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Interleukin-17 producing mucosal associated invariant T cells - emerging players in chronic inflammatory diseases?
Pisarska, MM, Dunne, MR, O'Shea, D, Hogan, AE
European journal of immunology. 2020;(8):1098-1108
Abstract
Mucosal associated invariant T (MAIT) cells are a population of evolutionarily conserved T cells, which express an invariant T cell receptor (TCR) and represent a significant subset of innate-like T cells in humans, yet their role in immunity is still emerging. Unlike conventional αβ T cells, MAIT cells are not restricted by MHC molecules, but instead uniquely recognize microbially derived vitamin metabolites presented by the MHC-I like molecule MR1. MAIT cells are enriched in mucosal sites and tissues including liver and adipose tissue where they are thought to play an important role in immunosurveillance and immunity against microbial infection. In addition to their putative role in antimicrobial immunity, recent research on MAIT cells, in particular IL-17 producing MAIT cells, has demonstrated their involvement in numerous chronic inflammatory conditions. In this review, we give an overview of the work to date on the function and subsets of MAIT cells. We also examine the role of IL-17 producing MAIT cells in chronic inflammatory diseases ranging from autoimmune conditions, metabolic diseases to cancer. Furthermore, we discuss the most recent findings from the clinic that might help deepen our understanding about the biology of MAIT cells.
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The trace aminergic system: a gender-sensitive therapeutic target for IBS?
Pretorius, L, Smith, C
Journal of biomedical science. 2020;(1):95
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Abstract
Due to a lack of specific or sensitive biomarkers, drug discovery advances have been limited for individuals suffering from irritable bowel syndrome (IBS). While current therapies provide symptomatic relief, inflammation itself is relatively neglected, despite the presence of chronic immune activation and innate immune system dysfunction. Moreover, considering the microgenderome concept, gender is a significant aetiological risk factor. We believe that we have pinpointed a "missing link" that connects gender, dysbiosis, diet, and inflammation in the context of IBS, which may be manipulated as therapeutic target. The trace aminergic system is conveniently positioned at the interface of the gut microbiome, dietary nutrients and by-products, and mucosal immunity. Almost all leukocyte populations express trace amine associated receptors and significant amounts of trace amines originate from both food and the gut microbiota. Additionally, although IBS-specific data are sparse, existing data supports an interpretation in favour of a gender dependence in trace aminergic signalling. As such, trace aminergic signalling may be altered by fluctuations of especially female reproductive hormones. Utilizing a multidisciplinary approach, this review discusses potential mechanisms of actions, which include hyperreactivity of the immune system and aberrant serotonin signalling, and links outcomes to the symptomology clinically prevalent in IBS. Taken together, it is feasible that the additional level of regulation by the trace aminergic system in IBS has been overlooked, until now. As such, we suggest that components of the trace aminergic system be considered targets for future therapeutic action, with the specific focus of reducing oxidative stress and inflammation.
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3.
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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Inflammation and Mitochondrial Dysfunction in Autism Spectrum Disorder.
Gevezova, M, Sarafian, V, Anderson, G, Maes, M
CNS & neurological disorders drug targets. 2020;(5):320-333
Abstract
Autism Spectrum Disorders (ASD) is a severe childhood psychiatric condition with an array of cognitive, language and social impairments that can significantly impact family life. ASD is classically characterized by reduced communication skills and social interactions, with limitations imposed by repetitive patterns of behavior, interests, and activities. The pathophysiology of ASD is thought to arise from complex interactions between environmental and genetic factors within the context of individual development. A growing body of research has raised the possibility of identifying the aetiological causes of the disorder. This review highlights the roles of immune-inflammatory pathways, nitro-oxidative stress and mitochondrial dysfunctions in ASD pathogenesis and symptom severity. The role of NK-cells, T helper, T regulatory and B-cells, coupled with increased inflammatory cytokines, lowered levels of immune-regulatory cytokines, and increased autoantibodies and microglial activation is elucidated. It is proposed that alterations in mitochondrial activity and nitrooxidative stress are intimately associated with activated immune-inflammatory pathways. Future research should determine as to whether the mitochondria, immune-inflammatory activity and nitrooxidative stress changes in ASD affect the development of amygdala-frontal cortex interactions. A number of treatment implications may arise, including prevention-orientated prenatal interventions, treatment of pregnant women with vitamin D, and sodium butyrate. Treatments of ASD children and adults with probiotics, sodium butyrate and butyrate-inducing diets, antipurinergic therapy with suramin, melatonin, oxytocin and taurine are also discussed.
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Bioactive Factors in Human Breast Milk Attenuate Intestinal Inflammation during Early Life.
Thai, JD, Gregory, KE
Nutrients. 2020;(2)
Abstract
Human breast milk is well known as the ideal source of nutrition during early life, ensuring optimal growth during infancy and early childhood. Breast milk is also the source of many unique and dynamic bioactive components that play a key role in the development of the immune system. These bioactive components include essential microbes, human milk oligosaccharides (HMOs), immunoglobulins, lactoferrin and dietary polyunsaturated fatty acids. These factors all interact with intestinal commensal bacteria and/or immune cells, playing a critical role in establishment of the intestinal microbiome and ultimately influencing intestinal inflammation and gut health during early life. Exposure to breast milk has been associated with a decreased incidence and severity of necrotizing enterocolitis (NEC), a devastating disease characterized by overwhelming intestinal inflammation and high morbidity among preterm infants. For this reason, breast milk is considered a protective factor against NEC and aberrant intestinal inflammation common in preterm infants. In this review, we will describe the key microbial, immunological, and metabolic components of breast milk that have been shown to play a role in the mechanisms of intestinal inflammation and/or NEC prevention.
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Probiotics with ameliorating effects on the severity of skin inflammation in psoriasis: Evidence from experimental and clinical studies.
Atabati, H, Esmaeili, SA, Saburi, E, Akhlaghi, M, Raoofi, A, Rezaei, N, Momtazi-Borojeni, AA
Journal of cellular physiology. 2020;(12):8925-8937
Abstract
Experimental and clinical studies have confirmed safety and the medical benefits of probiotics as immunomodulatory medications. Recent advances have emphasized the critical effect of gastrointestinal bacteria in the pathology of inflammatory disorders, even, outside the gut. Probiotics have shown promising results for curing skin-influencing inflammatory disorders through modulating the immune response by manipulating the gut microbiome. Psoriasis is a complex inflammatory skin disease, which exhibits a microbiome distinct from the normal skin. In the present review, we considered the impact of gastrointestinal microbiota on the psoriasis pathogenesis, and through literature survey, attempted to explore probiotic species utilized for psoriasis treatment.
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Stress-induced disturbances along the gut microbiota-immune-brain axis and implications for mental health: Does sex matter?
Audet, MC
Frontiers in neuroendocrinology. 2019;:100772
Abstract
Women are roughly twice as likely as men to suffer from stress-related disorders, especially major depression and generalized anxiety. Accumulating evidence suggest that microbes inhabiting the gastrointestinal tract (the gut microbiota) interact with the host brain and may play a key role in the pathogenesis of mental illnesses. Here, the possibility that sexually dimorphic alterations along the gut microbiota-immune-brain axis could play a role in promoting this female bias of mood and anxiety disorders will be discussed. This review will also analyze the idea that gut microbes and sex hormones influence each other, and that this reciprocal crosstalk may come to modulate inflammatory players along the gut microbiota-immune-brain axis and influence behavior in a sex-dependent way.
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Key Role of Inflammation in Myeloproliferative Neoplasms: Instigator of Disease Initiation, Progression. and Symptoms.
Mendez Luque, LF, Blackmon, AL, Ramanathan, G, Fleischman, AG
Current hematologic malignancy reports. 2019;(3):145-153
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Abstract
PURPOSE OF REVIEW Chronic inflammation is a characteristic feature of myeloproliferative neoplasm (MPN) and impacts many aspects of the disease including initiation, progression, and symptomatology. RECENT FINDINGS The chronic inflammatory state of MPN results from disruption of immune signaling pathways leading to overproduction of inflammatory cytokines by both the neoplastic clones and bystander immune cells. This chronic inflammation may allow for the neoplastic clone to gain a selective advantage. The symptomatic burden felt by MPN patients may be a result of the chronic inflammation associated with MPN, as several cytokines have been linked with different symptoms. Pharmacologic as well as nonpharmacologic treatments of the inflammatory component of this disease may lead to decreased symptomatic burden, prevention of disease progression, and improvement in overall disease trajectory. Inflammation plays a key role in the pathogenesis of MPN and represents an important therapeutic target.
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Immune Dysfunction and Risk of Infection in Chronic Kidney Disease.
Syed-Ahmed, M, Narayanan, M
Advances in chronic kidney disease. 2019;(1):8-15
Abstract
Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.
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Interplay between the Adaptive Immune System and Insulin Resistance in Weight Loss Induced by Bariatric Surgery.
Villarreal-Calderón, JR, Cuéllar, RX, Ramos-González, MR, Rubio-Infante, N, Castillo, EC, Elizondo-Montemayor, L, García-Rivas, G
Oxidative medicine and cellular longevity. 2019;:3940739
Abstract
Low-grade chronic inflammation plays a pivotal role among other pathophysiological mechanisms involved in obesity. Innate and adaptive immune cells undergo systemic proinflammatory polarization that gives rise to an increased secretion of proinflammatory cytokines, which in turn leads to insulin resistance. Bariatric surgery is currently the most effective treatment for obesity, as it brings on significant weight loss, glucose metabolism improvement, and a decrease in systemic inflammation biomarkers. After bariatric surgery, several changes have been reported to occur in adaptive immunity, including reduction in CD4+ and CD8+ T cell counts, a decrease in the Th1/Th2 ratio, an increase in B regulatory cells, and reduction in proinflammatory cytokine secretion. Overall, there seems to be a major shift in several lymphocyte populations from a proinflammatory to an anti-inflammatory phenotype. Furthermore, increased antioxidant activity and reduced lipid and DNA oxidation products have been reported after bariatric surgery in circulating mononuclear cells. This paper highlights the shift in the adaptive immune system in response to weight loss and improved insulin sensitivity, as well as the interplay between immunological and metabolic adaptations as a result of bariatric surgery. Finally, based on data from research, we propose several mechanisms such as changes in adaptive immune cell phenotypes and their by-products, recruitment in adipose tissue, reduced oxidative stress, and modification in metabolic substrate availability as drivers to reduce low-grade chronic inflammation after bariatric surgery in severe obesity.