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Exploring the Evidence for an Immunomodulatory Role of Vitamin D in Juvenile and Adult Rheumatic Disease.
Zou, J, Thornton, C, Chambers, ES, Rosser, EC, Ciurtin, C
Frontiers in immunology. 2020;:616483
Abstract
Vitamin D is synthesized in the skin following exposure to UVB radiation or is directly absorbed from the diet. Following hydroxylation in the liver and kidneys, vitamin D becomes its bioactive form, 1,25(OH)2D, which has been described to have potent immunomodulatory capacity. This review will focus on the effect of vitamin D in modulating the dysregulated immune system of autoimmune rheumatic diseases (ARD) patients across age, in particular in arthritis (rheumatoid arthritis and juvenile idiopathic arthritis), and systemic lupus erythematosus (with adult and juvenile onset). As well as delineating the impact of vitamin D on the innate and adaptive immune functions associated with each disease pathology, this review will also summarize and evaluate studies that link vitamin D status with disease prevalence, and supplementation studies that examine the potential benefits of vitamin D on disease outcomes. Exploring this evidence reveals that better designed randomized controlled studies are required to clarify the impact of vitamin D supplementation on ARD outcomes and general health. Considering the accessibility and affordability of vitamin D as a therapeutic option, there is a major unmet need for evidence-based treatment recommendations for the use of vitamin D in this patient population.
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2.
Time to dissect the autoimmune etiology of cancer antibody immunotherapy.
Dougan, M, Pietropaolo, M
The Journal of clinical investigation. 2020;(1):51-61
Abstract
Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
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3.
Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers.
Koźmiński, P, Halik, PK, Chesori, R, Gniazdowska, E
International journal of molecular sciences. 2020;(10)
Abstract
Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer's disease or myasthenia gravis will be discussed.
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4.
How does methotrexate work?
Alqarni, AM, Zeidler, MP
Biochemical Society transactions. 2020;(2):559-567
Abstract
Developed over 70 years ago as an anti-folate chemotherapy agent, methotrexate (MTX) is a WHO 'essential medicine' that is now widely employed as a first-line treatment in auto-immune, inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and Crone's disease. When used for these diseases patients typically take a once weekly low-dose of MTX - a therapy which provides effective inflammatory control to tens of millions of people worldwide. While undoubtedly effective, our understanding of the anti-inflammatory mechanism-of-action of low-dose MTX is incomplete. In particular, the long-held dogma that this disease-modifying anti-rheumatic drug (DMARD) acts via the folate pathway does not appear to hold up to scrutiny. Recently, MTX has been identified as an inhibitor of JAK/STAT pathway activity, a suggestion supported by many independent threads of evidence. Intriguingly, the JAK/STAT pathway is central to both the inflammatory and immune systems and is a pathway already targeted by other RA treatments. We suggest that the DMARD activity of MTX is likely to be largely mediated by its inhibition of JAK/STAT pathway signalling while many of its side effects are likely associated with the folate pathway. This insight into the mechanism-of-action of MTX opens the possibility for repurposing this low cost, safe and effective drug for the treatment of other JAK/STAT pathway-associated diseases.
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5.
Transcriptional Regulators of T Helper 17 Cell Differentiation in Health and Autoimmune Diseases.
Capone, A, Volpe, E
Frontiers in immunology. 2020;:348
Abstract
T helper (Th) 17 cells are a subtype of CD4 T lymphocytes characterized by the expression of retinoic acid-receptor (RAR)-related orphan receptor (ROR)γt transcription factor, encoded by gene Rorc. These cells are implicated in the pathology of autoimmune inflammatory disorders as well as in the clearance of extracellular infections. The main function of Th17 cells is the production of cytokine called interleukin (IL)-17A. This review highlights recent advances in mechanisms regulating transcription of IL-17A. In particular, we described the lineage defining transcription factor RORγt and other factors that regulate transcription of Il17a or Rorc by interacting with RORγt or by binding their specific DNA regions, which may positively or negatively influence their expression. Moreover, we reported the eventual involvement of those factors in Th17-related diseases, such as multiple sclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease, characterized by an exaggerated Th17 response. Finally, we discussed the potential new therapeutic approaches for Th17-related diseases targeting these transcription factors. The wide knowledge of transcriptional regulators of Th17 cells is crucial for the better understanding of the pathogenic role of these cells and for development of therapeutic strategies aimed at fighting Th17-related diseases.
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6.
The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease.
Kiernan, K, MacIver, NJ
Frontiers in immunology. 2020;:622468
Abstract
Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly via the leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation.
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7.
[Wilkie's syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism: a case report and literature review].
Cervantes Pérez, E, Martínez-Soto Holguín, MC, Diaz Juárez, JP, Reyes Ramírez, ALDC
Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru. 2020;(3):274-277
Abstract
Wilkie's syndrome or superior mesenteric artery syndrome is an unusual cause of proximal intestinal obstruction, primarily attributed to recent weight loss. We report the case of a 19-year-old woman comes to our clinic and reports weight loss, abdominal pain, nausea, and vomiting. Laboratory tests revealed anemia, hypoalbuminemia, hypomagnesemia, and a suppressed thyroid stimulating hormone secondary to levothyroxine. A barium swallow test showed gastric dilatation, delayed gastric emptying and an axial computed tomography revealed an aortomesenteric angle of 11.7°. Conservative management with total parenteral and enteral nutrition was initiated, being the first-line treatment. In refractory cases surgery is a safe and effective option.
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8.
Targeting Vitamin D Deficiency to Limit Exacerbations in Respiratory Diseases: Utopia or Strategy With Potential?
Maes, K, Serré, J, Mathyssen, C, Janssens, W, Gayan-Ramirez, G
Calcified tissue international. 2020;(1):76-87
Abstract
Patients with respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or asthma often experience an acute worsening of respiratory symptoms, termed exacerbations. Although the course of exacerbations is disease specific, they are mostly triggered by a respiratory infection. Exacerbations often require hospitalization and are an important cause of mortality. Treatments of exacerbations aim to minimize the negative impact and to prevent subsequent events. Despite many existing therapy options, many patients do not benefit from therapy and suffer from recurrent events. Vitamin D deficiency is a worldwide problem and is extremely prevalent in these patients. Vitamin D, known for its calcemic effects, also has immunomodulatory and anti-infectious actions and can therefore be a possible agent to treat or prevent exacerbations. This review will focus on vitamin D as a potential candidate to treat or prevent exacerbations in CF, COPD, and asthma.
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9.
Interaction between food antigens and the immune system: Association with autoimmune disorders.
Vojdani, A, Gushgari, LR, Vojdani, E
Autoimmunity reviews. 2020;(3):102459
Abstract
It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.
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10.
Vitamin D in autoimmune bullous disease.
Tukaj, S
Acta biochimica Polonica. 2020;(1):1-5
Abstract
Numerous epidemiological studies have suggested a link between vitamin D deficiency and the development of various autoimmune diseases, including diabetes mellitus type 1, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis or systemic lupus erythematosus. More recently, such a link has been also proposed for autoimmune bullous diseases (AIBD). This is a relatively rare and potentially life-threatening, organ-specific group of inflammatory skin diseases characterized by the presence of tissue-bound and circulating autoantibodies against various molecules present in desmosomes (in pemphigus diseases) or hemidesmosomes (in pemphigoid diseases). In addition to the well-known role of vitamin D in calcium and phosphate homeostasis, the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol), exerts potent effects on cellular differentiation and regulation of immune responses via binding to the vitamin D receptor present in most cells of the immune system. Since cells of both, the innate and adaptive immune systems, are known to be relevant in AIBD, the role of vitamin D analogues in the treatment of patients with these disorders deserves much attention. This mini-review summarizes recent epidemiological and experimental studies on vitamin D involvement in the autoimmune bullous diseases.