Showing papers in "Clinical Reviews in Allergy & Immunology in 2016"
TL;DR: This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options.
Abstract: For centuries, itch was categorized as a submodality of pain. Recent research over the last decade has led to the realization that itch is in fact a separate and distinct, albeit closely related, sensation. Chronic itch is a common complaint and has numerous etiologies. Various receptors (TRPA1, TRPV1, PAR2, gastrin-releasing peptide receptor (GRPR), Mas-related G proteins), secreted molecules (histamine, nerve growth factor (NGF), substance P (SP), proteases), and cytokines/chemokines (thymic stromal lymphopoietin (TSLP), IL-2, IL-4, IL-13, and IL-31) are implicated as mediators of chronic pruritus. While much remains unknown regarding the mechanisms of chronic itch, this much is certain: there is no singular cause of itch. Rather, itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system. Clinicians are in possession of an arsenal of different treatment options ranging from moisturizers, topical immunomodulators, topical anesthetic ion channel inhibitors, systemic immunomodulators, as well as oral drugs capable of reducing neural hypersensitization. Emerging targeted therapies on the horizon, such as dupilumab, promise to usher in a new era of highly specific and efficacious treatments. Alternative medicine, stress reduction techniques, and patient education are also important treatment modalities. This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options.
280 citations
TL;DR: Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis, as well as developing increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules.
Abstract: Psoriasis is a chronic inflammatory autoimmune disease characterized by an excessively aberrant hyperproliferation of keratinocytes. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. However, psoriasis is thought to result from a combination of genetic, epigenetic, and environmental influences. Recent studies have identified that epigenetic factors including dysregulated DNA methylation levels, abnormal histone modification and microRNAs expressions are involved in the development of psoriasis. The interplay of immune cells and cytokines is another critical factor in the pathogenesis of psoriasis. These factors or pathways include Th1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasis due to its pro-inflammatory effects and its involvement in an integrated inflammatory loop with dendritic cells and keratinocytes, contributing to an overproduction of antimicrobial peptides, inflammatory cytokines, and chemokines that leads to amplification of the immune response. In addition, other pathways and signaling molecules have been found to be involved, including Th9, Th22, regulatory T cells, γδ T cells, CD8(+) T cells, and their related cytokines. Understanding the pathogenesis of psoriasis will allow us to develop increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules. There is no cure for psoriasis at the present time, and much of the treatment involves managing the symptoms. The biologics, while lacking the adverse effects associated with some of the traditional medications such as corticosteroids and methotrexate, have their own set of side effects, which may include reactivation of latent infections. Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis.
278 citations
TL;DR: Recent findings on TLR pathway regulation in various autoimmune diseases are summarized, suggesting that TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases.
Abstract: Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location; the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. In particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS, are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathway regulation in various autoimmune diseases, including Sjogren’s syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis.
202 citations
TL;DR: Immunologic and molecular mechanisms underlying the propensity of AD patients to microbial infections, including Staphylococcus aureus skin infections, are reviewed to have important clinical implications for the prevention and treatment of skin infections in this common skin disease.
Abstract: Atopic dermatitis (AD) is the most common allergic skin disease in the general population. It is a chronic inflammatory skin disease complicated by recurrent bacterial and viral infections that, when left untreated, can lead to significant complications. The current article will review immunologic and molecular mechanisms underlying the propensity of AD patients to microbial infections. These infections include Staphylococcus aureus (S. aureus) skin infections, eczema herpeticum, eczema vaccinatum, and eczema coxsackium. Previous studies have shown that skin barrier defects, a decrease in antimicrobial peptides, increased skin pH, or Th2 cytokines such as IL-4 and IL-13 are potential contributing factors for the increased risk of skin infections in AD. In addition, bacterial virulence such as methicillin-resistant S. aureus (MRSA) produces significantly higher number of superantigens that increase their potential in causing infection and more severe cutaneous inflammation in AD patients. More recent studies suggest that skin microbiome including Staphylococcus epidermidis or other coagulase-negative staphylococci may play an important role in controlling S. aureus skin infections in AD. Other studies also suggest that genetic variants in the innate immune response may predispose AD patients to increased risk of viral skin infections. These genetic variants include thymic stromal lymphopoietin (TSLP), type I interferon (α, s, ω), type II interferon (γ), and molecular pathways that lead to the production of interferons (interferon regulatory factor 2). A common staphylococcal toxin, α-toxin, may also play a role in enhancing herpes simplex virus skin infections in AD. Further understanding of these disease processes may have important clinical implications for the prevention and treatment of skin infections in this common skin disease.
168 citations
TL;DR: OX40 and OX40L expression in human autoimmune disease, identified associations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases are reviewed.
Abstract: The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.
160 citations
TL;DR: The epidemiology, pathophysiology, evaluation, and treatment of scombroid disease are discussed, which go far beyond that of fish and have broader implications for the important issues of food safety.
Abstract: Histamine fish poisoning, also known as scombroid poisoning, is the most common cause of ichythyotoxicosis worldwide and results from the ingestion of histamine-contaminated fish in the Scombroidae and Scomberesocidae families, including mackerel, bonito, albacore, and skipjack. This disease was first described in 1799 in Britain and re-emerged in the medical literature in the 1950s when outbreaks were reported in Japan. The symptoms associated with histamine fish poisoning are similar to that of an allergic reaction. In fact, such histamine-induced reactions are often misdiagnosed as IgE-mediated fish allergy. Indeed, histamine fish poisoning is still an underrecognized disease. In this review, we discuss the epidemiology, pathophysiology, evaluation, and treatment of scombroid disease. Because more than 80 % of fish consumed in the USA is now imported from other countries, the disease is intimately linked with the global fish trade (National Marine Fisheries Service, 2012). Preventing future scombroid outbreaks will require that fishermen, public health officials, restaurant workers, and medical professionals work together to devise international safety standards and increase awareness of the disease. The implications of scombroid poisoning go far beyond that of fish and have broader implications for the important issues of food safety.
150 citations
TL;DR: A number of factors, including oncostatin M, have been shown to promote osteoblast formation both in vitro and in vivo and how this can be used to direct new bone anabolic approaches is discussed.
Abstract: The contribution of inflammation to bone loss is well documented in arthritis and other diseases with an emphasis on how inflammatory cytokines promote osteoclastogenesis. Macrophages are the major producers of cytokines in inflammation, and the factors they produce depend upon their activation state or polarization. In recent years, it has become apparent that macrophages are also capable of interacting with osteoblasts and their mesenchymal precursors. This interaction provides growth and differentiation factors from one cell that act on the other and visa versa-a concept akin to the requirement for a feeder layer to grow hemopoietic cells or the coupling that occurs between osteoblasts and osteoclasts to maintain bone homeostasis. Alternatively, activated macrophages are the most likely candidates to promote bone formation and have also been implicated in the tissue repair process in other tissues. In bone, a number of factors, including oncostatin M, have been shown to promote osteoblast formation both in vitro and in vivo. This review discusses the different cell types involved, cellular mediators, and how this can be used to direct new bone anabolic approaches.
148 citations
TL;DR: The eosinophil’s unique biology and structure is reviewed, including its characteristic granules and the effects of its proteins, the authors' developing understanding of its role in innate and adaptive immunity and importance in immunomodulation, and the part it plays in defense against parasitic, viral, fungal and bacterial infections.
Abstract: First described by Paul Ehrlich in 1879, who noted its characteristic staining by acidophilic dyes, for many years, the eosinophil was considered to be an end-effector cell associated with helminth infections and a cause of tissue damage. Over the past 30 years, research has helped to elucidate the complexity of the eosinophil’s function and establish its role in host defense and immunity. Eosinophils express an array of ligand receptors which play a role in cell growth, adhesion, chemotaxis, degranulation, and cell-to-cell interactions. They play a role in activation of complement via both classical and alternative pathways. Eosinophils synthesize, store and secrete cytokines, chemokines, and growth factors. They can process antigen, stimulate T cells, and promote humoral responses by interacting with B cells. Eosinophils can function as antigen presenting cells and can regulate processes associated with both T1 and T2 immunity. Although long known to play a role in defense against helminth organisms, the interactions of eosinophils with these parasites are now recognized to be much more complex. In addition, their interaction with other pathogens continues to be investigated. In this paper, we review the eosinophil’s unique biology and structure, including its characteristic granules and the effects of its proteins, our developing understanding of its role in innate and adaptive immunity and importance in immunomodulation, and the part it plays in defense against parasitic, viral, fungal and bacterial infections. Rather than our worst enemy, the eosinophil may, in fact, be one of the most essential components in host defense and immunity.
128 citations
TL;DR: Steroids are currently the mainstay of therapy, but the roles of other drugs such as leukotriene inhibitors, mast cell stabilizers, interleukin-5 inhibitors, and anti-immunoglobulin E, along with other targets in the immune pathway are currently being explored.
Abstract: Eosinophilic gastrointestinal disorders, including eosinophilic esophagitis, gastroenteritis, and colitis, refer to a spectrum of clinical diseases that present with variable degrees of infiltration of the gastrointestinal tract by eosinophils in the absence of other known causes of tissue eosinophilia. Clinical symptoms and laboratory findings are usually non-specific and may or may not be accompanied by peripheral blood eosinophilia. The extent of eosinophilic infiltration of the gastrointestinal wall varies from mucosal to transmural and serosal involvement. Diagnosis requires presence of gastrointestinal symptoms, demonstration of gastrointestinal eosinophilia by biopsy, and exclusion of other known causes of tissue eosinophilia. Many studies have pointed toward the eosinophil as the major offender; however, the exact functional role of the eosinophil in the pathogenesis of eosinophilic gastrointestinal disorders remains unclear. The roles of T-helper-2 cytokines and other mediators, such as eotaxin-1 and interleukin-5, have gained significant importance in the pathobiology of eosinophilic gastrointestinal disorders. Current understanding of treatment is based on case reports and a few case series, as there is a lack of large prospective studies. Steroids are currently the mainstay of therapy, but the roles of other drugs such as leukotriene inhibitors, mast cell stabilizers, interleukin-5 inhibitors, and anti-immunoglobulin E, along with other targets in the immune pathway, are currently being explored.
124 citations
TL;DR: Progress in three separate areas has catalyzed the understanding of hereditary angioedema, including the recognition that HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor, and the understanding that tissue swelling is enhanced contact system activation leading to increased generation of bradykinin.
Abstract: Remarkable progress in understanding the pathophysiology and underlying mechanisms of hereditary angioedema has led to the development of effective treatment for this disorder. Progress in three separate areas has catalyzed our understanding of hereditary angioedema. The first is the recognition that HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. This observation has led to a detailed understanding of the SERPING1 mutations responsible for this deficiency as well as the molecular regulation of C1 inhibitor expression and function. The second is that the fundamental cause of swelling is enhanced contact system activation leading to increased generation of bradykinin. Substantial progress has been made in defining the parameters regulating bradykinin generation and catabolism as well as the receptors that transduce the biologic effects of kinins. The third is the understanding that tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions. This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema. While there has been considerable progress made, large gaps still remain in our knowledge. Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor. The phenotypic variability of hereditary angioedema has been extensively documented but never understood. The mechanisms discussed in this chapter likely contribute to this variability. Future progress in understanding these mechanisms should provide new means to improve the diagnosis and treatment of hereditary angioedema.
115 citations
TL;DR: Genetic variants and epigenetic alteration might be the key tools for the molecular taxonomy of AD and provide the background for the personalized management.
Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by a combination of genetic and environmental factors. Genetic evidences depict a complex network comprising by epidermal barrier dysfunctions and dysregulation of innate and adaptive immunity in the pathogenesis of AD. Mutations in the human filaggrin gene (FLG) are the most significant and well-replicated genetic mutation associated with AD, and other mutations associated with epidermal barriers such as SPINK5, FLG-2, SPRR3, and CLDN1 have all been linked to AD. Gene variants may also contribute to the abnormal innate and adaptive responses found in AD, including mutations in PRRs and AMPs, TSLP and TSLPR, IL-1 family cytokines and receptors genes, vitamin D pathway genes, FCER1A, and Th2 and other cytokines genes. GWAS and Immunochip analysis have identified a total of 19 susceptibility loci for AD. Candidate genes at these susceptibility loci identified by GWAS and Immunochip analysis also suggest roles for epidermal barrier functions, innate and adaptive immunity, interleukin-1 family signaling, regulatory T cells, the vitamin D pathway, and the nerve growth factor pathway in the pathogenesis of AD. Increasing evidences show the modern lifestyle (i.e., the hygiene hypothesis, Western diet) and other environmental factors such as pollution and environmental tobacco smoke (ETS) lead to the increasing prevalence of AD with the development of industrialization. Epigenetic alterations in response to these environmental factors, including DNA methylation and microRNA related to immune system and skin barriers, have been found to contribute to the pathogenesis of AD. Genetic variants and epigenetic alteration might be the key tools for the molecular taxonomy of AD and provide the background for the personalized management.
TL;DR: A comprehensive review on the etiology, pathogenesis, clinical features, and management of these rare eosinophilic dermatoses with an emphasis on recent advances and current consensus is presented.
Abstract: Eosinophilic skin diseases, commonly termed as eosinophilic dermatoses, refer to a broad spectrum of skin diseases characterized by eosinophil infiltration and/or degranulation in skin lesions, with or without blood eosinophilia. The majority of eosinophilic dermatoses lie in the allergy-related group, including allergic drug eruption, urticaria, allergic contact dermatitis, atopic dermatitis, and eczema. Parasitic infestations, arthropod bites, and autoimmune blistering skin diseases such as bullous pemphigoid, are also common. Besides these, there are several rare types of eosinophilic dermatoses with unknown origin, in which eosinophil infiltration is a central component and affects specific tissue layers or adnexal structures of the skin, such as the dermis, subcutaneous fat, fascia, follicles, and cutaneous vessels. Some typical examples are eosinophilic cellulitis, granuloma faciale, eosinophilic pustular folliculitis, recurrent cutaneous eosinophilic vasculitis, and eosinophilic fasciitis. Although tissue eosinophilia is a common feature shared by these disorders, their clinical and pathological properties differ dramatically. Among these rare entities, eosinophilic pustular folliculitis may be associated with human immunodeficiency virus (HIV) infection or malignancies, and some other diseases, like eosinophilic fasciitis and eosinophilic cellulitis, may be associated with an underlying hematological disorder, while others are considered idiopathic. However, for most of these rare eosinophilic dermatoses, the causes and the pathogenic mechanisms remain largely unknown, and systemic, high-quality clinical investigations are needed for advances in better strategies for clinical diagnosis and treatment. Here, we present a comprehensive review on the etiology, pathogenesis, clinical features, and management of these rare entities, with an emphasis on recent advances and current consensus.
TL;DR: The relationship between the skin changes and myositis-associated autoantibodies should help the clinician in the early diagnosis of DM, for a quick recognition of cutaneous signs that may be the symptom of onset before muscle inflammation.
Abstract: Dermatomyositis (DM) is a common idiopathic inflammatory myopathy. The pathogenesis is considered to be microangiopathy affecting skin and muscle. The cutaneous manifestations of DM are the most important aspect of this disease, and their correct evaluation is important for early diagnosis. The skin signs are various: Some are pathognomonic or highly characteristic, and others are compatible with DM. Recently, DM has been categorized into several disease subsets based on the various autoantibodies present in patients. Sometimes, characteristic cutaneous manifestations are strongly associated with the presence of specific autoantibodies. For example, anti-Mi-2 antibody is associated with the classic features of DM, including heliotrope rash, Gottron’s papules, the V-neck sign, the shawl sign, cuticular overgrowth, and photosensitivity. Frequent cutaneous features in anti-transcriptional intermediary factor 1 gamma (TIF1γ)-positive patients are diffuse photoerythema, including “dusky red face,” while skin ulcerations, palmar papules (inverse Gottron), diffuse hair loss, panniculitis, and oral pain and/or ulcers are sometimes associated with anti-melanoma differentiation-associated gene 5 product (MDA5) antibody. Here, we review important cutaneous manifestations seen in patients with DM, and we examine the relationship between the skin changes and myositis-associated autoantibodies. Correct evaluation of cutaneous manifestations and myositis-associated autoantibodies should help the clinician in the early diagnosis of DM, for a quick recognition of cutaneous signs that may be the symptom of onset before muscle inflammation.
TL;DR: The aim of this study is to review the types and rates of medical complications of permanent tattoos and to postulate that the antigens contained in dyes or pigments are such small molecules that they need to be haptenized in order to become immunogenic.
Abstract: Tattoos are defined as the introduction of exogenous pigments into the dermis in order to produce a permanent design. This process may occur unintentional or may be deliberately administered for cosmetic or medical reasons. Tattoos have been around for over 5000 years and over time have evolved to represent a common cosmetic practice worldwide. Currently, adverse reactions are relatively rare and generally unpredictable and predominantly include immune-mediated reactions and skin infections. Along with better healthcare standards and more stringent public health mandates such as the provision of disposable needles, major infectious complications related to hepatitis and human retroviral infections have decreased significantly. When they do occur, skin infections are most frequently associated with Staphylococcus aureus or Streptococcus pyogenes. The aim of this study is to review the types and rates of medical complications of permanent tattoos. PubMed search and search dates were open ended. Acute local inflammation is the most common complication, but infections, allergic contact dermatitis, and other inflammatory or immune responses that are not well-characterized may occur. As many patients with immune reactions to tattoos do not react on skin or patch testing, it is postulated that the antigens contained in dyes or pigments are such small molecules that they need to be haptenized in order to become immunogenic. Red ink is associated more frequently with long-term reactions, including granulomatous and pseudolymphomatous phenomena or morphea-like lesions and vasculitis. Exacerbation of preexisting psoriasis, atopic dermatitis, and pyoderma gangrenosum may occur after tattooing. There is no well-defined association between cancer and tattoos. The treatment of tattoo-related complications may include local destructive measures (cryotherapy, electro-surgery, dermabrasion, chemical destruction, ablative laser destruction), surgical excision, and thermolysis of the pigment using Q-switched laser therapy.
TL;DR: This work will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity.
Abstract: The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive.
TL;DR: Large scale, in-depth genetic studies are expected not only to answer these emerging questions but also to further elucidate many of the unmet aspects of angioedema pathogenesis.
Abstract: Contemporary genetic research has provided evidences that angioedema represents a diverse family of disorders related to kinin metabolism, with a much greater genetic complexity than was initially considered. Convincing data have also recently been published indicating that the clinical heterogeneity of hereditary angioedema due to C1 inhibitor deficiency (classified as C1-INH-HAE) could be attributed at least in part, either to the type of SERPING1 mutations or to mutations in genes encoding for enzymes involved in the metabolism and function of bradykinin. Alterations detected in at least one more gene (F12) are nowadays considered responsible for 25 % of cases of hereditary angioedema with normal C1-INH (type III hereditary angioedema (HAE), nlC1-INH-HAE). Interesting data derived from genetic approaches of non-hereditary angioedemas indicate that other immune pathways might be implicated in the pathogenesis of HAE. More than 125 years after the recognition of the hereditary nature of HAE by Osler, the heterogeneity of clinical expressions, the genetics of this disorder, and the genotype-phenotype relationships, still presents a challenge that will be discussed in this review. Large scale, in-depth genetic studies are expected not only to answer these emerging questions but also to further elucidate many of the unmet aspects of angioedema pathogenesis. Uncovering genetic biomarkers affecting the severity of the disease and/or the effectiveness of the various treatment modalities might lead to the prevention of attacks and the optimization of C1-INH-HAE management that is expected to provide a valuable benefit to the sufferers of angioedema.
TL;DR: The Wnt and BMP signaling pathways have emerged as critical in the regulation of osteoblast function and the outcome for bone in rheumatic diseases, and these pathways have been implicated in both bone loss in RA and bone formation in AS.
Abstract: Dysregulated bone remodeling occurs when there is an imbalance between bone resorption and bone formation. In rheumatic diseases, including rheumatoid arthritis (RA) and seronegative spondyloarthritis, systemic and local factors disrupt the process of physiologic bone remodeling. Depending upon the local microenvironment, cell types, and local mechanical forces, inflammation results in very different effects on bone, promoting bone loss in the joints and in periarticular and systemic bone in RA and driving bone formation at enthesial and periosteal sites in diseases such as ankylosing spondylitis (AS), included within the classification of axial spondyloarthritis. There has been a great deal of interest in the role of osteoclasts in these processes and much has been learned over the past decade about osteoclast differentiation and function. It is now appreciated that osteoblast-mediated bone formation is also inhibited in the RA joint, limiting the repair of erosions. In contrast, osteoblasts function to produce new bone in AS. The Wnt and BMP signaling pathways have emerged as critical in the regulation of osteoblast function and the outcome for bone in rheumatic diseases, and these pathways have been implicated in both bone loss in RA and bone formation in AS. These pathways provide potential novel approaches for therapeutic intervention in diseases in which inflammation impacts bone.
TL;DR: The anti-immunosenescence action of Bach and the role of epigenetic modifications of these transcription factors may be important in the mechanism of Bach transcription factors in mediating oxidative stress and cellular immunity.
Abstract: The transcription factors Bach1 and Bach2, which belong to a basic region-leucine zipper (bZip) family, repress target gene expression by forming heterodimers with small Maf proteins. With the ability to bind to heme, Bach1 and Bach2 are important in maintaining heme homeostasis in response to oxidative stress, which is characterized by high levels of reactive oxygen species (ROS) in cells and thereby induces cellular damage and senescence. The inactivation of Bach1 exerts an antioxidant effect. Thus, Bach1 may be a potential therapeutic target of oxidative stress-related diseases. Bach2 participates in oxidative stress-mediated apoptosis and is involved in macrophage-mediated innate immunity as well as the adaptive immune response. Bach1 and Bach2 promote the differentiation of common lymphoid progenitors to B cells by repressing myeloid-related genes. Bach2 is able to regulate class-switch recombination and plasma cell differentiation by altering the concentration of mitochondrial ROS during B cell differentiation. Furthermore, Bach2 maintains T cell homeostasis, influences the function of macrophages, and plays a role in autoimmunity. Bach2-controlling genes with super enhancers in T cells play a key role in immune regulation. However, in spite of new research, the role of Bach1 and Bach2 in immune cells and immune response is not completely clear, nor are their respective roles of in oxidative stress and the immune response, in particular with regard to the clinical phenotypes of autoimmune diseases. The anti-immunosenescence action of Bach and the role of epigenetic modifications of these transcription factors may be important in the mechanism of Bach transcription factors in mediating oxidative stress and cellular immunity.
TL;DR: It is imperative to control the local eosinophilic inflammation not only to give symptomatic relief to the patient but also to prevent complications such as esophageal stricture and food impaction.
Abstract: Eosinophilic esophagitis (EoE) is an emerging chronic atopic clinical-pathologic disease with an estimated prevalence of 1/1000 similar to the one of Crohn’s diseases. Usually, EoE is firstly suspected due to symptoms that are caused by esophageal dysfunction and/or fibrosis. EoE diagnosis is confirmed if the esophageal biopsy shows at least 15 eosinophils per high power field (eos/hpf) as a peak value in one or more of at least four specimens obtained randomly from the esophagus. Most of the patients affected by EoE have other atopic diseases such as allergic rhinitis, asthma, IgE-mediated food allergies, and/or atopic dermatitis. The local inflammation is a T helper type 2 (Th2) flogosis, which most likely is driven by a mixed IgE and non-IgE-mediated reaction to food and/or environmental allergens. Recently published genetic studies showed also that EoE is associated with single nucleotide polymorphism (SNP) on genes which are important in atopic inflammation such as thymic stromal lymphopoietin (TSLP) located close to the Th2 cytokine cluster (IL-4, IL-5, IL-13) on chromosome 5q22. When the EoE diagnosis is made, it is imperative to control the local eosinophilic inflammation not only to give symptomatic relief to the patient but also to prevent complications such as esophageal stricture and food impaction. EoE is treated like many other atopic diseases with a combination of topical steroids and/or food antigen avoidance.
TL;DR: The mechanisms that are responsible for bradykinin production in hereditary angioedema (HAE) and the central role that the coagulation factor XII (FXII) plays in it are described and the paradigm that FXII functions as a ‘sensor molecule’ to detect conditions that require bradykinsin release via crosstalk with cell-derived enzymes is put forward.
Abstract: Episodic and recurrent local cutaneous or mucosal swelling are key features of angioedema. The vasoactive agents histamine and bradykinin are highly implicated as mediators of these swelling attacks. It is challenging to assess the contribution of bradykinin to the clinical expression of angioedema, as accurate biomarkers for the generation of this vasoactive peptide are still lacking. In this review, we will describe the mechanisms that are responsible for bradykinin production in hereditary angioedema (HAE) and the central role that the coagulation factor XII (FXII) plays in it. Evidently, several plasma parameters of coagulation change during attacks of HAE and may prove valuable biomarkers for disease activity. We propose that these changes are secondary to vascular leakage, rather than a direct consequence of FXII activation. Furthermore, biomarkers for fibrinolytic system activation (i.e. plasminogen activation) also change during attacks of HAE. These changes may reflect triggering of the bradykinin-forming mechanisms by plasmin. Finally, multiple lines of evidence suggest that neutrophil activation and mast-cell activation are functionally linked to bradykinin production. We put forward the paradigm that FXII functions as a ‘sensor molecule’ to detect conditions that require bradykinin release via crosstalk with cell-derived enzymes. Understanding the mechanisms that drive bradykinin generation may help to identify angioedema patients that have bradykinin-mediated disease and could benefit from a targeted treatment.
TL;DR: A meta-analysis of clinical trials identified in systematic searches of MEDLINE, EMBASE, Wanfang database, Cochrane Database, and Google scholar found that TNF inhibitors appear to have net clinical benefits with regard to adverse cardiovascular events in Pso and/or PsA.
Abstract: TNF inhibitors have been used in psoriasis (Pso) and psoriatic arthritis (PsA), which were associated with increased risk of cardiac and cerebrovascular events. However, whether TNF inhibitors reduce cardiovascular event is still unclear. Therefore, we aimed to evaluate the effect of TNF inhibitors on adverse cardiovascular events (CVEs) in Pso with or without PsA. We undertook a meta-analysis of clinical trials identified in systematic searches of MEDLINE, EMBASE, Wanfang database, Cochrane Database, and Google scholar through December 31, 2015. Five studies (49,795 patients) were included. Overall, compared with topical/photo treatment, TNF inhibitors were associated with a significant lower risk of CVE (RR, 0.58; 95 % CI, 0.43 to 0.77; P < 0.001; I
2 = 66.2 %). Additionally, compared with methotrexate (MTX) treatment, risk of CVE was also markedly decreased in the TNF inhibitor group (RR, 0.67; 95 % CI, 0.52 to 0.88; P = 0.003; I
2 = 9.3 %). Meanwhile, TNF inhibitors were linked to reduced incidence of myocardial infarction compared with topical/photo or MTX treatment (RR, 0.73; 95 % CI, 0.59 to 0.90; P = 0.003; I
2 = 56.2 % and RR, 0.65; 95 % CI, 0.48 to 0.89; P = 0.007; I
2 = 0.0 %, respectively). Furthermore, there was a trend of decreased rate of mortality in the TNF inhibitor group compared with other therapy (RR, 0.90; 95 % CI, 0.54 to 1.50; P = 0.68; I
2 = 70.9 %). TNF inhibitors appear to have net clinical benefits with regard to adverse cardiovascular events in Pso and/or PsA. Rigorous randomized controlled trials will need to evaluate whether TNF inhibitors truly result in reduction of cardiovascular diseases.
TL;DR: Off-label uses of omalizumab in the last recent years in diseases in which IgE maybe or certainly has a corner role such as allergic rhinitis, allergic bronchopulmonary aspergillosis, anaphylaxis, keratoconjunctivitis, food allergy, drug allergy, urticaria, angioedema, non-atopic asthma, atopic dermatitis, nasal polyps and others are summarized.
Abstract: The off-label use of medicines is a common and extensive clinical practice. Omalizumab has been licensed for use in severe allergic asthma and chronic urticaria. Omalizumab dosing was based on body weight and baseline serum IgE concentration. All patients are required to have a baseline IgE between 30 and 700 IU/ml and body weight not more than 150 kg. The use of off-label drugs may lead to several problems including adverse effects and an increased risk/benefit balance. In this article, there are summarized off-label uses of omalizumab in the last recent years in diseases in which IgE maybe or certainly has a corner role such as allergic rhinitis, allergic bronchopulmonary aspergillosis, anaphylaxis, keratoconjunctivitis, food allergy, drug allergy, urticaria, angioedema, non-atopic asthma, atopic dermatitis, nasal polyps, Churg-Strauss syndrome, eosinophilic otitis media, chronic rhinosinusitis, bullous pemphigoid, contact dermatitis, and others. Use in pregnancy asthmatic women and pre-co-administration with specific immunotherapy will also be revised.
TL;DR: Recent advances on the roles of various cytokines in different phases ofHBV infection and cytokine-related mechanisms for impaired viral control and liver damage during HBV infection are discussed, and experimental therapeutic applications of cytokines are focused on to gain a better understanding of this newly emerging aspect of disease pathogenesis.
Abstract: Hepatitis B virus (HBV) infection is a worldwide health problem, with approximately one third of populations have been infected, among which 3–5 % of adults and more than 90 % of children developed to chronic HBV infection. Host immune factors play essential roles in the outcome of HBV infection. Thus, ineffective immune response against HBV may result in persistent virus replications and liver necroinflammations, then lead to chronic HBV infection, liver cirrhosis, and even hepatocellular carcinoma. Cytokine balance was shown to be an important immune characteristic in the development and progression of hepatitis B, as well as in an effective antiviral immunity. Large numbers of cytokines are not only involved in the initiation and regulation of immune responses but also contributing directly or indirectly to the inhibition of virus replication. Besides, cytokines initiate downstream signaling pathway activities by binding to specific receptors expressed on the target cells and play important roles in the responses against viral infections and, therefore, might affect susceptibility to HBV and/or the natural course of the infection. Since cytokines are the primary causes of inflammation and mediates liver injury after HBV infection, we have discussed recent advances on the roles of various cytokines [including T helper type 1 cells (Th1), Th2, Th17, regulatory T cells (Treg)-related cytokines] in different phases of HBV infection and cytokine-related mechanisms for impaired viral control and liver damage during HBV infection. We then focus on experimental therapeutic applications of cytokines to gain a better understanding of this newly emerging aspect of disease pathogenesis.
TL;DR: Improved awareness of HAE amongst the general public, family members, and physicians has reduced the long delay in diagnosis and increased the number of patients receiving effective and up-to-date therapies to improve the physical impact of the disorder.
Abstract: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disorder characterized by intermittent and unpredictable episodes of swelling which cause disfigurement, disability, pain, or, in case of laryngeal swelling, risk of death. Historical factors, including the intermittent nature of the disorder, the lack of awareness of this ultra-rare condition amongst medical personnel, lack of specialist centers, and limited treatment options have contributed to under-diagnosis and under-treatment of the condition. Incorrect treatment of attacks has been common, even when medical help is sought. This has lead to reduced health-seeking behavior and alternative coping strategies, sometimes even denial, in many families, while a minority of HAE-affected patients have become serial emergency room attenders with chronic pain and ongoing requirement for opiate-based painkillers. Both strategies have incurred not only physical but also psychological and economic consequences.In the last 10 years, new and effective acute therapies have been made available, some of which have also provided short-term and long-term prophylaxis options, together with a better understanding of older prophylactic drugs. Improved awareness of HAE amongst the general public, family members, and physicians has reduced the long delay in diagnosis and increased the number of patients receiving effective and up-to-date therapies to improve the physical impact of the disorder.Data on the impact of treatment on the psychological outcomes is scarce, but the limited information available suggests that access to specialist advice and treatment leads to psychological as well as physical improvement.HAE also has profound effects on individual and family economic output, directly via absenteeism from school or work and indirectly via lost opportunities. Economic improvements associated with better treatments are offset by the high cost of new acute treatments, resulting in difficult pharmaco-economic calculations. Worldwide, cost considerations present potentially insurmountable barriers to treatment for many patients, depending on the healthcare system in the individual country.
TL;DR: Understanding of the complex osteoimmune cell interactions should provide new avenues of therapeutic intervention for RA, and there is growing evidence that the chemotactic signals guiding osteoclast precursors to inflamed articular sites contribute to disease and are of great interest.
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints. Self-reactive B and T lymphocytes cooperate to promote antibody responses against self proteins and are major drivers of disease. T lymphocytes also promote RA independently of B lymphocytes mainly through the production of key inflammatory cytokines, such as IL-17, that promote pathology. While the innate signals that initiate self-reactive adaptive immune responses are poorly understood, the disease is predominantly caused by inflammatory cellular infiltration and accumulation in articular tissues, and by bone erosions driven by bone-resorbing osteoclasts. Osteoclasts are giant multinucleated cells formed by the fusion of multiple myeloid cells that require short-range signals, such as the cytokines MCSF and RANKL, for undergoing differentiation. The recruitment and positioning of osteoclast precursors to sites of osteoclast differentiation by chemoattractants is an important point of control for osteoclastogenesis and bone resorption. Recently, the GPCR EBI2 and its oxysterol ligand 7a, 25 dihydroxycholesterol, were identified as important regulators of osteoclast precursor positioning in proximity to bone surfaces and of osteoclast differentiation under homeostasis. In chronic inflammatory diseases like RA, osteoclast differentiation is also driven by inflammatory cytokines such as TNFa and IL-1, and can occur independently of RANKL. Finally, there is growing evidence that the chemotactic signals guiding osteoclast precursors to inflamed articular sites contribute to disease and are of great interest. Furthering our understanding of the complex osteoimmune cell interactions should provide new avenues of therapeutic intervention for RA.
TL;DR: Co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis, including paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteocLastogenesis and immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors can promote osteoc lastogenesis.
Abstract: Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. Receptor activator for NF-κB ligand (RANKL or TNFSF11), a tumor necrosis factor (TNF) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptors, DNAX-associated protein 12 kDa size (DAP12) and FceRI gamma chain (FcRγ). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain and, therefore, must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including triggering receptor expressed on myeloid cells 2 (TREM2), myeloid DAP12-associated lectin (MDL-1), and sialic acid-binding immunoglobulin-type lectin 15 (Siglec-15); while FcRγ pairs with a different set of receptors including osteoclast-specific activating receptor (OSCAR), paired immunoglobulin receptor A (PIR-A), and Fc receptors. The ligands for many of these receptors in the bone microenvironment remain unknown. Here, we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis. Co-stimulation and the effects of ITAM-signaling have turned out to be complex, and now include paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis.
TL;DR: Combination therapy with ursodeoxycholic acid (UDCA) and immunosuppression provided better short-term responses in PBC patients with AIH features, defined by multiple criteria, and higher aspartate aminotransferase (AST) level at accession suggested better prognosis for P BC patients withAIH features while worse prognosis in patients without AIh features.
Abstract: Although a variant of primary biliary cirrhosis (PBC) characterized by features of autoimmune hepatitis (AIH) has been recognized for many years, few studies with ample numbers of patients have focused on its natural history. This study aimed to clarify the natural history, prognosis, and response to therapy in a cohort of patients with PBC with AIH features. We retrospectively analyzed 277 PBC patients without AIH features and 46 PBC patients with AIH features seen between September 2004 and April 2014. The 5-year adverse outcome-free survival of PBC patients with AIH features was 58% compared to 81% in PBC patients without AIH features. Multivariate analysis in the patients with AIH features indicated that total bilirubin ≥ 2.70× the upper limit of normal predicted a poor prognosis (p = 0.008, relative risk 8.39, 95% confidence interval (CI) 1.73, 40.73). Combination therapy with ursodeoxycholic acid (UDCA) and immunosuppression provided better short-term responses in PBC patients with AIH features, defined by multiple criteria. Higher aspartate aminotransferase (AST) level at accession suggested better prognosis for PBC patients with AIH features while worse prognosis for PBC patients without AIH features. PBC patients with AIH features differ from those without AIH features in terms of natural history, prognostic indicators, and response to therapy.
TL;DR: The HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression and is the focus of the present review.
Abstract: Due to marked heterogeneity of clinical presentations, comprehensive knowledge of angioedema phenotypes is crucial for correct diagnosis and choosing the appropriate therapeutic approach. One of the ways to a meaningful clinical distinction can be made between forms of angioedema occurring “with or without wheals.” Angioedema with wheals (rash) is a hallmark of urticaria, either acute or chronic, spontaneous or inducible. Angioedema without wheals may still be manifested in about 10 % of patients with urticaria, but it may also occur as a separate entity. Several classifications of angioedema as part of urticaria were published over time, while a latest one, released in 2014 (HAWK group consensus, see below), provided a classification of all forms of “angioedema without wheals” distinct from urticaria, which will be the focus of the present review. At this time, the HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression. According to this classification, three types of hereditary angioedema (genetic C1-INH deficiency, normal C1-INH with factor XII mutations, and unknown origin) and four types of acquired angioedema (C1-INH deficiency, related to ACE inhibitors intake, idiopathic histaminergic, and idiopathic non-histaminergic) are presented. We will review the distinctive clinical features of each phenotype in details.
TL;DR: In this article, topical corticosteroids and calcineurin inhibitors were used to reduce the time to the next eczematous flare in patients with atopic dermatitis.
Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin condition that requires a manifold approach to therapy. The goal of therapy is to restore the function of the epidermal barrier and to reduce skin inflammation. This can be achieved with skin moisturization and topical anti-inflammatory agents, such as topical corticosteroids and calcineurin inhibitors. Furthermore, proactive therapy with twice weekly use of both topical corticosteroids and calcineurin inhibitors in previously affected areas has been found to reduce the time to the next eczematous flare. Adjunctive treatment options include wet wrap therapy, anti-histamines, and vitamin D supplementation. Bacterial colonization, in particular Staphylococcus aureus, can contribute to eczematous flares and overt infection. Use of systemic antibiotics in infected lesions is warranted; however, empiric antibiotics use in uninfected lesions is controversial. Local antiseptic measures (i.e., bleach baths) and topical antimicrobial therapies can be considered in patients with high bacterial colonization. Difficult-to-treat AD is a complex clinical problem that may require re-evaluation of the initial diagnosis of AD, especially if the onset of disease occurs in adulthood. It may also necessitate evaluation for contact, food, and inhaled allergens that may exacerbate the underlying AD. There are a host of systemic therapies that have been successful in patients with difficult-to-treat AD, however, these agents are limited by their side effect profiles. Lastly, with further insight into the pathophysiology of AD, new biological agents have been investigated with promising results.
TL;DR: The topic of eosinophilic presence, activity, and pathology in the respiratory tract is explored, as well as current and future treatment options are discussed through a detailed literature review.
Abstract: The eosinophil is a fully delineated granulocyte that disseminates throughout the bloodstream to end-organs after complete maturation in the bone marrow. While the presence of eosinophils is not uncommon even in healthy individuals, these granulocytes play a central role in inflammation and allergic processes. Normally appearing in smaller numbers, higher levels of eosinophils in the peripheral blood or certain tissues typically signal a pathologic process. Eosinophils confer a beneficial effect on the host by enhancing immunity against molds and viruses. However, tissue-specific elevation of eosinophils, particularly in the respiratory system, can cause a variety of short-term symptoms and may lead to long-term sequelae. Eosinophils often play a role in more commonly encountered disease processes, such as asthma and allergic responses in the upper respiratory tract. They are also integral in the pathology of less common diseases including eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and drug reaction with eosinophilia and systemic symptoms. They can be seen in neoplastic disorders or occupational exposures as well. The involvement of eosinophils in pulmonary disease processes can affect the method of diagnosis and the selection of treatment modalities. By analyzing the complex interaction between the eosinophil and its environment, which includes signaling molecules and tissues, different therapies have been discovered and created in order to target disease processes at a cellular level. Innovative treatments such as mepolizumab and benralizumab will be discussed. The purpose of this article is to further explore the topic of eosinophilic presence, activity, and pathology in the respiratory tract, as well as discuss current and future treatment options through a detailed literature review.