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TREM2/PLCĪ³2 signalling in immune cells: function, structural insight, and potential therapeutic modulation.
Magno, L, Bunney, TD, Mead, E, Svensson, F, Bictash, MN
Molecular neurodegeneration. 2021;(1):22
Abstract
The central role of the resident innate immune cells of the brain (microglia) in neurodegeneration has become clear over the past few years largely through genome-wide association studies (GWAS), and has rapidly become an active area of research. However, a mechanistic understanding (gene to function) has lagged behind. That is now beginning to change, as exemplified by a number of recent exciting and important reports that provide insight into the function of two key gene products - TREM2 (Triggering Receptor Expressed On Myeloid Cells 2) and PLCĪ³2 (Phospholipase C gamma2) - in microglia, and their role in neurodegenerative disorders. In this review we explore and discuss these recent advances and the opportunities that they may provide for the development of new therapies.
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Novel Systemic Inflammation Markers to Predict COVID-19 Prognosis.
Karimi, A, Shobeiri, P, Kulasinghe, A, Rezaei, N
Frontiers in immunology. 2021;:741061
Abstract
Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic, challenging both the medical and scientific community for the development of novel vaccines and a greater understanding of the effects of the SARS-CoV-2 virus. COVID-19 has been associated with a pronounced and out-of-control inflammatory response. Studies have sought to understand the effects of inflammatory response markers to prognosticate the disease. Herein, we aimed to review the evidence of 11 groups of systemic inflammatory markers for risk-stratifying patients and prognosticating outcomes related to COVID-19. Numerous studies have demonstrated the effectiveness of neutrophil to lymphocyte ratio (NLR) in prognosticating patient outcomes, including but not limited to severe disease, hospitalization, intensive care unit (ICU) admission, intubation, and death. A few markers outperformed NLR in predicting outcomes, including 1) systemic immune-inflammation index (SII), 2) prognostic nutritional index (PNI), 3) C-reactive protein (CRP) to albumin ratio (CAR) and high-sensitivity CAR (hsCAR), and 4) CRP to prealbumin ratio (CPAR) and high-sensitivity CPAR (hsCPAR). However, there are a limited number of studies comparing NLR with these markers, and such conclusions require larger validation studies. Overall, the evidence suggests that most of the studied markers are able to predict COVID-19 prognosis, however NLR seems to be the most robust marker.
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Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis.
Domingues, RG, Hepworth, MR
Frontiers in immunology. 2020;:116
Abstract
Recent years have seen a revolution in our understanding of how cells of the immune system are modulated and regulated not only via complex interactions with other immune cells, but also through a range of potent inputs derived from diverse and varied biological systems. Within complex tissue environments, such as the gastrointestinal tract and lung, these systems act to orchestrate and temporally align immune responses, regulate cellular function, and ensure tissue homeostasis and protective immunity. Group 3 Innate Lymphoid Cells (ILC3s) are key sentinels of barrier tissue homeostasis and critical regulators of host-commensal mutualism-and respond rapidly to damage, inflammation and infection to restore tissue health. Recent findings place ILC3s as strategic integrators of environmental signals. As a consequence, ILC3s are ideally positioned to detect perturbations in cues derived from the environment-such as the diet and microbiota-as well as signals produced by the host nervous, endocrine and circadian systems. Together these cues act in concert to induce ILC3 effector function, and form critical sensory circuits that continually function to reinforce tissue homeostasis. In this review we will take a holistic, organismal view of ILC3 biology and explore the tissue sensory circuits that regulate ILC3 function and align ILC3 responses with changes within the intestinal environment.
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Acute bouts of exercise induce a suppressive effect on lymphocyte proliferation in human subjects: A meta-analysis.
Siedlik, JA, Benedict, SH, Landes, EJ, Weir, JP, Vardiman, JP, Gallagher, PM
Brain, behavior, and immunity. 2016;:343-51
Abstract
OBJECTIVE Lymphocyte proliferative responses are commonly used to assess immune function in clinical settings, yet it is unclear how proliferative capacity is altered by exercise. This analysis aims to quantitatively assess the proliferative response of lymphocytes following an acute bout of exercise. METHODS Electronic databases were searched for articles containing the keywords "exercise" OR "acute" OR "aerobic" OR "resistance training" OR "immune function" AND "proliferation" AND "lymphocyte." Initial results yielded 517 articles of which 117 were reviewed in full. Twenty-four articles met the inclusion criteria. Calculated standardized mean difference (SMD) and corresponding standard errors (SE) were integrated using random-effect models. RESULTS Analyses uncovered evidence for suppression of proliferative capacity following acute exercise in general (SMD=-0.18, 95% CI: -0.21, -0.16) with long duration, high intensity exercise exhibiting a moderate suppressive effect (SMD=-0.55, 95% CI: -0.86, -0.24). Discordant proliferative responses for long duration, high intensity exercise in competitive versus non-competitive settings were identified with enhanced proliferation (SMD=0.46, 95% CI: 0.03, 0.89) observed following competitive events and a large suppressive effect detected for similar activities outside of a competitive environment (SMD: -1.28, 95% CI: -1.61, -0.96) (p=0.02). CONCLUSION Evidence suggests lymphocyte proliferation is suppressed following acute bouts of exercise, with exercise lasting longer than one hour having a greater magnitude of effect regardless of exercise intensity. Variations in observed effect sizes across intensity, duration, and competitive environment further highlight our need to acknowledge the impact of study designs in advancing our understanding of exercise immunology.
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Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.
Eberl, G, Colonna, M, Di Santo, JP, McKenzie, AN
Science (New York, N.Y.). 2015;(6237):aaa6566
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Abstract
Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.
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Signaling in lymphocyte activation.
Cantrell, D
Cold Spring Harbor perspectives in biology. 2015;(6)
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Abstract
The fate of T and B lymphocytes, the key cells that direct the adaptive immune response, is regulated by a diverse network of signal transduction pathways. The T- and B-cell antigen receptors are coupled to intracellular tyrosine kinases and adaptor molecules to control the metabolism of inositol phospholipids and calcium release. The production of inositol polyphosphates and lipid second messengers directs the activity of downstream guanine-nucleotide-binding proteins and protein and lipid kinases/phosphatases that control lymphocyte transcriptional and metabolic programs. Lymphocyte activation is modulated by costimulatory molecules and cytokines that elicit intracellular signaling that is integrated with the antigen-receptor-controlled pathways.
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Obesity-related immune responses and their impact on surgical outcomes.
Quante, M, Dietrich, A, ElKhal, A, Tullius, SG
International journal of obesity (2005). 2015;(6):877-83
Abstract
The obesity epidemic represents a critical disease burden with broad clinical consequences. At the same time, obesity has been linked to inferior surgical outcomes and considered a contraindication for some elective surgical procedures. A growing body of mechanistic evidence has accumulated linking obesity to changes of metabolism and immune responses. This concept provides an integrated inflammatory network based on the perception of obesity as a state of chronic low-grade inflammation. With a more detailed understanding of this dynamic network and mechanistic insights, novel treatment and management strategies may be developed with the goal to optimize surgical outcomes in obese patients.
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Molecular regulation of CRAC channels and their role in lymphocyte function.
Shaw, PJ, Qu, B, Hoth, M, Feske, S
Cellular and molecular life sciences : CMLS. 2013;(15):2637-56
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Abstract
Calcium (Ca(2+)) influx is required for the activation and function of all cells in the immune system. It is mediated mainly by store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels located in the plasma membrane. CRAC channels are composed of ORAI proteins that form the channel pore and are activated by stromal interaction molecules (STIM) 1 and 2. Located in the membrane of the endoplasmic reticulum, STIM1 and STIM2 have the dual function of sensing the intraluminal Ca(2+) concentration in the ER and to activate CRAC channels. A decrease in the ER's Ca(2+) concentration induces STIM multimerization and translocation into puncta close to the plasma membrane where they bind to and activate ORAI channels. Since the identification of ORAI and STIM genes as the principal mediators of CRAC channel function, substantial advances have been achieved in understanding the molecular regulation and physiological role of CRAC channels in cells of the immune system and other organs. In this review, we discuss the mechanisms that regulate CRAC channel function and SOCE, the role of recently identified proteins and mechanisms that modulate the activation of ORAI/STIM proteins and the consequences of CRAC channel dysregulation for lymphocyte function and immunity.
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Cellular and molecular aspects of iron and immune function.
Brock, JH, Mulero, V
The Proceedings of the Nutrition Society. 2000;(4):537-40
Abstract
Fe plays a critical role in the immune system and defence against infection. However, many aspects of the way in which Fe influences these processes at the molecular and cellular level are unclear. The present review summarizes the role of Fe in lymphocyte activation and proliferation, and discusses how Fe is handled by macrophages.