Pigs are currently the preferred species for future organ xenotransplantation. With advances in the development of genetically modified pigs, clinical xenotransplantation is becoming closer to reality. In preclinical studies (pig-to-nonhuman primate), the xenotransplantation of livers from pigs transgenic for human CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/− transgenic for human CD46, is associated with survival of approximately 7–9 days. Although hepatic function, including coagulation, has proved to be satisfactory, the immediate development of thrombocytopenia is very limiting for pig liver xenotransplantation even as a ‘bridge’ to allotransplantation. Current studies are directed to understand the immunobiology of platelet activation, aggregation and phagocytosis, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes and Kupffer cells, toward identifying interventions that may enable clinical application.
α1,3-galactosyltransferase gene-knockout; hCD46; liver; liver failure; nonhuman primate; pig; xenotransplantation
Patients with systemic lupus erythematosus have a significantly increased risk of cardiovascular events due to atherosclerosis. Traditional cardiac risk factors cannot fully explain this increased risk. Recent evidence strongly suggests that atherosclerotic plaque is largely driven by inflammation and an active immunological response, in contrast to the long-held belief that plaque is a passive accumulation of lipids in the arterial wall. Current approaches to the prevention of atherosclerosis in systemic lupus erythematosus involve targeting modifiable cardiac risk factors. Future preventive strategies may include therapies that counteract the immunologic responses that lead to plaque formation.
apoA-1; atherosclerosis; HMG-CoA reductase inhibitors; homocysteine; oxidized LDL; proinflammatory HDL; statins; systemic lupus erythematosus
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. A number of molecules, including ion channels and other proteins at the neuromuscular junction, may be targeted by autoantibodies leading to abnormal neuromuscular transmission. In approximately 85% of patients, autoantibodies, directed against the postsynaptic nicotinic acetylcholine receptor can be detected in the serum and confirm the diagnosis, but in general, do not precisely predict the degree of weakness or response to therapy. Antibodies to the muscle-specific tyrosine kinase are detected in approximately 50% of generalized myasthenia gravis patients who are seronegative for anti-acetylcholine receptor antibodies, and levels of anti-muscle-specific tyrosine kinase antibodies do appear to correlate with disease severity and treatment response. Antibodies to other muscle antigens may be found in the subsets of myasthenia gravis patients, potentially providing clinically useful diagnostic information, but their utility as relevant biomarkers (measures of disease state or response to treatment) is currently unclear.
AChR; biomarkers; diagnosis; MuSK; myasthenia gravis
Photodynamic therapy (PDT) employs the triple combination of photosensitizers, visible light and ambient oxygen. When PDT is used for cancer, it has been observed that both arms of the host immune system (innate and adaptive) are activated. When PDT is used for infectious disease, however, it has been assumed that the direct antimicrobial PDT effect dominates. Murine arthritis caused by methicillin-resistant Staphylococcus aureus in the knee failed to respond to PDT with intravenously injected Photofrin®. PDT with intra-articular Photofrin produced a biphasic dose response that killed bacteria without destroying host neutrophils. Methylene blue was the optimum photosensitizer to kill bacteria while preserving neutrophils. We used bioluminescence imaging to noninvasively monitor murine bacterial arthritis and found that PDT with intra-articular methylene blue was not only effective, but when used before infection, could protect the mice against a subsequent bacterial challenge. The data emphasize the importance of considering the host immune response in PDT for infectious disease.
bacterial arthritis; bioluminescence imaging; methicillin-resistant Staphylococcus aureus; methylene blue; neutrophils; photodynamic therapy; Photofrin®; preventative PDT
Cardiovascular disease (CVD) and autoimmune diseases (ADs) are the first and third highest causes of death in the USA, respectively. Men have an increased incidence of the majority of CVDs, including atherosclerosis, myocarditis, dilated cardiomyopathy and heart failure. By contrast, nearly 80% of all ADs occur in women. However, in one category of ADs, rheumatic diseases, CVD is the main cause of death. Factors that link rheumatic ADs to CVD are inflammation and the presence of autoantibodies. In this review we will examine recent findings regarding sex differences in the immunopathogenesis of CVD and ADs, explore possible reasons for the increased occurrence of CVD within rheumatic ADs and discuss whether autoantibodies, including rheumatoid factor, could be involved in disease pathogenesis.
autoimmune disease; cardiovascular disease; pathogenesis; rheumatic disease; sex differences
Over the past few decades, neutrophils and macrophages had co-occupied center stage as the critical innate immune cells underlying the pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease and lung parenchymal destruction (i.e., emphysema). While chronic exposure to smoke facilitates the recruitment of innate immune cells into the lung, a clear role for adaptive immunity in emphysema has emerged. Evidence from human studies specifically point to a role for recruitment and activation of pathogenic lymphocytes and lung antigen-presenting cells in emphysema; similarly, animal models have confirmed a significant role for autoimumnity in progressive smoke-induced emphysema. Increased numbers of activated antigen-presenting cells, Th1 and Th17 cells, have been associated with smoke-induced lung inflammation and production of the canonical cytokines of these cells, IFN-γ and IL-17, correlates with disease severity. These exciting new breakthroughs could open new avenues for developing effective new therapies for smoke-induced emphysema.
adaptive immunity; antigen-presenting cells; cytokines; Th1; Th17
The immune system has evolved to mount immune responses against foreign pathogens and to remain silent against self-antigens. A balance between immunity and tolerance is required as any disturbance may result in chronic inflammation or autoimmunity. Dendritic cells (DCs) actively participate in maintaining this balance. Under steady-state conditions, DCs remain in an immature state and do not mount an immune response against circulating self-antigens in the periphery, which maintains a state of tolerance. By contrast, foreign antigens result in DC maturation and DC-induced T-cell activation. Inappropriate maturation of DCs due to infections or tissue injury may cause alterations in the balance between the tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases. This article provides an overview of the effects of advancing age on DC functions and their implications in autoimmunity.
aging; autoimmunity; dendritic cells; self-tolerance
Endometriosis is a common, complex gynecologic disorder characterized by the presence of endometrial glands and stroma at extrauterine (ectopic) sites. In women who develop this disease, alterations in specific biological processes involving both the endocrine and immune systems have been observed, which may explain the survival and growth of displaced endometrial tissue in affected women. In the past decade, a considerable amount of research has implicated a role for alterations in progesterone action at both eutopic and ectopic sites of endometrial growth which may contribute to the excessive inflammation associated with progression of endometriosis; however, it remains unclear whether these anomalies induce the condition or are simply a consequence of the disease process. In this article, we summarize current knowledge of alterations within the immune system of endometriosis patients and discuss how endometrial cells from women with this disease not only have the capacity to escape immunosurveillance, but also use inflammatory mechanisms to promote their growth within the peritoneal cavity. Finally, we discuss evidence that exposure to an environmental endocrine disruptor, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, can mediate the development of an endometrial phenotype that exhibits both reduced progesterone responsiveness and hypersensitivity to proinflammatory stimuli mimicking the endometriosis phenotype. Future studies in women with endometriosis should consider whether a heightened inflammatory response within the peritoneal microenvironment contributes to the development and persistence of this disease.
chemokines; cytokines; dioxin; endocrine-disrupting chemicals; endometriosis; estrogen; immune–endocrine interactions; inflammation; peritoneum; progesterone; TCDD
Understanding the evolutionary adaptation of the immune system to the developing fetus and placenta represents one of the most fascinating problems in reproductive biology. Recent work has focused on how the behavior of dendritic cells (DCs) is altered at the maternal–fetal interface to suit the unique requirements of pregnancy. This work has provided a significant new perspective into the long-standing immunological paradox of fetomaternal tolerance, and has opened up a new and intriguing area of research into the potential trophic role of uterine DCs in the peri-implantation period. Further research on the biology of uterine DCs promises to give insight into the pathogenesis of many clinically important disorders of pregnancy.
angiogenesis; decidua; dendritic cells; fetomaternal tolerance; lymphatic vessel; myometrium; pregnancy
Heterogeneity in the clinical presentation and basic science findings of systemic sclerosis (SSc) has hindered the understanding of pathogenesis and development of effective treatments. Genome-wide profiling of SSc has measured this heterogeneity. Gene expression studies of diffuse SSc skin have shown reproducible, disease-specific gene expression signatures when compared with healthy controls and, surprisingly, disease-specific gene expression was found in both lesional and non-lesional skin. SSc-specific gene expression in peripheral blood cells and the lungs has also been demonstrated. Hypothesis-driven approaches that assess the contribution of individual pathways provide insight into the etiology of gene expression subsets.
animal models; gene expression profiling; intrinsic subsets; scleroderma; signaling; systemic sclerosis; TGF-β
Mepolizumab (Bosatria®, GlaxoSmithKline) is a biologic agent developed to treat asthma. It represents a humanized monoclonal antibody of IgG1 κ type, which targets human IL-5 and thus prevents its interaction with the α-chain of the IL-5 receptor. To date, it has not been approved for use in any eosinophil-related disorder; however, several studies have suggested some therapeutic benefit across a spectrum of eosinophil-related disorders. This article evaluates the currently available preclinical and clinical studies, and the impact of mepolizumab against a variety of eosinophilic disorders.
anti-IL-5; eosinophilic gastrointestinal disorders; eosinophils; human; IL-5; mepolizumab
STAT4 has been identified as a genetic risk factor for the development of autoimmune diseases including systemic sclerosis. STAT4 regulates Th1 cell development and cell-mediated immunity, but it is not known how it may regulate the development of dermal fibrosis. Using the bleomycin-induced dermal fibrosis model, it has now been demonstrated that STAT4-deficient mice have reduced dermal fibrosis in part via STAT4-dependent alterations in T-cell proliferation and cytokine production. These data stress the importance of STAT4 in autoimmune diseases such as systemic sclerosis and provide an important direction for future research to improve our understanding of systemic sclerosis pathogenesis.
dermal fibrosis; STAT4; systemic sclerosis
The research reviewed in this article provides examples of autoantibody-mediated receptor activation that likely contributes to disease. The classic example is Graves’ hyperthyroidism, in which autoantibodies activate the thyroid-stimulating hormone receptor resulting in overproduction of thyroid hormones. Other compelling examples come from the cardiovascular literature and include agonistic autoantibodies targeting the cardiac β1-adrenergic receptor, which are associated with dilated cardiomyopathy. Autoantibodies capable of activating α1-adrenergic receptors are associated with refractory hypertension and cardiomyopathy. A prominent example is preeclampsia, a hypertensive disease of pregnancy, characterized by the presence of autoantibodies that activate the major angiotensin receptor, AT1. AT1 receptor-activating autoantibodies are also observed in kidney transplant recipients suffering from severe vascular rejection and malignant hypertension. AT1 receptor-activating autoantibodies and antibodies that activate the endothelin-1 receptor, ETA, are prevalent in individuals diagnosed with systemic sclerosis. Thus, the presence of agonistic autoantibodies directed to G protein-coupled receptors has been observed in numerous cardiovascular disease states. Rapidly emerging evidence indicates that receptor-activating autoantibodies contribute to disease, and that efforts to detect and remove these pathogenic autoantibodies or block their actions will provide promising therapeutic possibilities.
agonistic autoantibodies; allograft rejection; α1-adrenergic receptor; angiotensin receptor; β1-adrenergic receptor; dilated cardiomyopathy; endothelin receptor; Graves’ disease; hypertension; preeclampsia; systemic sclerosis; thyroid-stimulating hormone receptor; thyrotropin receptor
Celiac sprue (CS) is a gluten-sensitive enteropathy with many autoimmune features. CS involves multiple organs through immune and nonimmune processes, and is frequently associated with other autoimmune disorders. This article reviews the co-occurrence of CS with autoimmune disorders of the cutaneous, nervous, endocrine, musculoskeletal, gastrointestinal and cardiovascular systems. The types of autoimmune disorders associated with CS and the prevalence of CS in other autoimmune disorders are also discussed. A brief review of the literature on the potential mechanisms behind these associations and the therapeutic effects of a gluten-free diet for autoimmune comorbidities in CS is also provided.
ataxia; autoimmune; autoimmune biliary cirrhosis; autoimmune hepatitis; celiac sprue; dermatitis herpetiformis; neuropathy; Sjögren’s syndrome; thyroid disorder; Type 1 diabetes
Inflammatory bowel disease (IBD) is a waxing and waning disease characterized by diarrhea, abdominal pain and weight loss. Recently, there has been an increased interest in the roles that sleep, circadian rhythms and melatonin could have as regulators of inflammation in the Gl tract. Advances in our understanding of the molecular machinery of the circadian clock, and the discovery of clock genes in the GI tract are opening up new avenues of research for a role of sleep in IBD. Altering circadian rhythm significantly worsens the development of colitis in animal models, and preliminary human studies have shown that patients with IBD are at increased risk for altered sleep patterns. Further research is needed to clarify the role of disturbances in IBD.
circadian rhythms; Crohn’s disease; inflammatory bowel disease; melatonin; sleep; ulcerative colitis
Photodynamic therapy (PDT) is a rapidly developing cancer treatment that utilizes the combination of nontoxic dyes and harmless visible light to destroy tumors by generating reactive oxygen species. PDT produces tumor-cell destruction in the context of acute inflammation that acts as a ‘danger signal’ to the innate immune system. Activation of the innate immune system increases the priming of tumor-specific T lymphocytes that have the ability to recognize and destroy distant tumor cells and, in addition, lead to the development of an immune memory that can combat recurrence of the cancer at a later point in time. PDT may be also successfully combined with immunomodulating strategies that are capable of overcoming or bypassing the escape mechanisms employed by the progressing tumor to evade immune attack. This article will cover the role of the immune response in PDT anti-tumor effectiveness. It will highlight the milestones in the development of PDT-mediated anti-tumor immunity and emphasize the combination strategies that may improve this therapy.
anti-tumor immunity; cancer vaccines; cytotoxic T-lymphocytes; damage-associated molecular patterns; dendritic cells; photodynamic therapy; Toll-like receptor agonists; tumor-associated antigens
The emergence of autoreactivity that ultimately destroys insulin-producing β-cells and causes Type 1 diabetes (T1D) is a result of genetic susceptibility and environmental factors, such as viral infections. The ability to induce strong cellular immune responses and to cause inflammation in the target organ makes viral infections prime candidates for the initiation of islet autoreactivity. Indeed, certain viruses have been linked to the occurrence of T1D based on epidemiological, serological and histological findings; and several rodent studies clearly demonstrate that viral infections can trigger autoimmunity. However, viruses have also been shown to efficiently prevent autoimmunity, which underlines the beneficial aspects of exposure to microbial agents as suggested by the hygiene hypothesis. Here, we will try to untangle some aspects of the complex interplay between viruses and the immune system and we will recapitulate by what rationale certain viruses have been associated with T1D.
autoimmunity; coxsackievirus; hygiene hypothesis; Type 1 diabetes; viral infections
The widely used nonobese diabetic (NOD) mouse model of autoimmune (Type 1) diabetes mellitus shares multiple characteristics with the human disease, and studies employing this model continue to yield clinically relevant and important information. Here, we review some of the recent key findings obtained from NOD mouse investigations that have both advanced our understanding of disease pathogenesis and suggested new therapeutic targets and approaches. Areas discussed include antigen discovery, identification of genes and pathways contributing to disease susceptibility, development of strategies to image islet inflammation and the testing of therapeutics. We also review recent technical advances that, combined with an improved understanding of the NOD mouse model’s limitations, should work to ensure its popularity, utility and relevance in the years ahead.
antigens; autoimmune diabetes; humanized mice; NOD mice; therapies; Type 1 diabetes
This article presents a brief review of the physiologic abnormalities seen in fibromyalgia, current theories of widespread pain, and treatment options, including emerging therapeutics, with a focus on the use of duloxetine to manage fibromyalgia symptoms. Major clinical trials that examine the efficacy and effectiveness of duloxetine to date are reviewed, and safety issues are discussed.
duloxetine; fibromyalgia; pain; serotonin and norepinephrine inhibitors; SNRI
The 10th International Congress of Neuroimmunology, including the 10th European School of Neuroimmunology Course, was held by the International Society of Neuroimmunology in Sitges (Barcelona, Spain) on 26–30 October 2010. The conference covered a wide spectrum of issues and challenges in both basic science and clinical aspects of neuroimmunology. Data and ideas were shared through a variety of programs, including review talks and poster sessions. One of the topics of the congress was whether multiple sclerosis is a homogenous or heterogenous disease, clinically and pathologically, throughout its course.
The care of inflammatory bowel disease has changed considerably with the introduction of a number of immunosuppressants including anti-metabolite and anti-TNF therapies. While efficacious, these medications also carry important risks, notably the potential risk of lymphoma. This risk is one of the most worrisome for both patients and physicians. Our current knowledge is still evolving; however, our understanding of what risks these drugs carry, both individually and synergistically, is critical in allowing informed decision making. In this article, we will describe the known lymphoma risks of commonly used immunosuppressant medications in inflammatory bowel disease, with an emphasis on non-Hodgkin’s lymphoma and hepatosplenic T-cell lymphoma.
hepatosplenic T-cell lymphoma; immunosuppression; inflammatory bowel disease; lymphoma; non-Hodgkin’s lymphoma
Crohn’s disease and ulcerative colitis are complex diseases that have required the use of multiple modalities to aid in treatment. With an increasing understanding of the underlying pathogenetic mechanisms and identification of specific therapeutic targets, monoclonal antibody treatment has been an ideal strategy for inducing and maintaining remission in these patients. This article addresses approved agents and the supporting data justifying their use in Crohn’s disease and ulcerative colitis, the safety of and immunologic reactions to these agents, as well as newer agents for treatment.
Crohn’s disease; infusion reaction; monoclonal antibody; tumor necrosis factor; ulcerative colitis
The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. In this article, we will discuss the specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.
effector memory T cells; inflammatory bowel disease; intraepithelial lymphocytes; lamina propria; mucosal barrier; regulatory T cells
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of antinuclear autoantibodies and the inflammatory infiltration of many organ systems. SLE is a complex disorder in which multiple genetic variants, together with environmental and hormonal factors, contribute to disease risk. In this article, we summarize our current understanding of the genetic contribution to SLE in light of recent genome-wide association studies, which have brought the total number of confirmed SLE susceptibility loci to 29. In the second section, we explore the functional implications of these risk loci and, in particular, highlight the role that many of these genes play in the Toll-like receptor and type I interferon signaling pathways. Finally, we discuss the genetic overlap between SLE and other autoimmune and inflammatory conditions as several risk loci are shared among multiple disorders, suggesting common underlying pathogenic mechanisms.
genome-wide association studies; pathogenesis; systemic lupus erythematosus; Toll-like receptor signaling; type I interferon signaling