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Scooped by
Gilbert C FAURE
September 12, 2018 4:39 AM
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Antiphospholipid syndrome (APS) is an autoimmune clotting disorder that may present catastrophically with multiple thromboses over a short period of time. In this article, we examine the case of a woman with undiagnosed APS whose first symptoms presented during a long-haul flight. A review of the literature on thrombosis at high altitudes and during long... [Read More]
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Scooped by
Gilbert C FAURE
September 11, 2018 5:20 AM
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Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation. Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease. The discovery of IL-17–producing T cells in a mouse model of autoimmunity transformed our understanding of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis. Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations. Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed.
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Scooped by
Gilbert C FAURE
September 9, 2018 10:26 AM
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Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defe…
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Scooped by
Gilbert C FAURE
September 6, 2018 12:18 PM
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Co-ordinated interaction between distinct cell types is a hallmark of successful immune function. A striking example of this is the carefully orchestrated cooperation between helper T cells and B cells that occurs during the initiation and fine-tuning of T-cell dependent antibody responses. While these processes have evolved to permit rapid immune defense against infection, it is becoming increasingly clear that such interactions can also underpin the development of autoimmunity. Here we discuss a selection of cellular and molecular pathways that mediate T cell / B cell collaboration and highlight how in vivo models and genome wide association studies link them with autoimmune disease. In particular, we emphasize how CTLA-4-mediated regulation of CD28 signaling controls the engagement of secondary costimulatory pathways such as ICOS and OX40, and profoundly influences the capacity of T cells to provide B cell help. While our molecular understanding of the co-operation between T cells and B cells derives from analysis of secondary lymphoid tissues, emerging evidence suggests that subtly different rules may govern the interaction of T and B cells at ectopic sites during autoimmune inflammation. Accordingly, the phenotype of the T cells providing help at these sites includes notable distinctions, despite sharing core features with T cells imparting help in secondary lymphoid tissues. Finally, we highlight the interdependence of T cell and B cell responses and suggest that
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Scooped by
Gilbert C FAURE
August 29, 2018 7:30 AM
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You've heard of the genome, and possibly the proteome – all the proteins in the human body. But have you heard about the glycome – the collection of sugars – that may hold the key to diagnosing disease?
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Scooped by
Gilbert C FAURE
August 29, 2018 7:28 AM
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Autoimmune Neurology Group DCN NDCN Contacts Test results: neuro.immunology@nhs.net, paddy.waters@ndcn.ox.ac.uk Clinical enquiries: sarosh.irani@ndcn.ox.ac.uk, maria.leite@ndcn.ox.ac.uk The immune system is our body's means of defence against harmful foreign substances such as bacteria and viruses. One of its roles is to produce antibodies, which are designed to selectively destroy disease-causing agents. Occasionally, however, antibodies attack the body itself, leading to an 'autoimmune' condition. Examples include rheumatoid arthritis, or thyroid disease, but can involve almost any organ. If the nervous system is affected, a variety of autoimmune neurological conditions can result. Such conditions can affect any part of the nervous system, and the part targeted by the autoantibody will reflect the symptoms. For example, the brain is affected in a condition called encephalitis, and the spinal cord can be affected in myelitis. Increasingly, the distinctive nature of the patient's symptoms can help identify the underlying condition. In many cases the autoantibodies can be depleted with treatment such as steroids and washing the blood with plasma exchange. But many patients don't respond well to the initial drugs, and require further medication to suppress the immune system. Patients are also often left with problems, typically involving memory, thinking or behaviour. There is a pressing need to develop new medications based on a better understanding of the conditions. OUR TEAM PARTICIPATE IN OUR RESEARCH Donations: You can contribute to our research here. Patient recruitment: Find out about the research projects for which we are recruiting participants here. SELECTED PUBLICATIONS N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications. Journal article Makuch M. et al, (2018), Ann Neurol, 83, 553 - 561 Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica. Journal article Wilson R. et al, (2018), Brain, 141, 1063 - 1074 Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. Journal article Lang B. et al, (2017), J Neurol Neurosurg Psychiatry, 88, 353 - 361 Neurexin-3α: A new antibody target in autoimmune encephalitis. Journal article Waters PJ. and Irani SR., (2016), Neurology, 86, 2222 - 2223 Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease. Journal article Juryńczyk M. et al, (2017), J Neurol Neurosurg Psychiatry, 88, 132 - 136 Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Journal article Irani SR. et al, (2010), Brain, 133, 2734 - 2748 OUR WORK We are trying to characterise the cells which produce the antibodies in patients with these diseases. This would allow us to begin to understand which medications can destroy these cells and help reduce antibody levels. We are also working to better understand the residual symptoms in patients which may respond to novel medications. Find out more about our diagnostics and research work. OUR TEAM Team members Alumni Visitors PARTNERSHIP AND FUNDING Wellcome Trust British Medical Association Epilepsy Research UK Association of British Neurologists Guarantors of Brain European Academy of Neurology UCB-Oxford Alliance Encephalitis Society Guthy-Jackson Foundation Donations NEWS AND EVENTS Patient and Public Engagement Vacancies
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Scooped by
Gilbert C FAURE
August 20, 2018 5:02 AM
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Inflammatory myopathies, collectively known as myositis, are heterogeneous disorders
characterised by muscle inflammation, and frequently accompanied by extramuscular
manifestations that affect the skin, lung, and joints.
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Suggested by
LIGHTING
August 17, 2018 12:11 PM
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Suggested by
Société Francaise d'Immunologie
August 16, 2018 10:39 AM
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B cell depletion has become standard-of-care for the treatment of ANCA-associated vasculitis, but can more be done to target B cells? In this Review, the authors look beyond rituximab to alternative B cell-targeting therapies and novel therapeutic combinations.
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Suggested by
Société Francaise d'Immunologie
August 14, 2018 8:50 AM
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The original work found that an anti-malaria drug or the neurotransmitter GABA could increase the number of insulin-producing pancreatic cells in mice.
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Scooped by
Gilbert C FAURE
August 12, 2018 1:50 AM
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Psoriasis is a chronic inflammatory skin disease resulting from genetic, epigenetic, environmental, and lifestyle factors. To date, several immunopathogenic mechanisms of psoriasis have been elucidated, and, in the current model, the crosstalk between autoreactive T cells and resident keratinocytes generates inflammatory and immune circuits responsible for the initiation, progression and persistence of the disease. Several autoantigens derived from keratinocytes (i. e. LL37 cathelecidin/nucleic acid complexes, newly generated lipid antigens) have been identified which may trigger initial activation of T cells, particularly IL-17-producing T cells, T-helper (Th)1 and Th22 cells. Hence, lymphokines released in skin lesions are pivotal for keratinocyte activation and production of inflammatory molecules which in turn lead to amplification of the local immune responses. Intrinsic genetic alterations of keratinocytes in the activation of signal transduction pathways dependent on T-cell derived cytokines are also fundamental. The current review emphasizes the aberrant interplay of immune cells and skin resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.
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Scooped by
Gilbert C FAURE
August 9, 2018 6:25 AM
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The presence of autoantibodies is one of several hallmarks of Sjögren's Syndrome, the detection of serum autoantibodies has a central role in the diag…
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Scooped by
Gilbert C FAURE
August 2, 2018 2:25 AM
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Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by a breakdown in immune tolerance that induces an attack on normal tissue
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Scooped by
Gilbert C FAURE
September 12, 2018 4:38 AM
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Don't Wonder. Know Discover LABScreen® Autoantibody Detection Testing for autoantibodies has never been more important as recent studies suggest a potential, long-term detrimental impact*. Employing single antigen bead technology, the LABScreen Autoantibody assays allow you to characterize and monitor a broad range of autoantibody targets in human sera. Following a familiar workflow and analysis algorithm, these assays can be easily integrated into your laboratory workflow without the need for new instrumentation or extensive retraining. Expand your antibody detection capabilities and get the answers you need. Expand your Antibody Detection Repertoire! REQUEST A QUOTE ❯ Recorded Webinar 2018 FEB 14 Non-HLA Antibodies: A New Perspective on Allograft Injury & Rejection Presenter: Annette M. Jackson, Ph.D | Johns Hopkins University, Baltimore, MD An introduction to non-HLA antibodies, their potential impact to transplantation, and review of new developments in their characterization. VIEW VIDEO ❯ * See References section. Features & Benefits Coverage by Researched Organs Kidney/Pancreas Heart/Lung HSCT Research Group 1 Vimentin AGT PECR CXCL11 CXCL9Agrin IFNG PLA2R PTPRN REG3A Enolase CD36 Myosin HNRNPK Tubulin CHAF1B GSTT1 FLRT2 IFIH1 AURKA PPIA EIF2A LMNA PRKCZPRKCH LMNB CXCL10 ARHGDIB GDNF GAPDH TNFA Group 2 LG3 (Perlecan) Group 3 Collagen I Collagen IICollagen IV Fibronectin Collagen V Collagen II
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Scooped by
Gilbert C FAURE
September 10, 2018 12:53 AM
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How unraveling more mysteries of the immune system will pave the way to better health outcomes for patients.
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Scooped by
Gilbert C FAURE
September 7, 2018 3:03 PM
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Objective：To investigate the role of IL-2 in the balance of Th17 and Tregs and elucidate the underlying mechanisms of enhanced Th17 differentiation in primary Sjögren's Syndrome (pSS) patients.Methods：This study involved 31 pSS patients, 7 Sicca patients and 31 healthy subjects. Th17 and Treg cells were determined by flow cytometry and immunohistochemistry. IL-2 and IL-6 levels were assessed by ELISA and qPCR. p-STAT5 and p-STAT3 in salivary glands (SG) were evaluated by immunohistochemistry. The binding of STAT5 and STAT3 to the Il17a gene locus was measured by chromatin-immunoprecipitation. Results：We found that the percentage of Th17 cells was increased in the periphery and SG of pSS patients compared with healthy subjects, but the Treg cells was unchanged. Meanwhile, IL-2 level was reduced and the IL-6 level was increased in the plasma of pSS patients. The ratio of IL-2 and IL-6 level was also decreased. The expression of Il6 and Il17a mRNA was significantly increased, whereas Foxp3, Tgfb1, Tnfa and Ifng mRNA were comparable. Furthermore, the level of STAT5 phosphorylation (p-STAT5) was reduced and p-STAT3 was enhanced in the SG. In vitro IL-2 treatment-induced p-STAT5 increased and competed with STAT3 binding in human Il17a locus, leading to decreased Th17 differentiation, which was associated with the reduced transcription activation marker H3K4me3.Conclusions：Our findings demonstrated a Treg-independent up-regulation of Th17 generation in pSS, which is likely du
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Scooped by
Gilbert C FAURE
September 5, 2018 2:31 PM
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Scooped by
Gilbert C FAURE
August 29, 2018 7:29 AM
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Inter-molecular epitope spreading during autoimmune pathogenesis leads to generation of new pathogenic epitopes on other autoantigens beyond the original one. It raises an important question as whether autoimmunity extends beyond the target tissues if new epitopes are on the molecules shared with...
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Scooped by
Gilbert C FAURE
August 29, 2018 7:27 AM
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The fuzz around a cell is its glycan coat. Being on the outside of our cells, glycans are the first point of contact for most cellular interactions and thus influence how our cells communicate with one another. by Emanual Maverakis, Carlito Lebrilla, and Jenny Wang ( August 29, 2018, Boston, Sri Lanka Guardian) When you think of sugar, you probably think of the sweet, white, crystalline table sugar that you use to make cookies or sweeten your coffee. But did you know that within our body, simple sugar molecules can be connected together to create powerful structures that have recently been found to be linked to health problems, including cancer, aging and autoimmune diseases. These long sugar chains that cover each of our cells are called glycans, and according to the National Academy of Sciences, creating a map of their location and structure will usher us into a new era of modern medicine. This is because the human glycome – the entire collection of sugars within our body – houses yet-to-be-discovered glycans with the potential to aid physicians in diagnosing and treating their patients. Thanks to the worldwide attention garnered by the 2003 completion of the Human Genome Project, most people have heard about DNA, genomics and even proteomics – the study of proteins. But the study of glycans, also known as glycomics, is about 20 years behind that of other fields. One reason for this lag is that scientists have not developed the tools to rapidly identify glycan structures and their attachment sites on people’s cells. The “sugar coat” has been somewhat of a mystery. Until now, that is. While most laboratories focus on cellular or molecular research, our labis dedicated to developing technology to rapidly characterize glycan structures and their attachment sites. Our ultimate goal is to catalog the hundreds of thousands of sugars and their locations on various cell types, and then to use this information to tailor medical therapies to each individual. Why do we care about glycans? In the future, it is likely that analysis of an individual’s glycans will be used to predict our risk for developing diseases like rheumatoid arthritis, cancer or even food allergies. This is because glycome alterations can be specifically tied to particular disease states. Also, biological processes like aging are linked to inflammation in our glycome. It remains to be tested if reversing these changes can help prevent disease, or even slow aging – an intriguing possibility. Along with DNA, proteins, and fats, glycans are one of the four major macromolecules essential for life. Of these four, glycans are the final arbiters of how our cells behave. DNA orchestrates what we look like, our capacity to think and behave, and even determines the diseases to which we are most susceptible. Within our DNA are short segments, genes, which often contain instructions for how to synthesize proteins. Proteins in turn are the “workhorses” of the cell, carrying out many of the functions necessary for life. However, how a protein behaves often depends on what glycans are attached to it. In other words, these sugar molecules can greatly influence how our proteins do their work, and even how our cells will respond to stimuli. For example, if you change a few glycans on the outside of a cell, it might trigger that cell to migrate to a different location in our body. The main job of glycans is to modify the proteins and fats that sit on the surface of our cells. Together, they create a thick sugar coat around the cell. If we consider the surface of the cell to be soil, then glycans would be the wonderfully diverse plant-life and foliage that sprout up and bring color and identity to the cell. In fact, if you were able to see a cell with your naked eye, it would look very fuzzy. Picture a peach with 10 times more fuzz. Glycans label our own cells and identify them as ‘self’ The fuzz around a cell is its glycan coat. Being on the outside of our cells, glycans are the first point of contact for most cellular interactions and thus influence how our cells communicate with one another. You can also think of the glycans as a unique cellular “barcode.” Thus, a kidney cell’s fuzz will look different from an immune cell’s fuzz. But there are also similarities. In fact, the immune cells that survey our body searching for pathogens know not to attack our own “self” cells because of common features in the glycan “barcode” which are shared by all cells of our body. In contrast, bacteria and parasites like malaria have different “sugar coats” that are not seen on human cells. When bacterial sugars are tagged as “foreign,” a person’s immune system targets the bacterium for destruction. However, some harmful bacterial pathogens like group B streptococcus, which commonly cause severe infections in babies, can avoid immune detection by impersonating human cells by carrying similar glycans as a disguise – like the wolf dressed in sheepskin. Unfortunately, some pathogens are also able to use our glycans to help them cause disease. Deadly viruses like HIV and Ebola have evolved to grab hold of specific glycans which they then “lock” onto as they infect our human cells. Therapies that either block these viruses from interacting with our glycans, or that attack virus-specific glycans may be a new avenue to treating these infections. New research has also shown that glycans play a huge role in the development of autoimmune diseases like rheumatoid arthritis and autoimmune pancreatitis. This is not surprising since glycans directly influence the function of immune cells. Normally, our immune cells act as our body’s “defense system,” and identify and destroy foreign invaders like harmful bacteria or viruses. But when the body mistakenly labels our own cells as the enemy and launches an internal attack on itself, autoimmunity is born. Interestingly, in such instances, it is the glycans present on the misbehaving self-attacking antibodies that will dictate the strength of the attack on the body. This abnormal immune response can even be directed against glycans. For example, the immune system can mistake “self” glycans as if they were “foreign” molecules. Our research team recently published an article that introduced the glycan theory of autoimmunity, which explains some of these relationships. Glycans in our food can trigger immune responses There have been many studies linking consumption of red meat with diseases like atherosclerosis and diabetes, but they have not been able to show why or how this occurs until recently. One intriguing studysuggests that the culprit was a sugar with the unwieldy name, nonhuman sialic N-glycolylneuraminic acid, or Neu5Gc for short. Neu5Gc is found in all mammals except humans, because the early humans that could make Neu5Gc died from an ancient malarial parasite. However, although we now lack the ability to produce Neu5Gc, our bodies still have the ability to incorporate it into the glycans on our cells if we obtain it by eating red meat. Once it becomes part of our cells’ glycan coat, our cells then have a “foreign” substance – Neu5Gc – surrounding them. This can trigger inflammation throughout the body because our immune system recognize Neu5Gc as “foreign” and attacks it. The chronic inflammation caused by these internal attacks can lead to heart attack, stroke and even cancer. Our bodies synthesize tens of thousands of unique glycans, often with branching structures formed from simple sugar building blocks. Proteins or fats can also be modified by dozens of unique glycans. These countless combinations make mapping glycans a difficult task because we need a practical and efficient way to analyze hundreds of thousands of glycan patterns. Our research team has now developed methods to rapidly and robustly monitor the human glycome. By capitalizing on engineering advancements and improvements in sample processing, our technique can monitor thousands of glycans at once, which allows us to characterize the glycans in cells from healthy controls and patients with a variety of different diseases. Our goal is to use this data to develop predictive models to help clinicians diagnose and treat all human diseases. We believe that a new wave of medical advancements will arrive as we unlock the “sugar code.” Jenny Wang was the co-lead author of this article. Emanual Maverakis: Associate Professor- Departments of Medical Microbiology & Immunology and Dermatology | Member- Foods For Health Institute | Member- Comprehensive Cancer Center | Director- Autoimmunity | Director- Immune Monitoring Core, University of California, Davis Carlito Lebrilla: Distinguished Professor of Chemistry, University of California, Davis Jenny Wang: Clinical Research Fellow, University of California, Davis | Medical Student, Albert Einstein College of Medicine, Yeshiva University Originally published on The Conversation
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Scooped by
Gilbert C FAURE
August 20, 2018 1:55 AM
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Lupus patients can experience photosensitivity as manifested by joint pain, fatigue, and skin rashes. To better understand the mechanisms behind this photosensitivity, Shipman et al. examined patient skin samples and mouse models of lupus. They saw that, in healthy mice and human skin exposed to ultraviolet radiation, Langerhans cells protected keratinocytes from apoptosis through a mechanism involving the metalloproteinase ADAM17 and EGFR ligands. In the lupus mice and patient samples, the Langerhans cells were unable to do this. Stimulating EGFR in the skin may bring relief to photosensitive lupus patients.
Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)–keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin–diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.
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Scooped by
Gilbert C FAURE
August 16, 2018 10:40 AM
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Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency
and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology,...
Cochrane Database of Systematic Reviews Abstract available in Background Cyclophosphamide, in combination with corticosteroids, has been first‐line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end‐stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. Objectives Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy‐proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? Search methods We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) and quasi‐RCTs comparing any immunosuppressive treatment for biopsy‐proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. Data collection and analysis Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. Main results In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty‐nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age. Induction therapy Sixty‐seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference. Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD. MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence. Maintenance therapy Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient‐outcome data were sparse leading to imprecise estimates. Authors' conclusions In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF. Plain language summary available in Immunosuppressive treatment for people with proliferative lupus nephritis What is the issue? In lupus, the body’s immune system for fighting infection attacks different parts of the body, including the kidneys. About half of all people with lupus have kidney problems. An estimated one in every 10 people who have lupus kidney disease (lupus nephritis) can develop kidney failure. The goal of treatment is to protect kidney function and avoid side‐effects. While the life expectancy of patients who have lupus has dramatically improved, available treatments can cause serious side effects such as hair loss, serious infection, and infertility. It is important to know about which treatments help to treat lupus while causing the fewest side‐effects. What did we do? We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 and we combined all studies testing treatments aimed to control the body’s immune system for lupus nephritis. What did we find? In this review update, 74 studies involving 5175 patients with lupus nephritis could be studied. Treatments included intravenous (given through a vein) cyclophosphamide, oral (tablets by mouth) mycophenolate mofetil (MMF), azathioprine, and tacrolimus (used alone or together with MMF). We also found studies of treatments called “biologic” therapies, that have been designed to change very specific parts of the body’s immune system that cause it to attack itself. We looked particularly at key outcomes such as whether treatment prevented patients from needing dialysis and controlled the lupus damage to the kidney tissue (called remission). We also looked at serious side‐effects including death, infection, infertility, and hair loss. After combining the available studies, compared with cyclophosphamide, MMF may be better at getting the lupus damage to the kidneys under control. However, the range where the actual effect may suggest that MMF may make little or no difference to disease remission compared to treatment with cyclophosphamide. MMF treatment given with tacrolimus may lead to more disease remission. MMF may result in less hair loss and worse diarrhoea, but we were not certain whether MMF reduces infertility or other serious side effects. MMF was better than azathioprine for preventing kidney disease in the longer term. None of the studies told us whether treatment had any effect on death or need for dialysis, and there was very low certainty of evidence for the use of biologics in patients with lupus nephritis. Conclusions Patients with lupus nephritis may have similar or slightly better outcomes when treated with MMF or MMF with tacrolimus compared to those patients who receive intravenous cyclophosphamide. We are still not certain which is the best treatment for lupus nephritis to protect against needing dialysis in the longer term. Unlock the full review
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
August 14, 2018 8:26 AM
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Autoimmune pancreatitis (AIP) is difficult to diagnose and can sometimes be confused with pancreatic cancer, which presents with similar symptoms. AIP is an inflammatory disease involving elevated IgG4, but the target autoantigen(s) is unidentified. This group’s previous work pointed to the extracellular matrix, and now, Shiokawa et al . show that a truncated form of laminin 511 may be a major autoantigen in AIP. They observed that half of AIP patients they analyzed had anti–laminin 511 antibodies, which were absent in healthy controls. Patient pancreatic tissues were positive for laminin 511, and immunization of mice with this protein induced AIP-like symptoms. These results reveal an autoimmune target in this disease and one day may aid AIP diagnosis.
Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.
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Scooped by
Gilbert C FAURE
August 9, 2018 11:45 AM
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Ca2+ release–activated Ca2+ channel regulator 2A (CRACR2A) is expressed abundantly in T cells and acts as a signal transmitter between TCR stimulation and activation of the Ca2+/NFAT and JNK/AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies and was shown to be one of the most sensitive targets of the widely used statin drugs. However, the physiological role of CRACR2A in T cell functions remains unknown. In this study, using transgenic mice for tissue-specific deletion, we show that CRACR2A promotes Th1 responses and effector function of Th17 cells. CRACR2A was abundantly expressed in Th1 and Th17 cells. In vitro, deficiency of CRACR2A decreased Th1 differentiation under nonpolarizing conditions, whereas the presence of polarizing cytokines compensated this defect. Transcript analysis showed that weakened TCR signaling by deficiency of CRACR2A failed to promote Th1 transcriptional program. In vivo, conditional deletion of CRACR2A in T cells alleviated Th1 responses to acute lymphocytic choriomeningitis virus infection and imparted resistance to experimental autoimmune encephalomyelitis. Analysis of CNS from experimental autoimmune encephalomyelitis–induced mice showed impaired effector functions of both Th1 and Th17 cell types, which correlated with decreased pathogenicity. Collectively, our findings demonstrate the requirement of CRACR2A-mediated TCR signaling in Th1 responses as well as pathogenic conversion of Th17 cells, which occurs at the site of inflammation.
This article is featured in In This Issue , p.[1107][1]
[1]: /lookup/volpage/201/1107
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Scooped by
Gilbert C FAURE
August 9, 2018 6:25 AM
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Primary Sjögren's syndrome (pSS) is a chronic autoimmune rheumatic disease characterized by inflammation of exocrine glands, mainly salivary and lacri…
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