenza virus in 1976 and the highly pathogenic H5N1 avian influenza virus in 1997 stimulated an increase in NHP research, because these agents are difficult to study in naturally infected patients and cannot be administered to human volunteers. In this paper, we review the published literature on the use of NHPs in influenza research from 1893 through the end of 2014. The first section summarizes observational studies of naturally occurring influenza-like syndromes in wild and captive primates, including serologic investigations. The second provides a chronological account of experimental infections of NHPs, beginning with Pfeiffer's study and covering all published research on seasonal and pandemic influenza viruses, including vaccine and antiviral drug testing. The third section reviews experimental infections of NHPs with avian influenza viruses that have caused disease in humans since 1997. The paper concludes with suggestions for further studies to more clearly define and optimize the role of NHPs as experimental animals for influenza research.
Approximately every 5 yr, Clinical Reviews in Allergy and Immunology deviates from its usual practice of publishing volumes devoted to one theme to including papers that cover a range of subjects. This issue is one such exception and arose following a symposium at the International Institute for Research in Autoimmune Diseases named AESKU.KIPP Institute at their Wendelsheim facility. The AESKU.KIPP Institute was a particularly venue because it was initially established by a German diagnostic company and a Swiss benefactor, Karl- Heinz Kipp. The goal of the Institute was to develop a unique atmosphere to encourage original research in the field of autoimmunity and clinical immunology. The thought was to create an institute where young scientists from throughout the world could come for short periods of time to learn newer methodologies in both clinical immunology and also molecular biology. This theme contains several of the papers presented at the opening of the Institute and are incorporated herein because they focus on several unique aspects of clinical immunology, often referred to as the mosaic of autoimmunity.
Clinicians are facing unexpected issues in everyday practice, and these may become counterintuitive or challenging. Illustrative examples are provided by the hypersensitivity to universally used immunosuppressants such as corticosteroids or antibiotics such as beta-lactam. Secondly, additional issues are represented by the discovery of new pathogenetic mechanisms involved in rheumatoid and psoriatic arthritis or other chronic inflammatory diseases, genomic susceptibility to enigmatic diseases such as giant cell arteritis, or the shared role of specific mediators such as semaphorins. Third, the therapeutic armamentarium has dramatically changed over the past decade following the introduction of biotechnological drugs, and new mechanisms are being proposed to reduce adverse events or increase the drug effectiveness, particularly on cardiovascular comorbidities. Finally, rare diseases continue to represent difficult cases, as for Cogan's syndrome, with limited literature available for clinical recommendations. For these reason, the present issue of Clinical Reviews in Allergy and Immunology is timely and dedicated to these and other unique topics in clinical immunology and allergy. The aim of this issue is thus to help clinicians involved in internal medicine as well as allergists and clinical immunologists while discussing new pathways that will prove important in the near future.
Uncommon or orphan diseases are less frequently addressed in mainstream medical journals and, as a consequence, their understanding and clinical recognition may rely on case series or anecdotal data with limited guidelines and management directions. The study of selected underrepresented autoimmune and allergy conditions is the subject of the present issue of Clinical Reviews in Allergy and Immunology to provide peculiar perspectives on common and rare themes. First, allergy remains a major concern for physicians worldwide despite the limited developments over the past years, particularly for antigens such as mite or Alternaria alternata, and due to the increasing incidence of drug hypersensitivity. Second, the female predominance of autoimmune diseases such as systemic sclerosis is well recognized but enigmatic, and a unifying hypothesis remains elusive. Third, the management of conditions triggered by infectious agents as in Guillain-Barre syndrome or mixed cryoglobulinemia is challenging, and clinical guidelines are needed in the setting of infections and autoimmunity. Fourth, gamma-delta T cells represent major players in innate immunity and are the subject of extensive studies in autoimmune diseases to provide new therapeutic targets for disease prevention or modulation in the near future. Ultimately, we acknowledge the major developments in the broad fields of rheumatology and immunology and expect that microbiota definition, epigenetics studies, and microRNA analysis will provide new exciting avenues toward the understanding and treatment of chronic and acute inflammation.
Novel approaches to the therapy for atopic dermatitis (AD) can now be considered because of recent advances in the pathogenesis of the disease. Several of these concepts are being tested in clinical trials. The effectiveness of cyclosporin A, plus reports of adoptive transfer of AD, or its clearing, following bone marrow transplantation, verify the criticalness of immune cells in AD pathogenesis. Thus, there is renewed interest in immunosuppressives, such as azathioprine and methotrexate, as well as new adhesion molecule and T-cell activation inhibitors. Therapy with the T-cell lymphokine, interferon-gamma, or the thymic hormone, thymopentin, is designed to inhibit the IL-4-dominated response of AD T-cells. This approach, rather than directly suppressing all immune responsiveness, represents a more specific targeting to improve the balance of a chronically disordered immune response. Recent findings of a therapeutic advantage of longer-wavelength phototherapy over UVB therapy may relate to specific immunologic events following UVB vs UVA photoinjury that are critical to the exacerbation of AD. Complex herbal mixtures used in traditional Chinese medicine are currently being evaluated, but toxicity and palatability may be limiting. Other dietary approaches, such as modifying the lipid balance, have generally not had much benefit. Because the safety and efficacy of the above treatments need further exploration, the physician must continue to utilize fundamental methods, such as mitigating trigger factors (i.e., microbes and stress, and certain foods in persons with documented sensitivity), on improving the abnormal epidermal lipid barrier to irritation, and on reducing cutaneous inflammation with mild topical steroids.
The innate immune response provides a first line of defense against common microorganisms and, for more complex and/or recurring situations where pathogens must be eliminated, an adaptive immune response has emerged and evolved to provide better protection against subsequent infections. However, such dichotomy has to be reevaluated because innate B cells (e.g., B1 and marginal zone B cells) and the newly described innate lymphoid cells (iLC) have been found to exhibit innate-like properties, such as antigen internalization, regulatory B cell functions, and helper T cell activities. In addition, the production and function of natural antibodies (nAbs) by innate B cells and their capacity to activate the classical complement pathway constitute additional important mechanisms at the junction of innate and adaptive immunity as well as the recent integration of platelets into the innate immune spectrum. There is no doubt that these mechanisms present an advantage in immunity and homeostasis particularly during the first years of life, but arguments are arising to consider that these precursors may have detrimental effects in a variety of autoimmune/inflammatory diseases, allergies and cancers, as well as in response to immunotherapy. Accordingly, and as presented in this special issue of Clinical Reviews in Allergy and Immunology, a better comprehension of the key molecular and cellular actors implicated at the crossroads of the innate and adaptive immune response represents a new challenge in our understanding of the immunological and immunopathological responses.
It has been suggested that arachidonate metabolites, leukotrienes, and thromboxane may play important roles in the pathogenesis of bronchial asthma. Biologic activities of these mediators are much more potent than those of histamine and acetylcholine on a molar basis in inducing bronchoconstriction, increase in microvascular permeability, formation of mucosal edema, and mucus secretion, which are characteristic features of bronchial asthma. Furthermore, recent studies have demonstrated the presence of these mediators in plasma, BALF, and urine in asthmatic patients after allergen challenge. Therefore, the regulation of the activities of these mediators may provide a novel therapeutic approach for the treatment of bronchial asthma. A large number of 5-lipoxygenase inhibitors, peptide leukotriene antagonists, thromboxane synthase inhibitors, and thromboxane antagonists have been actively developed by the pharmaceutical industry, and there are increasing findings to demonstrate a clinical efficacy by these compounds. Among them, a thromboxane synthase inhibitor, OKY-046, first became available as an antiasthmatic agent in Japan. This is a significant step in the management of bronchial asthma. Preclinical and clinical results have suggested that these inhibitors and antagonists may be capable of inhibiting airway obstruction with airway inflammation and bronchial hyperresponsiveness, which are important characteristics of bronchial asthma. Further results from clinical studies with newly developed leukotriene and thromboxane antagonists are eagerly awaited.
Oral food challenges remain the gold standard for the diagnosis of food allergy. Nevertheless, the allergy workup is based on the presence of a clinical history, which is evocative of an immune-allergic reaction, and the first assessment is usually the performance of skin prick tests. Based on these results, allergists are used to evaluate the presence of serum-specific IgE, which are today the most commonly prescribed in vitro test for the evaluation of a possible food allergy. Other in vitro tests include the basophil activation test, that is becoming more and more employed by clinicians and not only by researchers, and the evaluation of serum IgG4, which is still an issue of debate in the allergy community. The present paper reviews the use of these in vitro tests for the diagnosis of food allergy.
Antihistamines are considered first-line therapy for the relief of symptoms from allergic rhinitis and chronic urticaria. The newer, second-generation, nonsedating antihistamines reduce the central nervous system and anticholinergic side effects commonly found with previous drugs. The availability of H1-receptor antagonists that produce therapeutic effects without causing unwanted CNS effects fulfills an important practical need, since these drugs are clearly preferable in patients who drive or operate heavy machinery, or who are involved in activities requiring full alertness. Physicians and patients alike are pleased with the efficacy and safety the second-generation antihistamines bring to the treatment of allergy symptoms. Loratadine is an especially effective second-generation H1-receptor antagonist and is comparable to many of the other second-generation antihistamines. Loratadine may be particularly advantageous because of its low dose and the convenience of once-daily dosing. A more subtle advantage, loratadine's antiallergic properties, may warrant its use for specific treatment situations as future research clarifies the nature of the inflammatory response and the mechanisms of action antiallergic antagonists have in this regard.
Recent textbooks of neurology and internal medicine cite food, or pharmacologic agents in foods, as provokers of migraine (1,2). Nevertheless, this area remains controversial. Many authorities recognize foods containing pharmacologic agents, such as tyramine, as possible provokers of migraine. However, the importance of foods lacking these properties is less clear. During the 1980s, there was renewed interest in food-induced migraine. Studies have attempted to address the incidence of food-induced migraine and have recently begun to study potential mechanisms. This paper will review the general features of migraine, including prevalence, differential diagnosis, and known provokers, and then focus on the link between food and migraine.
The elevated cardiovascular morbidity in rheumatoid arthritis, systemic lupus erythematosus, and the antiphospholipid syndrome is well known, as well as the pulmonary involvement observed in these conditions and to a major extent in systemic sclerosis. These manifestations constitute a major challenge for clinicians involved in patient management. Moreover, several issues regarding the link between autoimmune rheumatic diseases and cardio pulmonary morbidity remain largely enigmatic. The mechanistic role of certain autoantibodies frequently observed in association with heart and lung diseases or the pathogenetic link between chronic inflammation and the pathways leading to atherosclerosis or pulmonary vascular changes are yet to be elucidated. As such, these questions as well as treatment strategies are of common interest to rheumatologists, immunologist, pulmonologists, and cardiologists and thus call for an interdisciplinary approach. This paradigm has been well established for rare conditions such as the Churg-Strauss syndrome. Nowadays, it seems that this approach should be expanded to encompass more common conditions such as coronary heart disease, pulmonary arterial hypertension or dilated cardiomyopathy. The present issue of Clinical Reviews in Allergy and Immunology addresses the new knowledge and concepts of autoimmune-related cardiopulmonary diseases. The issue derives from the 2010 International Autoimmunity Meeting held in Ljubljana, Slovenia and is thus timely and dedicated to the latest developments in this new multidisciplinary field.
The first textbook on autoimmunity was published by Ian Mackay and McFarland Burnett in 1963. It was the first attempt to summarize existing knowledge on human autoimmunity. Since that time, there have been tens of thousands of experimental papers and numerous textbooks that focus on the diagnosis and treatment of human autoimmunity. There have been at least as many, if not more, directed at similar issues in animal models. Enormous strides have been made not only in diagnosis, but also in the pathophysiology and especially in treatment. We have gone from the era of simple HLA typing to deep sequencing and, more recently, epigenetic analysis. We have gone from the era of white blood cell differentials to detailed lymphoid phenotyping. We have gone from the era of simple antinuclear antibodies to detailed and sophisticated immunodiagnosis with recombinant autoantigens and disease-specific epitopes. We have gone from the era of using only corticosteroids to selective biologic agents. Diseases that were previously considered idiopathic are now very much understood as autoimmune. We are in the era of autoinflammatory reactions and the concept of both innate versus adaptive immunity in mediating immunopathology. In this edition of Clinical Reviews in Allergy and Immunology, we focus on key and cutting-edge issues in the pathophysiology of autoimmunity. The issues are very much oriented and driven by hypothesis, i.e., a prediction of events expected to occur based on observations. It is not meant to be a complete summary of potential mechanisms of autoimmunity, but rather an attempt to accelerate discussion and better understanding. The primary goal is obviously to help our patients with autoimmune disease.
Health equity is achieved when all individuals can reach their full health potential. In food-induced anaphylaxis, this goal remains unmet. Disparities in prevalence, diagnosis, and care are influenced by race, income, and environmental determinants. This article reviews emerging evidence on inequities in food allergy, emphasizing the need to understand who is most affected and why, and outlining strategies to promote equitable prevention and treatment.
A wide variety of fish are known to induce allergic reactions following ingestion or inhalation of vapors by sensitized individuals. Although the exact prevalence of fish sensitivity is not known, fish are among the most important food allergens; and as consumption of fish increases, rates of sensitization are expected to increase. Diagnosis of fish allergy is aided by clinical history, skin prick testing, and in vitro assays; however, double-blind placebo-controlled food challenges are the most reliable method to confirm fish allergy and to identify putative species. It appears from RAST inhibition and SDS-PAGE/Western blot studies that the current policy of recommending that fish-sensitive individuals avoid all species of fish should be reevaluated. The major allergen in codfish (Gad cI) is one of the most extensively studied of all allergens. It is a calcium-chelating protein, with a mol wt of 12,328 kDa and an isoelectric point of 4.75. As an allergen, Gad cI is very stable and its allergenic activity appears to be dependent on amino acid sequence. Crossreactivity among some fish species may be the result of common structures within related proteins.
The most difficult component to understand in autoimmune disease has been the issue of causation. In contrast, there have been enormous gains in improved diagnostics as well as improved therapy. Indeed, the use of biologics have changed the profile of numerous autoimmune diseases. In this issue, we discuss two such aspects. Firstly, we place in perspective the use of anti-citrullinated protein antibodies in rheumatoid arthritis. Second, we discuss the increasing use of B cell depletion in the treatment of autoimmunity. Clinical Reviews in Allergy and Immunology is a unique venue for these themes because it covers the spectrum of allergy through autoimmunity. Indeed, we also present a special paper on the relationships of the hepatitis B virus and autoimmunity. Although the Th1 to Th2 dichotomy is well known to both murine and human immunologists, it is really in the study of specific inflammatory responses that they are correctly placed in the perspective of the continuum of immunopathology.
AD is a disorder that affects up to 12% of the pediatric population. This disease is multifactorial and encompasses a wide array of etiologic factors. Strong evidence has existed in the literature over the past century for the role of inhalant and food allergies in the pathogenesis of AD. Much work is currently ongoing to delineate the role of individual cellular components, cytokines, and other mediators in the pathogenesis of AD. The answers to these questions, as well as a more comprehensive understanding of hereditary factors, will provide key information to our overall understanding of AD and our ability to treat patients with this disease more effectively in the future.
Autoimmunity is believed to develop when genetically predisposed individuals encounter epigenetic modifications in response to environmental factors. Recent advances in the understanding of epigenetic mechanisms, their contribution to the immune function, and to the development of autoimmunity are presented in this special issue of Clinical Reviews in Allergy and Immunology. Potential new therapeutic strategies and biomarkers are also addressed.
A complex interplay of liver, bile ducts, and the gut critically determines functioning of these organs in health and disease. Biochemical and physiological aspects of their interaction and the role of inflammatory cells, cytokines, bile acids, visceral hormones, neuropeptides and other messengers in the pathogenesis of model immune-mediated hepatobiliary disorders are discussed in the actual issue of Clinical Reviews in Allergy and Immunology. Potential molecular targets for future therapeutic approaches are also addressed.