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1.
Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis.
Wu, Y, Qian, Q, Liu, Q, Wang, R, Pu, X, Li, Y, Zhang, H, You, Z, Miao, Q, Xiao, X, et al
Clinical reviews in allergy & immunology. 2024
Abstract
Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10-6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.
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2.
Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis.
Chen, R, Tang, R, Ma, X, Gershwin, ME
Clinics in liver disease. 2022;(4):583-611
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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3.
Ehlers-Danlos Syndrome: Immunologic contrasts and connective tissue comparisons.
Islam, M, Chang, C, Gershwin, ME
Journal of translational autoimmunity. 2021;:100077
Abstract
Ehlers-Danlos Syndrome (EDS) is a family of multisystemic hereditary connective tissue disorders now comprised of 13 recognized subtypes, classical, classical-like, cardiac-valvular, vascular, hypermobile, arthrochlasia, dermosparaxis, kyphoscoliotic, brittle cornea syndrome, spondylodysplastic, musculocontractural, myopathic, and periodontal, as designated by the most recent 2017 International classification system. Clinical presentation of this disease can range from mild manifestations including skin hyperextensibility and joint hypermobility, to more severe complications such as vascular and organ rupture. While there may be accompanying inflammation in some of the subtypes of EDS, the pathogenic mechanisms have not been clearly defined. Thorough evaluation incorporates clinical examination, family history, laboratory testing, and imaging. In recent years, studies have identified multiple gene variants involved in the pathogenesis of specific EDS subtypes as well as elaborate clinical diagnostic criteria and classification models used to differentiate overlapping conditions. The differential diagnosis of EDS includes hypermobility spectrum disorders, Marfan syndrome, Loey-Dietz syndrome, Cutis laxa syndromes, autosomal dominant polycystic kidney disease, osteogenesis Imperfecta Type 1, fibromyalgia, depression, and chronic fatigue syndrome. Surgical treatment is reserved for complications, or emergencies involving vascular or orthopedic injury because of the risk of poor wound healing. Management techniques each have their own consequences and benefits, which will also be discussed in this review article. Patients affected by this spectrum of disorders are impacted both phenotypically and psychosocially, diminishing their quality of life.
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4.
The challenges of primary biliary cholangitis: What is new and what needs to be done.
Terziroli Beretta-Piccoli, B, Mieli-Vergani, G, Vergani, D, Vierling, JM, Adams, D, Alpini, G, Banales, JM, Beuers, U, Björnsson, E, Bowlus, C, et al
Journal of autoimmunity. 2019;:102328
Abstract
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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5.
The microbiome and autoimmunity: a paradigm from the gut-liver axis.
Li, B, Selmi, C, Tang, R, Gershwin, ME, Ma, X
Cellular & molecular immunology. 2018;15(6):595-609
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Plain language summary
The incidence of autoimmune and inflammatory diseases has been increasing worldwide. Changes in environmental factors, such as modern lifestyle, diet, antibiotics and hygiene are thought to play a critical role in the development of various autoimmune diseases. It is the mucosal microbial flora that is shaped by our environment and communicates with the innate and adaptive immune systems, and when disrupted, can lead to the loss of immune tolerance and dysregulated immune cells. This review paper provides an overview of the interactions between the intestinal microbiome and the immune system. It explains how these interactions affect host autoimmunity locally and systemically and sheds light on the molecular mechanisms, utilised by microbes that may contribute to systemic autoimmunity in genetically susceptible individuals. The links between the gut microbiome and various autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis, as well as the gut-liver axis, involving intestinal microbiome and autoimmune liver diseases, are discussed in more detail.
Abstract
Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
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The critical role of epigenetics in systemic lupus erythematosus and autoimmunity.
Long, H, Yin, H, Wang, L, Gershwin, ME, Lu, Q
Journal of autoimmunity. 2016;:118-138
Abstract
One of the major disappointments in human autoimmunity has been the relative failure on genome-wide association studies to provide "smoking genetic guns" that would explain the critical role of genetic susceptibility to loss of tolerance. It is well known that autoimmunity refers to the abnormal state that the dysregulated immune system attacks the healthy cells and tissues due to the loss of immunological tolerance to self-antigens. Its clinical outcomes are generally characterized by the presence of autoreactive immune cells and (or) the development of autoantibodies, leading to various types of autoimmune disorders. The etiology and pathogenesis of autoimmune diseases are highly complex. Both genetic predisposition and environmental factors such as nutrition, infection, and chemicals are implicated in the pathogenic process of autoimmunity, however, how much and by what mechanisms each of these factors contribute to the development of autoimmunity remain unclear. Epigenetics, which refers to potentially heritable changes in gene expression and function that do not involve alterations of the DNA sequence, has provided us with a brand new key to answer these questions. In the recent decades, increasing evidence have demonstrated the roles of epigenetic dysregulation, including DNA methylation, histone modification, and noncoding RNA, in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE), which have shed light on a new era for autoimmunity research. Notably, DNA hypomethylation and reactivation of the inactive X chromosome are two epigenetic hallmarks of SLE. We will herein discuss briefly how genetic studies fail to completely elucidate the pathogenesis of autoimmune diseases and present a comprehensive review on landmark epigenetic findings in autoimmune diseases, taking SLE as an extensively studied example. The epigenetics of other autoimmune diseases such as rheumatic arthritis, systemic sclerosis and primary biliary cirrhosis will also be summarized. Importantly we emphasize that the stochastic processes that lead to DNA modification may be the lynch pins that drive the initial break in tolerance.
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7.
The Basis of Structure/Function Claims of Nutraceuticals.
Borchers, AT, Keen, CL, Gershwin, ME
Clinical reviews in allergy & immunology. 2016;(3):370-382
Abstract
In the United States, as in most of the world, there are large numbers of nutraceuticals that are sold and which people take to boost their immune response. There are, in addition, almost an equal number of products sold to reduce allergies. However, very few consumers, and indeed physicians, are aware of what a structure/function claim is. Structure/function claims are labeling claims that can be used to describe the potential effects of a dietary ingredient or similar substance on the structure or function of the human body. This category of claims was created by legislation contained in the Dietary Supplement Health and Education Act. The intent was to supply consumers with reasonably substantiated information that would allow them to make educated choices about their diet and health. They were not intended to have the same weight and substantiation as the claims made for conventional prescription pharmaceuticals. Rather, they were proposed to fill the gap between consumer desire for over-the-counter supplements and foods, and rigorous and generally more potent and potentially "toxic" prescription medications. The legally mandated disclaimer, stating that the U.S. Food and Drug Administration has not evaluated the structure/function claim, often leads to misinterpretation. While there should be a biologic premise underlying the claim, there is not an absolute requirement for a conventional rigorous placebo-controlled dose response trial. While this may not be the clinical standard that a typical scientific oriented society might desire, it reflects the attempts of the FDA to find common grounds and to allow consumers to use products that are generally considered as safe based on historical use and biologic comparisons. The logic of, indeed need for, structure/function claims is straightforward; however, of equal importance is that nutraceuticals should be properly labeled, have accuracy in their ingredients, be free of contamination, be safe, and have a reasonable body of data that supports their efficacy.
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8.
Integrative medicine in allergy and immunology.
Chang, C, Gershwin, ME
Clinical reviews in allergy & immunology. 2013;(3):208-28
Abstract
Integrative medicine is a relatively new discipline which attempts to combine allopathic medicine with alternative or complementary medicine, to reap the benefits of both forms of medicine in optimizing the care of patients. Integrative medicine concentrates on treating the patient as a whole, both in body and mind. While the scientific method and "evidence-based" clinical research drives the management and treatment of diseases in conventional Western medicine, alternative or complementary medicine is based on unproven yet potentially beneficial techniques that have been developed throughout history, dating back to the ancient cultures in the Middle East, Africa, and China. In spite of the lack of evidence of most alternative medicine techniques, these methodologies have been practiced for centuries with great acceptance in many countries. It is in the Western world, where "modern" medicine is dictated by the scientific method, that the most controversy in the use of these alternative modes of therapy exists. Since the science behind alternative medicine is incomplete or non-existent, it is difficult for those trained in Western medicine to accept or adopt this approach. But perhaps it is the failure of Western medicine to adequately guarantee our well being and good health that have led to the ongoing debate between the medical profession and the general public as to the benefits of these alternative treatments. In one sense, integrative medicine may be a futile attempt to coin a new term in the hope of legitimizing alternative medicine. On the other hand, there is a wealth of historical experience in the use of the techniques. Studies to evaluate the scientific basis behind ancient medical techniques are ongoing, and it is to be expected that the results will neither be uniformly positive nor negative. Of particular interest is the effect of traditional medicine, herbal formulations, and manipulative techniques on the immune system, and its application in the treatment of autoimmune and allergic diseases. Studies are being designed or conducted to investigate immune effects of herbal formulations or their components. Herbal plants or medicines may lead to skewing of the Th1/Th2 balance in either direction, thus may offer potential application in the treatment of allergic or autoimmune diseases.
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Novel trends in celiac disease.
Matthias, T, Neidhöfer, S, Pfeiffer, S, Prager, K, Reuter, S, Gershwin, ME
Cellular & molecular immunology. 2011;(2):121-5
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Abstract
Celiac disease (CD) is one of the most common food intolerances in developed world. It affects genetically susceptible individuals and has severe consequences if it remains undiagnosed. A disease known for more than a century, it is still the focus for experts from various fields of research and development. Geneticists, pathologists, immunologists, food engineers and dieticians share their knowledge and expertise to improve the conditions of CD patients. With new insights in the pathomechanism of gluten processing and antigen presentation in CD, it was possible to improve the diagnostic antigen mimicking the primary epitope in CD. These celiac neo-epitopes are comprised of a complex of gliadin peptides crosslinked with transglutaminase (tTg). They are an early diagnostic marker for CD which occurs up to 6 months earlier than classical markers known to miss a certain amount of CD patients.
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10.
Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis.
Powell, C, Chang, C, Gershwin, ME
Clinical reviews in allergy & immunology. 2011;(1):102-13
Abstract
The pathophysiology of non-traumatic osteonecrosis is more complex than that of traumatic osteonecrosis, and corticosteroid-induced osteonecrosis presents the greatest challenge because of the multiple effects of corticosteroids on multi-system pathways; these pathways include the effects of corticosteroids on osteoblast differentiation, osteoblast and osteoclast apoptosis, lipid metabolism, coagulation pathways, and calcium metabolism. These pathways are frequently interrelated with each other, which makes the pathogenesis even more difficult to understand. Host factors and underlying disease have been shown to play a significant role in the risk of developing osteonecrosis, and our understanding of the pathogenesis must be able to explain why some patients are at greater risk than others. Identification of genetic variants that convey additional risk will also help to personalize the way we deliver care, both in the prevention and treatment of osteonecrosis. Further understanding of the intricate immunologic and genetic pathways contributing to osteonecrosis is at the forefront of research and may soon lead to viable and less invasive non-surgical therapeutic strategies.