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The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders.
Arts, RJW, Joosten, LAB, Netea, MG
Frontiers in immunology. 2018;:298
Abstract
During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.
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Autoimmune Retinopathy.
Tsang, SH, Sharma, T
Advances in experimental medicine and biology. 2018;:223-226
Abstract
The autoimmune retinopathies (AIRs) are a group of inflammatory-mediated retinopathies that present with unexplained visual loss (both central and peripheral), visual field defects, usually a ring scotoma, photoreceptor dysfunction as evident on electroretinography (ERG), and circulating autoantibodies against retinal antigens. The fundus may be normal or may show vascular attenuation, retinal atrophy with or without pigmentary changes or waxy pallor of the optic disc, and no or minimal inflammatory cells.
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Myokines, physical activity, insulin resistance and autoimmune diseases.
Díaz, BB, González, DA, Gannar, F, Pérez, MCR, de León, AC
Immunology letters. 2018;:1-5
Abstract
Myokines are peptides produced and released by myocytes of muscle fibers that influence physiology of muscle and other organs and tissues. They are involved in mediating the beneficial effects that exercise has on health. More than one hundred have been identified and among them are IL6, myostatin, irisin, mionectin and decorin. Physical inactivity leads to an altered response of the secretion of myokines and resistance to them; this leads to a pro-inflammatory state that favors sarcopenia and fat accumulation, promoting the development of cardiovascular diseases, insulin resistance, and diabetes mellitus type 2. Some myokines, including irisin, are responsible for the improvement that exercise produces in many chronic diseases such as type 2 diabetes and cardiovascular diseases, some types of cancer and many autoimmune diseases such as idiopathic inflammatory myopathy, rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease.
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Are Anti-Retinal Autoantibodies a Cause or a Consequence of Retinal Degeneration in Autoimmune Retinopathies?
Adamus, G
Frontiers in immunology. 2018;:765
Abstract
Autoantibodies (AAbs) against various retinal proteins have been associated with vision loss in paraneoplastic and non-paraneoplastic autoimmune retinopathies (AR). There are two major paraneoplastic syndromes associated anti-retinal AAbs, cancer-associated retinopathy (CAR), and melanoma-associated retinopathy. Some people without a cancer diagnosis may present symptoms of CAR and have anti-retinal AAbs. The etiology and pathogenesis of those entities are not fully understood. In this review, we provide evidence for the role of AAbs in retinal death and degeneration. Studies of epitope mapping for anti-recoverin, anti-enolase, and anti-carbonic anhydrase II revealed that although patients' AAbs may recognize the same retinal protein as normal individuals they bind to different molecular domains, which allows distinguishing between normal and diseased AAbs. Given the great diversity of anti-retinal AAbs, it is likely some antibodies have greater pathogenic potential than others. Pathogenic, but not normal antibodies penetrate the target cell, reach their specific antigen, induce apoptosis, and impact retinal pathophysiology. Photoreceptors, dying by apoptosis, induced by other than immunologic mechanisms produce substantial amounts of metabolic debris, which consequently leads to autoimmunization and enhanced permeability of the blood-retinal barrier. AAbs that were made as a part of anti-cancer response are likely to be the cause of retinal degeneration, whereas others, generated against released antigens from damaged retina, contribute to the progression of retinopathy. Altogether, AAbs may trigger retinal degeneration and may also exacerbate the degenerative process in response to the release of sequestered antigens and influence disease progression.
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5.
[What's new in internal medicine?].
Doutre, MS
Annales de dermatologie et de venereologie. 2018;:VIIS24-VIIS31
Abstract
What's new in internal medicine will be dedicated to three topics: i) inflammatory myopathies constituting a heterogenous group of diseases whose clinical manifestations, immunological abnormalities, treatment response and outcomes vary widely; ii) alterations of gut microbiota contributing to the occurrence or development of a range of conditions, including autoimmune diseases for which further work is necessary to understand the correlation of dysbiosis with these diseases; iii) the reciprocal relationship between obesity, metabolic syndrome, atherosclerosis and autoimmune diseases. New data concerning systemic sclerosis, cutaneous vasculitis, adult Still's disease, autoantibodies anti DFS70, Epstein Barr virus and autoimmune diseases were also highlighted.
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Clinical Features of Japanese Patients With Anti-α-enolase Antibody-Positive Autoimmune Retinopathy: Novel Subtype of Multiple Drusen.
Ando, R, Saito, W, Kanda, A, Kase, S, Fujinami, K, Sugahara, M, Nakamura, Y, Eguchi, S, Mori, S, Noda, K, et al
American journal of ophthalmology. 2018;:181-196
Abstract
PURPOSE To evaluate clinical features of Japanese patients with anti-α-enolase antibody-positive autoimmune retinopathy (anti-enolase AIR). DESIGN Multicenter retrospective observational case series. METHODS Forty-nine eyes of 25 Japanese anti-enolase AIR patients (16 female and 9 male; mean age at first visit, 60.8 years) were included. Fundus characteristics, perimetry, spectral-domain optical coherence tomography (SD-OCT), electroretinography (ERG), best-corrected visual acuity (BCVA), and complicating systemic tumors were assessed. Protein localization of α-enolase was examined by immunohistochemistry in an enucleated eye of 1 patient. RESULTS Patients were classified into 3 groups: multiple drusen (48%), retinal degeneration (36%), and normal fundus (16%). Drusen varied in size from small deposits to vitelliform-like lesions. Images on SD-OCT revealed dome-shaped hyperreflectivity beneath the retinal pigment epithelium (RPE), corresponding to drusen. Perimetry showed that ring scotoma was the most frequent (39%). Rod-system and/or single-flash cone responses revealed decreased responses in 81% of the eyes. Combined rod and cone system responses demonstrated significantly lower a-wave amplitudes in the degeneration group than in the drusen group (P = .005). BCVA was improved or maintained in 80% of the eyes during follow-up. Malignant or benign tumors were detected in 30% of patients. The RPE and photoreceptor layers were immunopositive for α-enolase. CONCLUSIONS The drusen subtype, scarcely described in the literature, is suggested to characterize Japanese patients with anti-enolase AIR. The different funduscopic features with different functional severities may have resulted from antibody-mediated damage to RPE as well as photoreceptor cells.
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Associated conditions in small fiber neuropathy - a large cohort study and review of the literature.
de Greef, BTA, Hoeijmakers, JGJ, Gorissen-Brouwers, CML, Geerts, M, Faber, CG, Merkies, ISJ
European journal of neurology. 2018;(2):348-355
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Abstract
BACKGROUND AND PURPOSE Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. METHODS A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. RESULTS No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. CONCLUSIONS Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.
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Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses.
Pandya, VB, Kumar, S, Sachchidanand, , Sharma, R, Desai, RC
Journal of medicinal chemistry. 2018;(24):10976-10995
Abstract
The nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORγ or RORc) is a key transcription factor for the production of pro-inflammatory cytokines implicated in the pathogenesis of autoimmune diseases. Recently, small molecule inhibitors of RORc drew the enormous attention of the research community worldwide as a possible therapy for autoimmune diseases, mediated by the IL-17 cytokine. With the clinical proof-of-concept inferred from a small molecule inhibitor VTP-43742 for psoriasis and recent inflow of several RORc inhibitors into the clinic for therapeutic interventions in autoimmune diseases, this field continues to evolve. This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases.
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The role of functional thyroid capacity in pituitary thyroid feedback regulation.
Hoermann, R, Midgley, JEM, Larisch, R, Dietrich, JW
European journal of clinical investigation. 2018;(10):e13003
Abstract
BACKGROUND Thyroid feedback regulation and equilibria between thyroid hormones differ in the presence or absence of a functioning thyroid remnant. MATERIALS AND METHODS This study examines the relationship between the sensitivity of TSH feedback and thyroid capacity in untreated patients with thyroid autoimmune disease (n = 86) and healthy controls (n = 271). Functional capacity was estimated at maximum TSH stimulation, and pituitary TSH response was FT4-standardised with two established indices, the TSH index and the thyrotroph thyroid hormone resistance index. RESULTS The two indices correlated inversely with thyroid volume and functional thyroid capacity. Relationships were shifted upwards in patients with thyroid autoimmune disease. This positioned patients with thyroid autoimmune disease predominantly at the lower capacity range and upper part of TSH index. The relationship was modulated by serum FT3 concentrations, shifting 0.19 [95%CI: 0.12, 0.26] mIU/L per pmol FT3 increase. FT3 correlated with TSH index in total group ( τ = 0.09, P = 0.009) and both subgroups. FT3 levels were maintained despite a substantial capacity loss by progressively increasing conversion rates of T3 from T4, only collapsing at capacities below <1.5 pmol/s. CONCLUSION Functional thyroid capacity and preferential T3 generation are essential elements in adjusting the sensitivity of hypothalamic-pituitary-thyroid feedback control and balancing system equilibria. This suggests that the indirect regulatory role of glandular T3 co-secretion exceeds its quantitative contribution to the thyroid hormone pool. Implications for clinical practice extend to the diagnostic use of TSH in patients with impaired thyroid reserve.
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Pathogenesis, diagnosis and treatment of anaemia in immune-mediated gastrointestinal disorders.
Bergamaschi, G, Di Sabatino, A, Corazza, GR
British journal of haematology. 2018;(3):319-329
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Abstract
Immune-mediated disorders affecting the gastrointestinal (GI) tract may compromise GI integrity, interfere with the absorption of nutrients and cause bleeding and inflammation. All these features contribute to the pathogenesis of anaemia, the most prevalent extra-intestinal manifestation of immune-mediated GI disorders. Anaemia is most commonly due to iron deficiency and/or inflammation, but vitamin deficiencies and, more infrequently, autoimmune haemolysis or drug-induced myelosuppression can be involved. Here we address several issues related to the differential diagnosis and treatment of anaemia in immune-mediated GI disorders, giving particular relevance to the problem of iron deficiency anaemia associated with inflammation. It is emphasized how, in most cases, anaemias due to iron or vitamin deficiencies are best treated by parenteral administration of the deficient factor(s), and how the available high dose intravenous (IV) iron formulations can reduce ambulatory and social costs of IV iron supplementation, while improving patient's compliance to treatment. Actual and future treatment possibilities for anaemia of inflammation, involving the use of erythropoiesis stimulating agents, biologicals and hepcidin inhibitors are discussed.