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Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society.
Ehl, S, Astigarraga, I, von Bahr Greenwood, T, Hines, M, Horne, A, Ishii, E, Janka, G, Jordan, MB, La Rosée, P, Lehmberg, K, et al
The journal of allergy and clinical immunology. In practice. 2018;(5):1508-1517
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.
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Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease).
Sergi, C, Shen, F, Bouma, G
World journal of gastroenterology. 2017;(4):573-589
Abstract
The upper digestive tract is routinely scoped for several causes of malabsorption, and the number of duodenal biopsy specimens has increased notably in the last 10 years. Gluten-sensitive enteropathy (GSE) is an autoimmune disease, which shows an increasing prevalence worldwide and requires a joint clinico-pathological approach. The classical histopathology of GSE with partial or total villous blunting is well recognized, but the classification of GSE is not straightforward. Moreover, several mimickers of GSE with intraepithelial lymphocytosis have been identified in the last 20 years, with drug interactions and medical comorbidities adding to the conundrum. In this review, we report on the normal duodenal mucosa, the clinical presentation and laboratory diagnosis of GSE, the duodenal intraepithelial lymphocytes and immunophenotype of GSE-associated lymphocytes, the GSE mimickers, the differences "across oceans" among guidelines in diagnosing GSE, and the use of a synoptic report for reporting duodenal biopsies in both children and adults in the 21st century.
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An Overview of Non-Neural Sources of Calcitonin Gene-Related Peptide.
Hu, R, Li, YJ, Li, XH
Current medicinal chemistry. 2016;(8):763-73
Abstract
Calcitonin gene-related peptide (CGRP) is extensively distributed throughout the central and peripheral nervous systems and has been shown to be a 37 amino acid multifunctional neuropeptide involved in a wide range of physiological and pathological processes. Recently, there is increasing evidence suggesting that CGRP also exists in non-nerve cells, such as epithelial cells, endothelial cells, endothelial progenitor cells (EPCs), T lymphocytes, B lymphocytes, peripheral blood mononuclear cells (PBMCs), and adipocytes. The existence of CGRP in non-neural tissue is of great importance to the regulation of multiple physiological and pathological processes via different pathways, especially through an autocrine/paracrine mode. This review integrates evidence from recent developments and aims to provide novel insights into non-neural sources of CGRP and its effects on physiological and pathological processes.
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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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Causes of upregulation of glycolysis in lymphocytes upon stimulation. A comparison with other cell types.
Stark, H, Fichtner, M, König, R, Lorkowski, S, Schuster, S
Biochimie. 2015;:185-94
Abstract
In this review, we revisit the metabolic shift from respiration to glycolysis in lymphocytes upon activation, which is known as the Warburg effect in tumour cells. We compare the situation in lymphocytes with those in several other cell types, such as muscle cells, Kupffer cells, microglia cells, astrocytes, stem cells, tumour cells and various unicellular organisms (e.g. yeasts). We critically discuss and compare several explanations put forward in the literature for the observation that proliferating cells adopt this apparently less efficient pathway: hypoxia, poisoning of competitors by end products, higher ATP production rate, higher precursor supply, regulatory effects, and avoiding harmful effects (e.g. by reactive oxygen species). We conclude that in the case of lymphocytes, increased ATP production rate and precursor supply are the main advantages of upregulating glycolysis.
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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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The clinical response to gluten challenge: a review of the literature.
Bruins, MJ
Nutrients. 2013;(11):4614-41
Abstract
The aim of this review was to identify, evaluate and summarize all relevant studies reporting on the clinical response to gluten challenge by adult or pediatric patients with suspected or diagnosed coeliac disease (CD) on a gluten-free diet. We evaluated the effect of gluten challenge on changes in symptoms, intestinal mucosa histology, and serum antibodies. A systematic electronic search was performed for studies published as of 1966 using PubMed and Scopus databases. In the reviewed studies, doses ranged from 0.2 to 30 g/day of wheat gluten or comprised a gluten-containing diet. The onset of symptoms upon gluten intake varied largely from days to months and did not parallel serum antibody or histological changes. Within 3 months of gluten challenge, 70%-100% of pediatric CD patients became positive for AGA-IgA and EMA-IgA antibodies and 50%-70% for AGA-IgG. A limited number of trials suggest that no more than half of adult patients developed positive AGA-IgA, EMA-IgA, tTG-IgA or DGP-IgA/IgG titers. Approximately 50%-100% of pediatric and adult patients experienced mucosal relapse of gluten provocation within 3 months, which was preceded by increased mucosal intra-epithelial lymphocytes within several days of challenge. A 3-month high-dose gluten challenge should be suitable to diagnose the majority of CD patients. In some cases prolonged challenge may be needed to verify diagnosis. Combination testing for antibodies and mucosal histology may fasten the diagnosis.