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ID PMID Title PublicationDate abstract
30514664 Regulatory and effector B cells: Friends or foes? 2019 Jan B cells have moved to the center stage in many autoimmune diseases including autoantibody-mediated diseases and T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. B cells play an important role for immune response beyond antibody production through mechanisms like antigen presentation and cytokine production. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by production of anti-inflammatory cytokines such as IL-10, IL-35, and TGF-β. Regulatory B cells have been found to be decreased and/or functionally impaired in various autoimmune diseases. In contrast, B cells also produce pro-inflammatory cytokines, such as IL-6, IFN-γ and GM - CSF. These effector B cells contribute to the pathogenesis of autoimmune diseases. Regulatory and effector B cell balance regulates immune response through the release of cytokines. Furthermore, a protocol that selectively depletes effector B cells while sparing regulatory B cells would represent a potent therapy for autoimmune diseases rather than pan-B cell depletion using anti-CD20 mAb.
31906087 Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal 2019 Dec 31 Mesenchymal stem/stromal cells (MSCs) represent a promising therapy for musculoskeletal diseases. There is compelling evidence indicating that MSC effects are mainly mediated by paracrine mechanisms and in particular by the secretion of extracellular vesicles (EVs). Many studies have thus suggested that EVs may be an alternative to cell therapy with MSCs in tissue repair. In this review, we summarize the current understanding of MSC EVs actions in preclinical studies of (1) immune regulation and rheumatoid arthritis, (2) bone repair and bone diseases, (3) cartilage repair and osteoarthritis, (4) intervertebral disk degeneration and (5) skeletal muscle and tendon repair. We also discuss the mechanisms underlying these actions and the perspectives of MSC EVs-based strategies for future treatments of musculoskeletal disorders.
31862128 Treg cells in health and autoimmune diseases: New insights from single cell analysis. 2020 Jun Autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA) are characterized by the breakdown of immunological tolerance. Defects of regulatory T cells have been described among the various mechanisms, that are important for the development of autoimmune diseases, due to their critical role as regulators of peripheral immune tolerance and homeostasis. Initially T suppressor cells have been described as one population of peripheral T cells. Based on new technological advances a new understanding of the heterogeneity of different Treg cell populations in the lymphoid and non-lymphoid tissue has evolved over the last years. While initially Foxp3 has been defined as the main master regulator of Treg cells, we have learned that Treg cells from various tissue can be identified by a specific transcriptomic and epigenetic signature. Epigenetic mechanisms allow Treg cell stability, but we have also learned that certain Treg subsets are plastic and can under specific circumstances even enhance autoimmunity and inflammatory processes. Quantitative and functional defects of Treg cells have been observed in a variety of autoimmune diseases. Due to our understanding of the nature of this cell population, Treg cells have been a target of new Treg based therapies, such as low-dose IL-2. In addition, ongoing clinical trials aim to test safety and efficacy of transferred, in vitro expanded Treg cells in patients with autoimmune diseases and transplant patients.
31814546 Recent Patents and Discovery of Anti-inflammatory Agents from Marine Source. 2019 BACKGROUND: Inflammation has become pathology in the majority of the prevalent diseases such as diabetes, atherosclerosis, epilepsy and neurodegenerative disorders. Anti-inflammatory drugs work wonder in all these conditions, where the patient has become refractory to standard treatment. However, available anti-inflammatory agents have side effects associated with chronic use, thus if we could develop safe and efficacious molecules, quality of health care provided will improve. Since plant sources have been extensively explored, the focus needs to be shifted on the alternative natural sources of anti-inflammatory agents. Water bodies especially the sea and ocean are under investigation to find agents which can tackle inflammation. OBJECTIVE: This article reviews anti-inflammatory agents obtained from five types of marine organisms namely microalgae, sea cucumber, mussels, sponges and corals. METHODS: A literature search was conducted using PubMed/Science Direct with keywords marine organisms, inflammation, marine sponges, sea cucumber, mussels, corals and microalgae. Patents were searched using the key terms inflammation, marine agents from www.google.com/patents, www.uspto.gov, http://espacenet.com, www.freepatentsonline.com, www.wipo.int/pctdb/en/searchsimp. jsp and www.freshpatents.com. RESULTS: Literature and current patents have revealed applications of anti-inflammatory agents from marine organisms in pharmaceuticals and cosmeceuticals. These agents are used to treat inflammatory disorders ranging from minor allergy to chronic conditions like rheumatoid arthritis. Marine waste is also a valuable resource for nutraceuticals and anti-inflammatory agents. CONCLUSION: The findings reveal that marine organisms could be a promising source of novel antiinflammatory agents. However, further investigations are suggested for the isolation and identification of bioactive, exploring the mechanism of action and evaluating the efficacy in various inflammatory conditions.
31763378 Nrf2 activation in osteoblasts suppresses osteoclastogenesis via inhibiting IL-6 expressio 2019 Dec Bone destructive diseases such as periodontitis and rheumatoid arthritis are caused by excessive activation of osteoclasts. Osteoclastogenesis is regulated by Receptor activator of nuclear factor kappa-β ligand (RANKL) produced by osteoclastogenesis supporting cells such as osteoblast and osteocyte. Previously, we reported that NF-E2-related factor-2 (Nrf2) activation in osteoclast precursors inhibited osteoclastogenesis and bone destruction via induction of anti-oxidation and thereby attenuated intracellular ROS signaling. However, it still remains unknown whether Nrf2 activation in cells other than osteoclasts give any negative influence on supporting property for osteoclastogenesis. Here we discovered that Nrf2 activation in osteoblasts suppresses indirectly osteoclastogenesis via inhibiting the expression of interleukin-6 (IL-6) which promotes osteoclastogenesis. In this study, 5-aminolevulinic acid hydrochloride (ALA) and sodium ferrous citrate (SFC) was used as the Nrf2 activator. in vitro experiments, using osteoblast cell line, MC3T3-E1, revealed that the expression of IL-6 was increased by LPS stimulation, but decreased after ALA/SFC treatment in mRNA and protein levels. Furthermore, RANKL expression was augmented by LPS, which was blocked by ALA/SFC treatment. Neutralizing antibody against IL-6 confirmed that LPS-mediated RANKL augmentation was dependent on IL-6 induction. in vivo experiments with LPS-mediated bone destruction in mice, confirmed that augmented IL-6 expression in osteoblasts by immunochemical analysis. ALA/SFC treatment attenuated LPS-mediated IL-6 upregulation. These results suggest that Nrf2 activation in osteoblasts suppress IL-6 and inflammatory bone destruction. The Nrf2 activator acts not only on osteoclasts but also on osteoblasts, in other word, Nrf2 activation indirectly suppresses osteoclastogenesis. In conclusion, the Nrf2 activator exhibits dual inhibitory effects via direct action on osteoclast and indirect action on osteoclast supporting cells.
31602910 [Pharmacodynamic effect and virulent effect of Tripterygium wilfordii based on network pha 2019 Aug To investigate the pharmacodynamic effect and virulent effect of the main components of the toxic Chinese medicine Tripterygium wilfordii,such as triptolide,tripchlorolide,tripterine,demethylzeylasteral,wilfotrine and euonine,the admet SAR online assessment system was used to calculate the properties of the main components of T. wilfordii. The potential targets of the components were mined and collected through multiple databases,and the potential targets were enriched by the bioinformatics database DAVID.Cytoscape software was used to establish a " target-pathway" network and perform topology analysis on the network. The main chemical components of T. wilfordii were able to penetrate the blood-brain barrier and had intestinal permeability. A total of 65 targets were predicted,including pathways in cancer,hepatitis B,rheumatoid arthritis,and chagas disease( American trypanosomiasis),Toll-like receptor signaling pathway,apoptosis,colorectal cancer,NF-kappa B signaling pathway,etc. T. wilfordii mainly plays a role in the treatment of immune diseases and cancer by regulating inflammatory signaling pathways and cancer signaling pathways. Its action on apoptosis pathway and drug metabolism enzymes may be the mechanism of its toxicity.
31551679 Vagus Nerve Stimulation in Rodent Models: An Overview of Technical Considerations. 2019 Over the last several decades, vagus nerve stimulation (VNS) has evolved from a treatment for select neuropsychiatric disorders to one that holds promise in treating numerous inflammatory conditions. Growing interest has focused on the use of VNS for other indications, such as heart failure, rheumatoid arthritis, inflammatory bowel disease, ischemic stroke, and traumatic brain injury. As pre-clinical research often guides expansion into new clinical avenues, animal models of VNS have also increased in recent years. To advance this promising treatment, however, there are a number of experimental parameters that must be considered when planning a study, such as physiology of the vagus nerve, electrical stimulation parameters, electrode design, stimulation equipment, and microsurgical technique. In this review, we discuss these important considerations and how a combination of clinically relevant stimulation parameters can be used to achieve beneficial therapeutic results in pre-clinical studies of sub-acute to chronic VNS, and provide a practical guide for performing this work in rodent models. Finally, by integrating clinical and pre-clinical research, we present indeterminate issues as opportunities for future research.
31447842 Fatigue, Sleep, and Autoimmune and Related Disorders. 2019 Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, chronic fatigue syndrome, and rheumatoid arthritis. Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases. In general, fatigue is defined by debilitating periods of exhaustion that interfere with normal activities. The severity and duration of fatigue episodes vary, but fatigue can cause difficulty for even simple tasks like climbing stairs or crossing the room. The exact mechanisms of fatigue are not well-understood, perhaps due to its broad definition. Nevertheless, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and sleepiness-all which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system-a region impacted either directly or indirectly in numerous autoimmune and related disorders. This review describes how inflammation and the central nervous system contribute to fatigue and suggests potential mechanisms involved in fatigue that are likely exhibited in autoimmune and related diseases.
31413852 Iatrogenic antibody deficiency from B-cell targeted therapies in autoimmune rheumatic dise 2019 B-cell targeted therapies (BCTT) are now widely used in autoimmune rheumatic diseases, including SLE, antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. Early studies suggested that rituximab did not influence serum immunoglobulins. However, subsequently, with increased patient numbers, longer follow-up duration and many patients having received multiple BCTT courses, multiple subsequent studies have identified hypogammaglobulinaemia as a potential side effect. Patients developing hypogammaglobulinaemia appear to fit into two principal categories: the majority who develop transient, often mild reduction in immunoglobulins without increased infection and a much smaller but clinically significant group with a more sustained antibody deficiency, who display increased risk of infection. Monitoring immunoglobulin levels represents an opportunity for the early detection of hypogammaglobulinaemia, and the prevention of avoidable morbidity. In the two major studies, approximately 4%-5% of BCTT-treated patients required immunoglobulin replacement due to recurrent infections in the context of hypogammaglobulinaemia. Despite this, monitoring of immunoglobulins is suboptimal, and there remains a lack of awareness of hypogammaglobulinaemia as an important side effect.
31365378 New trajectories in the treatment of interstitial lung disease: treat the disease or treat 2019 Sep PURPOSE OF REVIEW: A subset of patients with interstitial lung diseases (ILDs), such as rheumatoid arthritis (RA)-associated ILD and chronic hypersensitivity pneumonitis, will experience a disease course similar to patients with idiopathic pulmonary fibrosis (IPF). They also often have a usual interstitial pneumonia (UIP) pattern of fibrosis. Although the standard of care for patients with RA-ILD and chronic hypersensitivity pneumonitis is immunosuppression, the optimal treatment for patients with progressive disease and a UIP pattern remains unknown. RECENT FINDINGS: Recent research has highlighted shared risk factors, disease behavior and pathobiology between RA-ILD, chronic hypersensitivity pneumonitis and IPF. The presence of a UIP pattern, in both RA-ILD and chronic hypersensitivity pneumonitis, is associated with a worse prognosis. Moreover, genetic risk factors, previously well characterized in IPF, are increasingly being linked to RA-ILD and chronic hypersensitivity pneumonitis. The MUC5B promoter variant rs5705950, telomerase complex mutations and short telomere lengths are also linked to an increased susceptibility to pulmonary fibrosis in RA and chronic hypersensitivity pneumonitis. SUMMARY: IPF shares several clinical, genetic and biological features with other ILDs exhibiting the UIP pattern. The optimal pharmacologic management of these patients remains uncertain. Several ongoing trials are evaluating the efficacy of antifibrotic medications in these other diagnoses and may change how we approach ILD treatment.
31288716 Current Status in the Discovery of Covalent Janus Kinase 3 (JAK3) Inhibitors. 2019 The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn't been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.
31240339 [Atopic dermatitis and general medical comorbidities]. 2019 Aug Atopic dermatitis (AD) is one of the most frequent chronic inflammatory skin diseases, characterized by pruritic eczematous lesions. Due to the fact that AD is accompanied by signs of systemic inflammation and that an increased number of novel systemic treatment options are currently emerging, research into general medical comorbidities in moderately to severely affected AD patients has received great impetus in recent years. These studies have confirmed an increased risk of atopic diseases such as allergic asthma in AD patients. Furthermore, an association between AD and dermatological diseases with autoimmune pathophysiology such as vitiligo and alopecia areata has been demonstrated. Moreover, several studies have revealed an increased risk for internal autoimmune diseases in AD patients, e.g. inflammatory bowel disease and rheumatoid arthritis. A differentiated view of the data on AD as a possible risk factor for cardiovascular disease is needed. Large cross-sectional studies in the US revealed a correlation between AD and cardiovascular comorbidities. This has not been confirmed as yet in large German, Danish and Canadian investigations. Whether diverse "coping" strategies in different countries can explain these variances remains to be discussed. In terms of microbial comorbidities, AD patients display a particular susceptibility to viral infections.
31144214 Recent advances in cyclosporine drug delivery: challenges and opportunities. 2019 Dec Cyclosporine has been established as a gold standard for its immunosuppressant action. Apart from this, the molecule is boon in treating broad spectrum of diseases like rheumatoid arthritis, psoriasis, and dry eye syndrome. The broad spectrum of cyclosporine demands efficient delivery systems by several routes. Neoral® and Sandimmune® are currently available formulations for oral route, whereas Restasis® is used for ocular delivery of cyclosporine. The available formulations serve the purpose only to a limited extent due to constraints like high molecular weight, low solubility, low permeability, bitter taste, and narrow therapeutic index of cyclosporine. Therefore, several novel formulations like microemulsion, self-emulsifying systems, nanoparticles, and microspheres were developed to overcome these constraints, exploring different routes like oral, ocular, and topical for cyclosporine. Additionally, iontophoresis and ultrasound-mediated delivery has also been studied to improve its poor permeability in topical delivery, whereas biodegradable implants were reported to increase the retention time in cornea and prolonged the release of cyclosporine by ocular route. Although these recent advances in cyclosporine delivery look promising, its clinical translation require in depth studies to deliver safe, efficacious, and stable formulation of cyclosporine. This review focuses on challenges of cyclosporine delivery and the recent advancements for overcoming the constraints.
31054154 Short-chain fatty acids: Bacterial messengers modulating the immunometabolism of T cells. 2019 Jun Short-chain fatty acids (SCFAs) are mainly generated by bacterial fermentation of non-digestible carbohydrates such as dietary fiber. In the last decade, new investigations have revealed that SCFAs have a very specific function and serve as active microbial metabolites, which are able to modulate the function of immune cells in the intestine and other tissues. Recent studies have highlighted the immunomodulatory potential of SCFAs in several autoimmune and inflammatory disorders such as multiple sclerosis, colitis, type 1 diabetes and rheumatoid arthritis. While the SCFA-mediated activation of GPR41/GPR43 signalling pathways and their inhibitory activity on histone deacetylases have been extensively investigated, the impact of SCFAs on the T cell metabolism is poorly understood. SCFAs induce metabolic alterations in T cells by enhancing the activity of the mTOR complex and by regulating their glucose metabolism. Once taken up into T lymphocytes, SCFA-derived acetyl groups contribute to the cellular acetyl-CoA pool, which influences the histone acetylation and cytokine gene expression. This article reviews how SCFAs modulate the metabolic status of T cells, thereby impacting on epigenetic modifications and T cell function. We will also discuss how the recent findings from SCFA biology might be utilized for potential immune therapies of various autoimmune diseases.
31001966 Moderate-to-severe psoriasis and pregnancy: impact on fertility, pregnancy outcome and tre 2019 Jun Psoriasis affects 2-4% of the world's population, with no difference between men and women and 70% of patients experiencing disease onset before the age of 40, which coincides with the reproductive years. Few data are available from literature on impact of psoriasis on fertility, course and outcome of pregnancy and risk associated with treatments. Recent studies on other immune-mediated inflammatory diseases, among which psoriasis is also included, indicate that rheumatoid arthritis and inflammatory bowel diseases can impact female fertility and pregnancy outcomes especially during active disease episodes. In psoriasis hormonal and metabolic comorbidities, unhealthy lifestyles and systemic inflammation could also influence the ability to conceive, pregnancy course and birth outcomes. In this article we review current knowledge on reproductive function, course and outcome of pregnancy in women affected by moderate-to-severe psoriasis. Systemic treatments are also considered with a special focus on TNF-alpha blocking agents and implication of molecular structure on placental transportation and fetal exposure.
30915637 Pro-inflammatory Cytokines and Osteocytes. 2019 Jun PURPOSE OF REVIEW: An elevated level of pro-inflammatory cytokines in inflammatory conditions causes bone loss and disrupts vital organ function. Osteocytes comprise > 95% of the cellular component in bone tissue, produce a range of cytokines and signaling molecules, and influence bone and other organ function. In this review, we hypothesized that an elevated level of pro-inflammatory cytokines in inflammatory conditions affects osteocyte survival and function thereby possibly amplifying inflammation, and causing bone loss and non-bone clinical complications. RECENT FINDINGS: Several studies have reported that the elevated level of pro-inflammatory cytokines in inflammatory conditions alters osteocyte mechanosensitivity, causes osteocyte apoptosis, and modulates osteocyte-derived production of various inflammatory cytokines and signaling molecules. Cytokines and signaling molecules released from osteocytes affect surrounding bone cells and distant organ function in a paracrine and endocrine fashion. Inflammatory diseases including diabetes, chronic kidney disease, rheumatoid arthritis, and periodontitis affect osteocyte survival and function, and upregulate osteocyte-derived expression of sclerostin, RANKL, TNFα, FGF23, DKK1, and other signaling molecules.
30907188 Treat to target approach for asthma. 2020 Jun Recognition that about half of asthma deaths might be preventable if recommended guidelines are followed suggests that better implementation of established management strategies is needed. However, to achieve a further substantive reduction in asthma mortality, novel strategies will also be required. It is well established that asthma is a disease of chronic inflammation, with episodes of worsening inflammation associated with increased symptoms and/or exacerbations; however, current guidelines paradoxically recommend that initial treatment is only symptomatic, rather than directed at the underlying inflammatory mechanism. The "Treat to target" (TTT) approach has become a popular concept in the medical management of several common chronic conditions, including rheumatoid arthritis (RA), diabetes, hypertension and hyperlipidemia. For example, as part of a TTT approach, rheumatologists recommend methotrexate for RA with onset within 6 months. Applying the TTT approach to asthma, the primary target could be clinical remission and the primary goals as follows: eliminate symptoms and exacerbation risk; prevent airway remodeling; and normalize lung function. To construct a TTT algorithm for chronic asthma, the proposal is to eradicate short-acting β2-agonists (SABA) at all asthma severity levels and replace SABA with "Anti-Inflammatory Reliever Therapy" (AIR), using inhaled corticosteroids (ICS)/SABA or ICS/formoterol. For individuals with equal to or less than 12 months' history of symptoms, fewer than two symptoms per month, no exacerbations in the last 12 months and normal lung function, the recommendation is early initiation of ICS/SABA or ICS/formoterol as AIR.
30818998 Altered morpho-functional features of bones in autoimmune disease-prone BXSB/MpJ- Yaa mice 2019 Apr Bone disease, such as osteoporosis and rheumatoid arthritis, increases because of the progression of an aging society. Autoimmune disease are important and predisposing factors for the pathogenesis of the bone disease; however, the pathological mechanism is unclear. We have demonstrated that systemic autoimmune disease in BXSB/MpJ- Yaa is closely associated with the morpho-functional abnormalities of bones including bone marrow and has complicated pathology. The abnormalities are characterized by altered regulations of serum calcium, anemia tendency, and hematopoiesis with increased WBCs and decreased PLs, short length and low mass of long bones, imbalance in the populations of osteoclasts and osteoblasts, and increased expression of candidate genes for causing and/or exacerbating their phenotypes. Therefore, BXSB/MpJ- Yaa serves as a model to elucidate bone phenotypes in systemic autoimmune disease that would be affected by the factors in the bone as well as the other immune and/or mineral metabolism organs both in human and experimental medicine.
30810910 Correction to: Interventions to improve vaccine acceptance among rheumatoid arthritis pati 2019 Jun The original version of this article contained error. Table 1 was shown in the wrong version, thus corrected table is shown in this article.
30671025 Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myelom 2018 The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteoporosis, and bone-metastatic cancers. In the latter, IL-6 can be released with growth factors into the bone marrow microenvironment (BMM) during osteolysis from bone matrix or from cancer cells and osteoblasts in an inflammatory response to cancer cells. Thus, IL-6 helps create an ideal microenvironment for oncogenesis and metastasis. Multiple myeloma (MM) is a blood cancer that homes to the BMM and is strongly tied to overexpression of IL-6 and bone loss. The roles of IL-6 in the progression of MM are discussed in this review, including roles in bone homing, cancer-associated bone loss, disease progression and drug resistance. MM disease progression often includes the development of drug-resistant clones, and patients commonly struggle with reoccurrence. As such, therapeutics that specifically target the microenvironment, rather than the cancer itself, are ideal and IL-6, and its myriad of downstream signaling partners, are model targets. Lastly, current and potential therapeutic interventions involving IL-6 and connected signaling molecules are discussed in this review.