Description

Each issue focuses on a specific theme of current interest to allergists and clinical immunologists, and is therefore designed for immediate clinical use.

Publisher details

Springer Verlag

Publications in this journal

• Cutting-edge Issues in Autoimmunity and Allergy of the Digestive System.

  Authors: Carlo Selmi

  Clinical reviews in allergy & immunology.

  Autoimmunity and allergy involving the digestive system may be considered as paradigmatic for numerous common themes of complex diseases secondary to tolerance breakdown. Among gastrointestinalAutoimmunity and allergy involving the digestive system may be considered as paradigmatic for numerous common themes of complex diseases secondary to tolerance breakdown. Among gastrointestinal autoimmune diseases, for example, we encounter diseases in which a clear environmental trigger is identified (i.e., celiac disease), serum autoantibodies are most specific (i.e., primary biliary cirrhosis), or in which the disease pathophysiology is clearly understood (i.e., autoimmune gastritis). Similarly, it is intriguing that the gastrointestinal tract and the liver circulation represent the crucial environment for the development of immune tolerance. This issue is dedicated to the discussion of recent concepts while identifying two major common issues, i.e., the need for serum biomarkers and the role of vitamin D. Other common themes characterize the etiology and effector mechanisms of these and other autoimmune diseases and are discussed in each cutting-edge overview.

• A Comprehensive Review of Legume Allergy.

  Authors: Alok Kumar Verma, Sandeep Kumar, Mukul Das, Premendra D Dwivedi

  Clinical reviews in allergy & immunology.

  Legumes belonging to Fabaceae family of the order Fabales are a rich and important source of proteins and many essential elements. Due to its nutritious elements, these are preferably included inLegumes belonging to Fabaceae family of the order Fabales are a rich and important source of proteins and many essential elements. Due to its nutritious elements, these are preferably included in human diet in most part of the world. But, unfortunately, IgE binding proteins have been identified in majority of legumes, and allergenic response to these legumes may range from mild skin reactions to life-threatening anaphylactic reaction. Overall, allergenicity due to consumption of legumes in decreasing order may be peanut, soybean, lentil, chickpea, pea, mung bean, and red gram. So far, several allergens from different legumes have been identified and characterized. Most of identified allergens belong to storage proteins family, profilins, or the pathogenesis-related proteins. Legumes also have property of immunological cross-reactivity among themselves and from other sources that also increases the severity of allergenic response to a particular legume. This review summarizes the currently available knowledge on legume allergy and describes the allergenic problems associated with different legumes. It also tries to explore about the legume allergens identified so far by different scientific groups. The culmination of knowledge about identification and characterization of allergens from different legumes will be helpful in diagnosis and treatment of allergy, for development of novel therapeutic strategies, for strict avoidance of particular legume in diet by susceptible individual and also to produce hypoallergenic cultivars of leguminous crop through conventional breeding or genetic modification.

• Cytokine-Based Therapy in Psoriasis.

  Authors: Anupam Mitra, Robyn S Fallen, Hermenio Cavalcante Lima

  Clinical reviews in allergy & immunology.

  Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2-3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorderPsoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2-3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL-17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment.

• Role of IL-17 in Psoriasis and Psoriatic Arthritis.

  Authors: Siba P Raychaudhuri

  Clinical reviews in allergy & immunology.

  The role of T cell subpopulations in human disease is in a transition phase due to continuous discovery of new subsets of T cell, one of which is Th17, characterized by the production of signatureThe role of T cell subpopulations in human disease is in a transition phase due to continuous discovery of new subsets of T cell, one of which is Th17, characterized by the production of signature cytokine IL-17. In the last couple of years, many articles are coming out on the role of Th17 and its signature cytokine IL-17 in different autoimmune diseases like rheumatoid arthritis, psoriasis, psoriatic arthritis (PsA), SLE and multiple sclerosis. Psoriasis and PsA are immune-mediated diseases, affecting the skin and joints, respectively. Initially, it was thought that psoriasis and PsA were Th1-mediated diseases; however, studies in knockout animal models (IL-17 knockout mice) as well as human experimental data indicate that Th17 and its signature cytokine IL-17 have a critical role in the pathogenesis of psoriatic disease. Th17 cells have been identified from the dermal extracts of psoriatic lesions. Subsequently, our research group has substantiated this observation that Th17 cells are enriched in the papillary dermis of psoriatic plaques and in freshly isolated effector T lymphocytes from the synovial fluid of PsA patients, and we have reported that the majority of these CD4 + IL-17+ T cells are of memory phenotype (CD4RO(+)CD45RA(-)CD11a(+)). Recent reports also suggest that the synovial tissue in psoriatic arthritis is enriched with IL-17R, and its most well recognized receptor IL-17RA is functionally active in psoriatic arthritis. In this review article, we have discussed the role of IL-17 in psoriatic disease and have narrated about the novel IL17/IL-17R antibodies currently in preparation for its therapeutic uses in autoimmune diseases.

• A Cutting Edge Overview: Psoriatic Disease.

  Authors: Siba P Raychaudhuri

  Clinical reviews in allergy & immunology.

  Psoriasis is a lifelong skin disease, affecting about 2% of the global population. Generalized involvement of the body (erythroderma), extensive pustular lesions, and an associated arthritis known asPsoriasis is a lifelong skin disease, affecting about 2% of the global population. Generalized involvement of the body (erythroderma), extensive pustular lesions, and an associated arthritis known as psoriatic arthritis (PsA) are severe complications of psoriasis. Genetic, immunologic, and environmental factors contribute to its pathogenesis. A complete understanding of the pathogenesis of psoriasis and psoriatic arthritis is lacking. Cytokines, chemokines, adhesion molecules, growth factors like NGF, neuropeptides, and T cell receptors all act in an integrated way to evolve into unique inflammatory and proliferative processes typical of psoriasis and PsA. Management of psoriasis requires exemplary skin care along with careful monitoring of arrays of comorbidities which includes arthritis and coronary artery disease. In many ways, psoriasis can be considered a model autoimmune disease. This statement itself is ironic considering that it was not recognized as immune mediated until relatively recently. Fortunately, the immunobiology has made enormous strides and there are now excellent therapeutic options for patients. In this thematic review, we have attempted to provide summaries of not only basic science and clinical research, but also an overview of future research directions.

• Inflammation, Atherosclerosis, and Psoriasis.

  Authors: David Siegel, Sridevi Devaraj, Anupam Mitra, Siba P Raychaudhuri, Smriti K Raychaudhuri, Ishwarlal Jialal

  Clinical reviews in allergy & immunology.

  Increasing evidence supports an important role for inflammation in all phases of atherosclerosis, from initiation of the fatty streak to final culmination in acute coronary syndromes. NumerousIncreasing evidence supports an important role for inflammation in all phases of atherosclerosis, from initiation of the fatty streak to final culmination in acute coronary syndromes. Numerous inflammatory biomarkers including cell adhesion molecules, cytokines, chemokines, and acute-phase reactants such as fibrinogen, serum amyloid A, and C-reactive protein (CRP) have been shown to predict cardiovascular (CVD) events. Several prospective studies have shown a consistent and robust relationship between levels of high-sensitivity CRP and the risk of future CVD events. Toll-like receptors are pattern recognition receptors and members of the innate immune system that contribute to inflammation and appear to play key roles in atherosclerosis. Lipoprotein-associated phospholipase A2 may also be an independent CVD risk factor. Psoriasis has been associated with an increasing risk for atherosclerosis, including coronary artery disease and stroke. Patients with psoriasis have a 5-year shorter life expectancy, most frequently due to CVD. Psoriasis is associated with a chronic inflammatory state and with elevated levels of CRP and other inflammatory cytokines and these may play a causative role in the increased risk of psoriatic patients for CVD. Patients with psoriasis may represent an emerging risk population and patients with moderate to severe psoriasis should be screened and aggressively treated for CVD risk factors.

• Biologic Therapies in the Treatment of Psoriasis: A Comprehensive Evidence-Based Basic Science and Clinical Review and a Practical Guide to Tuberculosis Monitoring.

  Authors: Raja K Sivamani, Heidi Goodarzi, Miki Shirakawa Garcia, Siba P Raychaudhuri, Lisa N Wehrli, Yoko Ono, Emanual Maverakis

  Clinical reviews in allergy & immunology.

  The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab, etanercept, adalimumab, efalizumab, golimumab, certolizumab, alefacept, secukinumab,The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab, etanercept, adalimumab, efalizumab, golimumab, certolizumab, alefacept, secukinumab, abatacept, and ustekinumab. These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications. Herein, we present a comprehensive, unbiased comparison of these medications focusing on their differences. For example, TNF antagonists can differ in the way they are dissolved and administered, the effector molecules they can bind, serum peak and trough levels, the types of intracellular signals they can induce, the in vivo complexes that they can form, their protein structure, and their incidence and timing of rare adverse events, among other things. A critical review of the clinical studies that have tested the efficacy of these molecules is also presented including head-to-head comparison trials. The safety of biologics in terms of their long-term adverse events is discussed, as is their use in different types of psoriasis and in different patient populations. Finally, all anti-TNF agents have been associated with a variety of serious and "routine" opportunistic infections, particularly tuberculosis. For this reason, anti-tuberculosis testing both prior to the initiation of a biologic therapy and annually during treatment is pertinent. The uses and limitations of both the tuberculin skin test (TST) and QuantiFeron®-TB Gold (QFT) are discussed, as is the care of patients who present with latent tuberculosis infection prior to the initiation of biologic therapy. Recommendations for tuberculosis monitoring are provided.

• Psoriatic Arthritis: a Critical Review.

  Authors: Varun Dhir, Amita Aggarwal

  Clinical reviews in allergy & immunology.

  Psoriatic arthritis is a chronic inflammatory arthritis that affects about 5-25% of patients with psoriasis. The prevalence varies from 20-420 per 100,000 population across the world except in JapanPsoriatic arthritis is a chronic inflammatory arthritis that affects about 5-25% of patients with psoriasis. The prevalence varies from 20-420 per 100,000 population across the world except in Japan where it is 1 per 100,000. Psoriatic arthritis affects both genders equally and in more than half it follows long-standing psoriasis. Psoriatic arthritis has been grouped into five subtypes: distal interphalangeal (DIP) predominant, symmetrical polyarthritis, asymmetrical oligoarthritis and monoarthritis, predominant spondylitis, and arthritis mutilans. Oligoarthritis occurs in nearly 60% during early disease but later polyarticular disease predominates mainly due to evolution of oligoarthritis to polyarthritis. In 50-60% polyarthritis is symmetrical. Dactylitis and enthesopathy are other major features seen in nearly one third of patients. The diagnosis of psoriatic arthritis is easy in the presence of typical skin lesions, however it can also be made in absence of skin lesions using Classification of Psoriatic Arthritis criteria. Though 30-40% of patients develop joint deformities at a follow-up of 5-10 years but most retain good functional status. Clinical damage has a strong relationship with number of swollen joints, erythrocyte sedimentation rate, and duration of arthritis. Radiological damage occurs early and erosions are present in nearly 50% at 10 years of disease. Spinal disease also has good outcome with maintained spinal mobility in majority of the patients. Screening of patients with psoriasis using questionnaire can help in early diagnosis. Nail dystrophy, scalp lesions, and intergluteal/perianal psoriasis are associated with higher chance of development of psoriatic arthritis. Early diagnosis will lead to early treatment and better outcome especially with advent of new drugs.

• Imaging in Psoriatic Arthritis.

  Authors: Allen Anandarajah

  Clinical reviews in allergy & immunology.

  Psoriatic arthritis (PsA), a chronic inflammatory arthritis associated with psoriasis, is often associated with significant inflammation and joint damage leading to a decrease in quality of lifePsoriatic arthritis (PsA), a chronic inflammatory arthritis associated with psoriasis, is often associated with significant inflammation and joint damage leading to a decrease in quality of life measures. Plain radiographs have traditionally been used to detect and estimate the extent of joint damage. Newer imaging modalities such as ultrasound and MRI however, have provided the ability to detect joint damage earlier and measure the extent of joint damage more accurately, than with radiographs. These imaging modalities also provide a sensitive means of assessing for the presence of and quantifying the amount of inflammation. Furthermore, these imaging modalities can help with the identification of enthesitis, tendonitis, and dactylitis, features that can help make a diagnosis of PsA. Additionally, MRI and scintigraphy can help in the early detection and assessment of sacroiliitis and axial disease. In addition to benefits with diagnosis and prognosis, recent advances in imaging techniques have led to their increased use in the assessment of efficacy of novel therapies for psoriatic arthritis. Imaging modalities therefore allow for early detection, assessment of joint inflammation and joint damage as well as in the estimation of disease activity of PsA and thereby enable the clinician to treat PsA early, adequately, and safely.

• Clinical and Histologic Diagnostic Guidelines for Psoriasis: A Critical Review.

  Authors: Mary Ann N Johnson, April W Armstrong

  Clinical reviews in allergy & immunology.

  Psoriasis is a common inflammatory skin disease that is associated with joint, psychiatric, and cardiovascular comorbidities. Diagnosis of plaque psoriasis is dependent primarily on characteristicPsoriasis is a common inflammatory skin disease that is associated with joint, psychiatric, and cardiovascular comorbidities. Diagnosis of plaque psoriasis is dependent primarily on characteristic physical findings and history. Given the varied clinical presentations of psoriasis and its mimicry to other papulosquamous skin diseases, it may be difficult for nondermatologists to diagnose psoriasis. Currently, no diagnostic criteria for plaque psoriasis have been validated in clinical studies. In this paper, we provide diagnostic guidelines for the nondermatologist to aid them in recognizing psoriasis.

• Allergic and Immunologic Reactions to Food Additives.

  Authors: Fatih Gultekin, Duygu Kumbul Doguc

  Clinical reviews in allergy & immunology.

  For centuries, food additives have been used for flavouring, colouring and extension of the useful shelf life of food, as well as the promotion of food safety. During the last 20 years, the studiesFor centuries, food additives have been used for flavouring, colouring and extension of the useful shelf life of food, as well as the promotion of food safety. During the last 20 years, the studies implicating the additives contained in foods and medicine as a causative factor of allergic reactions have been proliferated considerably. In this review, we aimed to overview all of the food additives which were approved to consume in EU and find out how common and serious allergic reactions come into existence following the consuming of food additives.

• The Genetics of Psoriasis and Psoriatic Arthritis.

  Authors: Vinod Chandran

  Clinical reviews in allergy & immunology.

  Genetic epidemiological studies have demonstrated a significant genetic basis to both psoriasis and psoriatic arthritis (PsA). Although candidate gene association studies had identified genes forGenetic epidemiological studies have demonstrated a significant genetic basis to both psoriasis and psoriatic arthritis (PsA). Although candidate gene association studies had identified genes for disease susceptibility, recent genome-wide association studies have demonstrated robust associations both within and outside the major histocompatibility region on chromosome 6p. The susceptibility genes identified include HLA-C, IL13, IL4, TNFAIP3, IL23A, IL23R, IL28RA, REL, IFIH1, ERAP, TRAF3IP2, NFKBIA, TYK2, ZNF313, NOS2, FBXL19 and NFKBIA in subjects of European ethnicity and HLA-C, IL12B, LCE3D, ERAP1, TNIP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A in subjects of Chinese ethnicity. These associations provide us with a model for the pathogenesis of psoriasis involving skin barrier function, innate and adaptive immunity. Gene-gene and gene-environmental interaction effects have also been demonstrated. However, loci identified to date do not fully account for the high heritability of psoriasis and PsA, and therefore many genetic as well as environmental factors and interaction effects remain to be determined. This article reviews the current status of genetic studies in psoriasis and PsA.

• The Practical Understanding and Treatment of Asthma.

  Authors: M Eric Gershwin, Timothy E Albertson

  Clinical reviews in allergy & immunology.

  Asthma is a syndrome which is seen by physicians in nearly every specialty and affects millions of people throughout the world. Although the geoepidemiology with respect to prevalence and incidenceAsthma is a syndrome which is seen by physicians in nearly every specialty and affects millions of people throughout the world. Although the geoepidemiology with respect to prevalence and incidence of asthma does vary, even under the most mild of circumstance, asthma is among the leading causes of school absenteeism, work loss, and physician visits. In the past, it was considered primarily a disorder of childhood. Hence, the adage that children outgrow their asthma. We now realize that children really only outgrow their pediatrician and the genetic predisposition to asthma and bronchial hyperactivity persists throughout life. This issue is devoted to key papers that focus on important clinical problems in allergies and asthma. This issue is dedicated to helping the many sufferers of asthma with the hope that this topic will eventually become a medical anachronism.

• Type I Interferons: Beneficial in Th1 and Detrimental in Th17 Autoimmunity.

  Authors: Robert C Axtell, Chander Raman, Lawrence Steinman

  Clinical reviews in allergy & immunology.

  In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. However,In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. However, within the RRMS population, 30-50% of MS patients are nonresponsive to this treatment, and it consistently worsens neuromyelitis optica (NMO), a disease once considered to be a form of RRMS. In contrast to RRMS, type I IFNs have been shown to have properties that drive the inflammatory pathologies in many other autoimmune diseases. These diseases include Sjögren's syndrome, system lupus erythematosus (SLE), neuromyelitis optica (NMO), rheumatoid arthritis (RA) and psoriasis. Historically, autoimmune diseases were thought to be driven by a TH1 response to auto-antigens. However, since the discovery of the TH17 in experimental autoimmune encephalomyelitis (EAE), it is now generally thought that TH17 plays an important role in MS and all other autoimmune diseases. In this article, we will discuss recent clinical and basic research advances in the field of autoimmunity and argue that IFN-β and other type I IFNs are immuno-modulatory in diseases driven predominantly by TH1 but in contrast are inflammatory in diseases that have a predominant Th17 response.

• The Future of Autoimmunity.

  Authors: Yehuda Shoenfeld

  Clinical reviews in allergy & immunology.

  There have been enormous strides in our understanding of autoimmunity. These strides have come under the umbrellas of epidemiology, immunological phenotype and function, disease definitions andThere have been enormous strides in our understanding of autoimmunity. These strides have come under the umbrellas of epidemiology, immunological phenotype and function, disease definitions and classification and especially new therapeutic reagents. However, while these advances have been herculean, there remains enormous voids. Some of these voids include genetic susceptibility and the interaction of genes and environment. The voids include induction of tolerance in preclinical disease and definitions of host susceptibility and responses to the expensive biologic agents. The voids include the so-called clustering of human autoimmune diseases and the issues of whether the incidence is rising in our western society. Other voids include the relationships between microbiology, vaccination, gut flora, overzealous use of antibiotics, and the role of nanoparticles and environmental pollution in either the induction or the natural history of disease. One cannot even begin to address even a fraction of these issues. However, in this special issue, we are attempting to discuss clinical issues in autoimmunity that are not usually found in generic reviews. The goal is to bring to the readership provocative articles that ultimately will lead to improvement in patient care.

• Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy.

  Authors: Jin Nakahara, Michiko Maeda, Sadakazu Aiso, Norihiro Suzuki

  Clinical reviews in allergy & immunology. 42(1):26-34.

  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects millions of patients worldwide. The current disease-modifying therapies (DMTs) that areMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects millions of patients worldwide. The current disease-modifying therapies (DMTs) that are widely used to treat MS only show modest effects. Because MS is a chronic disease, it is important to develop treatments that have better long-term efficacy. Recently, several new-generation DMTs have been developed, most of which target specific immune molecules based on the assumption that MS is an autoimmune disease. These DMTs are designed to inhibit inflammation that is thought to directly cause demyelination. Preliminary studies suggest that these new therapies are likely to show a greater effect in reducing relapses in early MS patients, although their long-term efficacy is still unknown. In contrast, it was recently reported that the initial course of MS does not significantly influence long-term disability and that disability increases approximately at the same rate despite variable relapse frequencies. Furthermore, new neuropathological evidence now argues against the autoimmune hypothesis and suggests that MS is a primary oligodendrogliopathy disease in which the inflammatory response may be a mere epiphenomenon. So can we be optimistic about the unproven long-term outcomes of new DMTs or should we reconsider the pathogenesis of MS when developing more disease-specific treatments?

• Mechanisms and pathophysiology of autoimmune disease.

  Authors: Wesley H Brooks

  Clinical reviews in allergy & immunology. 42(1):1-4.

  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, thereThe 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.

• The therapeutic potential of epigenetics in autoimmune diseases.

  Authors: Maria De Santis, Carlo Selmi

  Clinical reviews in allergy & immunology. 42(1):92-101.

  Autoimmune diseases now include over 100 conditions and are estimated to affect over 20 million people in the United States or 5% of the world population with numerous geographical differences coinedAutoimmune diseases now include over 100 conditions and are estimated to affect over 20 million people in the United States or 5% of the world population with numerous geographical differences coined as geoepidemiology. Further, concordance rates in monozygotic twins are significantly higher compared to dizygotic sets while being significantly below 50% for most autoimmune diseases. These lines of evidence suggest that additional mechanisms are needed to link the individual susceptibility with the proposed chemical and infectious factors in the environment. Epigenetics may well constitute this missing link to include DNA methylation, histone changes, and microRNA which contribute to the epigenome characterizing specific diseases. Importantly, these epigenetic changes may be ideal targets for new personalized treatments as suggested by data in cancer. A number of chemical and physical factors, along with proposed infectious agents or aging, are involved in the etiopathogenesis of autoimmune diseases through epigenetic changes. The most prominent evidence on the association between environment and autoimmunity has been reported in systemic lupus erythematosus, but similar mechanisms were proposed in rheumatoid arthritis, systemic sclerosis, and type 1 diabetes.

• Umbilical cord blood immunology: relevance to stem cell transplantation.

  Authors: Syh-Jae Lin, Dah-Chin Yan, Yen-Chang Lee, Hsiu-Shan Hsiao, Pei-Tzu Lee, Yu-Wen Liang, Ming-Ling Kuo

  Clinical reviews in allergy & immunology. 42(1):45-57.

  Because of its easier accessibility and less severe graft-versus-host disease, umbilical cord blood (UCB) has been increasingly used as an alternative to bone marrow for hematopoietic stem cellBecause of its easier accessibility and less severe graft-versus-host disease, umbilical cord blood (UCB) has been increasingly used as an alternative to bone marrow for hematopoietic stem cell transplantation. Naiveté of UCB lymphocytes, however, results in delayed immune reconstitution and infection-related mortality in transplant recipients. This review updates the phenotypic and functional deficiencies of various immune cell populations in UCB compared with their adult counterparts and discusses clinical implications and possible therapeutic strategies to improve the outcome of stem cell transplantation.

• The role of prolonged viral gastrointestinal infections in the development of immunodeficiency-related enteropathy.

  Authors: Annick A J M van de Ven, David P Hoytema van Konijnenburg, Annemarie M J Wensing, Joris M van Montfrans

  Clinical reviews in allergy & immunology. 42(1):79-91.

  Patients with primary immunodeficiencies are prone to develop enteropathy of unknown pathogenesis. We hypothesize that ineffective clearance of gastrointestinal pathogens, particularly viruses, inPatients with primary immunodeficiencies are prone to develop enteropathy of unknown pathogenesis. We hypothesize that ineffective clearance of gastrointestinal pathogens, particularly viruses, in combination with defective immune regulation may cause inflammatory enteropathy in certain immunodeficient hosts. We reviewed publications related to prolonged enteric viral infection, immunodeficiency, and the subsequent development of inflammatory enteropathy. Prolonged infection with especially enteroviral infections was reported more often in immunocompromised hosts than in healthy individuals. Protracted enteric viral shedding was not always associated with the presence or duration of gastrointestinal symptoms. The development of immunodeficiency-associated enteropathy after prolonged viral infections was described in sporadic cases. Clinical consequences of viral gut infections in immunocompromised hosts comprise isolation issues and supportive care. Prospective studies in cohorts of immunodeficient patients are required to study the impact of prolonged enteric viral replication with respect to the pathogenesis of non-infectious enteropathy.

• Autoimmune diseases and polyamines.

  Authors: Wesley H Brooks

  Clinical reviews in allergy & immunology. 42(1):58-70.

  Genetics and environmental factors have important roles in autoimmune diseases but neither has given us sufficient understanding of these mysterious diseases. Therefore, we are now looking closer atGenetics and environmental factors have important roles in autoimmune diseases but neither has given us sufficient understanding of these mysterious diseases. Therefore, we are now looking closer at epigenetics, an interface between genetics and environmental factors. Epigenetics can be defined as reversible heritable changes to chromatin that can alter gene expression without altering the gene's DNA sequence. Methylation of DNA and histones are primary means of epigenetic control. By adding methyl groups to DNA and histones, it can limit accessibility of the underlying gene thereby altering the amount of gene expression. The methyl group is derived from an essential molecule in the cell, S-adenosylmethionine (SAM). However, a group of small molecules called polyamines also require SAM for their synthesis. Polyamines are essential for many cellular functions and polyamine activity is increased in many autoimmune diseases. Presented here is the "polyamine hypothesis" in which increased polyamine synthesis competes with cellular methylation (epigenetic control) for SAM. It is proposed that increased polyamine activity can cause disruption of cellular methylation, which can lead to abnormal expression of previously sequestered genes and disruption of other methylation-dependent cellular processes.

• Leaky gut and autoimmune diseases.

  Authors: Alessio Fasano

  Clinical reviews in allergy & immunology. 42(1):71-8.

  Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impairedAutoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.

• Animal models in autoimmune diseases: lessons learned from mouse models for Sjögren's syndrome.

  Authors: Byung Ha Lee, Adrienne E Gauna, Kaleb M Pauley, Yun-Jong Park, Seunghee Cha

  Clinical reviews in allergy & immunology. 42(1):35-44.

  The mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidateThe mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidate underlying causes of multifactorial autoimmune conditions, including pathological immune components and specific signaling pathways. This review summarizes the more recent mouse models for Sjögren's syndrome, a systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine glands, such as the salivary and lacrimal glands, and loss of secretory function, resulting in dry mouth and dry eyes in patients. Although every Sjögren's syndrome mouse model resembles the major symptoms or phenotypes of Sjögren's syndrome conditions in humans, the characteristics of each model are variable. Moreover, to date, there is no single mouse model that can completely replicate the human conditions. However, unique features of each mouse model provide insights into the roles of potential etiological and immunological factors in the development and progression of Sjögren's syndrome. Here, we will overview the Sjögren's syndrome mouse models. Lessons from these mouse models will aid us to understand underlying immune dysregulation in autoimmune diseases in general, and will guide us to direct future research towards appropriate diagnostic and therapeutic strategies.

• Bronchial Thermoplasty: A New Treatment Paradigm for Severe Persistent Asthma.

  Authors: Katherine S Cayetano, Andrew L Chan, Timothy E Albertson, Ken Y Yoneda

  Clinical reviews in allergy & immunology.

  Patients with severe asthma represent only a minority of the total asthma population; however, they account for the majority of the mortality, morbidity, and health care-related cost of this chronicPatients with severe asthma represent only a minority of the total asthma population; however, they account for the majority of the mortality, morbidity, and health care-related cost of this chronic illness. Bronchial thermoplasty is a novel treatment modality that employs radiofrequency energy to alter the smooth muscles of the airways. This therapy represents a radical change in our treatment paradigm from daily repetitive dosing of medications to a truly long-term and potentially permanent attenuation of perhaps the most feared component of asthma-smooth muscle-induced bronchospasm. A large, multicentered, double-blinded, randomized controlled trial employed the unprecedented (but now industry standard for bronchoscopic studies) approach of using sham bronchoscopy as a control. It demonstrated that bronchial thermoplasty is safe, improved quality of life, and decreased frequency of severe exacerbations in the treatment group compared to the control group. Although the mechanism of action of bronchial thermoplasty is not currently completely understood, it should be considered as a valid and potentially valuable option for patients who have severe persistent asthma and who remain symptomatic despite inhaled corticosteroids and long-acting beta-2 agonists. Such patients should however be carefully evaluated at centers with expertise in managing severe asthma patients and with physicians who have experience with this promising new treatment modality.

• Molecular mimicry as a mechanism of autoimmune disease.

  Authors: Matthew F Cusick, Jane E Libbey, Robert S Fujinami

  Clinical reviews in allergy & immunology. 42(1):102-11.

  A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen sharesA variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

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