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1.
Zim CHIC: A cohort study of immune changes in the female genital tract associated with initiation and use of contraceptives.
Achilles, SL, Meyn, LA, Mhlanga, FG, Matubu, AT, Stoner, KA, Beamer, MA, Chirenje, ZM, Hillier, SL
American journal of reproductive immunology (New York, N.Y. : 1989). 2020;(3):e13287
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Abstract
PROBLEM Contraceptive hormones are systemically active, potent, and likely to invoke biological responses other than known fertility regulation impacts. We hypothesized that initiation of depot medroxyprogesterone acetate (DMPA) would increase genital HIV-target-cells and soluble immune mediators compared with baseline and initiation of other contraceptive methods. METHOD OF STUDY We collected cervical cytobrushes and cervicovaginal fluid from healthy Zimbabwean women aged 18-34 to assess immune cell populations, cytokines, and innate anti-HIV activity at baseline and after 30, 90, and 180 days use of DMPA (n = 38), norethisterone enanthate (n = 41), medroxyprogesterone acetate/estradiol cypionate (n = 36), levonorgestrel implant (n = 43), etonogestrel implant (n = 47), or copper intrauterine device (Cu-IUD) (n = 45). Cells were quantified by flow cytometry, cytokines were detected by multiplex assays, and innate anti-HIV activity was assessed by in vitro HIV challenge. RESULTS Compared to baseline, the number of cervical HIV target cells (#CD4 cells P < .04 and #CD11c cells P < .04), the concentration of the inflammatory cytokine IL-1β (P < .01), and the innate in vitro anti-HIV activity (P < .001) significantly decreased following DMPA initiation. In Cu-IUD users, genital HIV target cells increased (#CD4 cells P < .001, #CD4CCR5 cells P = .02, #CD4CD69 cells P < .001, #CD8CD69 P = .01, and #CD11c cells P = .003) at day 30 and resolved by day 180. IFN-γ (P < .001), IL-1β (P < .001), IL-6 (P < .001), IL-8 (P < .001), IL-10 (P < .01), and RANTES (P < .001) were also significantly increased at day 30. Minimal alterations were observed following initiation of subdermal implantable contraceptives. CONCLUSIONS This head-to-head study compared six contraceptives and found increased HIV target cells and cervical inflammation temporally associated with Cu-IUD initiation. Use of hormonal contraception, including DMPA, did not increase cervical HIV target cells or inflammation. Clinical Trial Number: NCT02038335.
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The immunobiology of autoimmune encephalitides.
Alexopoulos, H, Dalakas, MC
Journal of autoimmunity. 2019;:102339
Abstract
Autoimmune encephalitides, with an estimated incidence of 1.5 per million population per year, although described only 15 years ago, have already had a remarkable impact in neurology and paved the field to autoimmune neuropsychiatry. Many patients traditionally presented with aberrant behavior, especially of acute or subacute onset, and treated with anti-psychotic therapies, turn out to have a CNS autoimmune disease with pathogenic autoantibodies against synaptic antigens responding to immunotherapies. The review describes the clinical spectrum of these disorders, and the pathogenetic role of key autoantibodies directed against: a) cell surface synaptic antigens and receptors, including NMDAR, GABAa, GABAb, AMPA and glycine receptors; b) channels such as AQP4 water-permeable channel or voltage-gated potassium channels; c) proteins that stabilize voltage-gated potassium channel complex into the membrane, like the LGI1 and CASPR2; and d) enzymes that catalyze the formation of neurotransmitters such as Glutamic Acid Decarboxylase (GAD). These antibodies, effectively target excitatory or inhibitory synapses in the limbic system, basal ganglia or brainstem altering synaptic function and resulting in uncontrolled neurological excitability disorder clinically manifested with psychosis, agitation, behavioral alterations, depression, sleep disturbances, seizure-like phenomena, movement disorders such as ataxia, chorea and dystonia, memory changes or coma. Some of the identified triggering factors include: viruses, especially herpes simplex, accounting for the majority of relapses occurring after viral encephalitis, which respond to immunotherapy rather than antiviral agents; tumors especially teratoma, SCLC and thymomas; and biological cancer therapies (immune-check-point inhibitors). As anti-synaptic antibodies persist after viral infections or tumor removal, augmentation of autoreactive B cells which release autoantigens to draining lymph nodes, molecular mimicry and infection-induced bystander immune activation products play a role in autoimmunization process or perpetuating autoimmune neuroinflammation. The review stresses the importance of early detection, clinical recognition, proper antibody testing and early therapy initiation as these disorders, regardless of a known or not trigger, are potentially treatable responding to systemic immunotherapy with intravenous steroids, IVIg, rituximab or even bortezomid.
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3.
Steroids and Autoimmunity.
Trombetta, AC, Meroni, M, Cutolo, M
Frontiers of hormone research. 2017;:121-132
Abstract
From the middle of the 19th century, it is known that endocrine and immune systems interact bi-directionally in different processes that ensure organism homeostasis. Endocrine and nervous systems have a pivotal role in the balancing of pro- and anti-inflammatory functions of immune system, and constitute a complex circadian neuroendocrine network. Autoimmune diseases have in fact a complex pathogenic origin in which the importance of endocrine system was demonstrated. In this chapter, we will mention the structure and function of steroidal hormones involved in the neuroendocrine immune network and we will address the ways in which endocrine and immune systems influence each other, in a bi-directional fashion. Adrenal hormones, sex hormones, vitamin D, and melatonin and prolactin importantly all contribute to the homeostasis of the immune system. Indeed, some of the steroidal hormone activities determine inhibition or stimulation of immune system components, in both physiological (i.e. suppression of an unwanted response in pregnancy, or stimulation of a protective response in infections) and pathological conditions. We will finally mention the rationale for optimization of exogenous administration of glucocorticoids in chronic autoimmune diseases, and the latest developments concerning these drugs.
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Clinical trials in minimal change disease.
Ravani, P, Bertelli, E, Gill, S, Ghiggeri, GM
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(suppl_1):i7-i13
Abstract
Minimal change disease (MCD) is a pathological condition characterized by subtle glomerular lesions causing massive and reversible proteinuria that is usually steroid sensitive. Recurrence of symptoms of active disease following successful treatment (including proteinuria, oedema and oliguria) and steroid toxicity requires the use of other drugs to attain or maintain remission. Unresolved MCD is considered the initial step in the pathological pathway leading to focal and segmental glomerulosclerosis (FSGS). Historically, cyclophosphamide, chlorambucil, mycophenolate and calcineurin inhibitors have been utilized with success in MCD; however, the chronic nature of the disease and the toxicity of long-term use of these medications has pushed the development of new therapies. Synthetic corticotropin (adrenocorticotropic hormone) and anti-CD20 monoclonal antibodies, for example, are currently under investigation in clinical trials. In addition, these new interventions have dramatically impacted our understanding of the mechanisms of the disease. Phase II-IV clinical trials targeting new mechanisms and/or molecules are in progress. The list is long and includes drugs blocking the adaptive immune system (abatacept and anti-CD40 antibodies), as well as retinoids and the sialic acid precursor N-acetyl-D-mannosamine (ManNAc), two agents that affect the sieving properties of the glomerular basement membrane. Other drugs are being tested against FSGS and, if successful, could also be utilized against MCD. Clinical trials currently in progress should furnish a proper solution to what appears to be a solvable problem.
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[Eosinophilic esophagitis - update - pathogenesis, diagnosis and therapy].
von Arnim, U, Miehlke, S, Madisch, A, Vieth, M, Straumann, A, Malfertheiner, P
Zeitschrift fur Gastroenterologie. 2014;(3):296-305
Abstract
Eosinophilic esophagitis (EoE) is a clinicopathological condition of the esophagus that has become increasingly recognised over the last decade. EoE represents a chronic immune-mediated inflammatory disease of the esophagus. In adults dysphagia is the predominant symptom. Upper gastrointestinal endoscopy is required in order to take biopsies from the esophagus. The diagnose is confirmed histologically by typical eosinophilic infiltration of the esophagus mucosa. Until now there is no approved therapy world-wide although we know that topic and systemic steroids are highly effective in EoE. Elimination diet is another option and in well selected patients endoscopic balloon dilation represents a therapeutic possibility.
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Treatment of VGKC complex antibody-associated limbic encephalitis: a systematic review.
Radja, GK, Cavanna, AE
The Journal of neuropsychiatry and clinical neurosciences. 2013;(4):264-71
Abstract
Limbic encephalitis is an autoimmune neuropsychiatric condition characterized by subacute cognitive symptoms, seizures, and affective changes. Although limbic encephalitis is usually caused by an immune reaction secondary to neoplasms, different types of potentially treatable non-paraneoplastic limbic encephalitis (nPLE) have recently been described. In particular, published studies have reported variable responses to immunosuppressive therapy in Voltage-Gated Potassium Channel (VGKC) complex antibody-associated nPLE. This systematic literature review found that the most significant improvements were reported by patients presenting with affective symptoms and consistent neuroradiological changes. In these patients, improved clinical outcomes correlated with the largest decreases in antibody titers.
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7.
Steroidogenesis in the skin: implications for local immune functions.
Slominski, A, Zbytek, B, Nikolakis, G, Manna, PR, Skobowiat, C, Zmijewski, M, Li, W, Janjetovic, Z, Postlethwaite, A, Zouboulis, CC, et al
The Journal of steroid biochemistry and molecular biology. 2013;:107-23
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Abstract
The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7Δ-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'.
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Upregulation of TLR2 and TLR4 in the human adrenocortical cells differentially modulates adrenal steroidogenesis.
Kanczkowski, W, Tymoszuk, P, Chavakis, T, Janitzky, V, Weirich, T, Zacharowski, K, Ehrhart-Bornstein, M, Bornstein, SR
Molecular and cellular endocrinology. 2011;(1-2):41-6
Abstract
Rapid activation of adrenal steroid release plays a pivotal role in an organism's first line of defense during sepsis. Adrenal gland function is often suppressed in critically ill patients and negatively impacts the overall survival rate. Increasingly, experimental and clinical evidence suggests that Toll-like receptors (TLRs), components of the innate immune system, play a key role in the mediation of systemic responses to invading pathogens during sepsis. In the present study, we aimed to elucidate the effect of TLR2, TLR4 and CD14 upregulation on adrenocortical cell steroidogenesis. We found that TLR4 and CD14 but not TLR2 overexpression in NCI-H295R cells inhibited basal and acute cortisol and aldosterone production. This effect could be partially explained by reduced expression of enzymes involved in the synthesis of latter steroids--CYP11B1 and CYP11B2. Together, these data suggest that TLR upregulation in the steroid producing cells may be involved in the adrenal gland dysfunction during sepsis.
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Effects of therapeutic agents on the inflammatory and fibrogenic factors in IgA nephropathy.
Ihm, CG, Jeong, KW, Lee, SH, Lee, TW, Park, JK
Nephrology (Carlton, Vic.). 2007;:S25-6
Abstract
It is desirable in the treatment of IgA nephropathy (IgAN) to prevent the downstream events after the immune response has involved the glomerulus. We and others observed that IgA itself could directly activate mesangial cells to produce monocyte chemotactic peptide-1 (MCP-1), interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) and this was suppressed by the treatment with steroid or angiotensin receptor blocker (ARB). It was shown in mesangial cells that the increased expression of TGF-beta and plasminogen activator inhibitor-1 induced by angiotensin II was suppressed by the treatment with ARB, calcium channel blocker (CCB), spironolactone or peroxisome proliferator-activated-receptor-gamma (PPAR-gamma) agonist. It was well known in the patients with IgAN that renal or intraglomerular TGF-beta1 gene expression was increased. Interestingly, treatment with angiotensin-converting enzyme (ACE) inhibitors induced significantly lower renal TGF-beta1 gene expression in patients with IgAN. It was reported in several studies that urinary levels of IL-6, IL-8, MCP-1 or TGF-beta were increased in patients with IgAN. The increase was suppressed by the treatment with steroid, ARB or ACE inhibitor. More effective agents are necessary to ameliorate pathogenetic abnormalities and so to prevent the progression of IgAN.
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Efficacy of interventions for bronchiolitis in critically ill infants: a systematic review and meta-analysis.
Davison, C, Ventre, KM, Luchetti, M, Randolph, AG
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2004;(5):482-9
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Abstract
BACKGROUND Viral bronchiolitis is the leading cause of respiratory failure among infants in the United States. Currently, the mainstay of treatment is supportive care. The effectiveness of treatments used for mechanically ventilated infants with bronchiolitis is unclear. OBJECTIVE To evaluate the strength of the evidence supporting the use of currently available treatments for critically ill infants with bronchiolitis. DATA SOURCE We searched PubMed, citations of relevant articles, personal files, and conference proceedings, and we contacted experts in the field. STUDY SELECTION Randomized, controlled trials evaluating any therapy for bronchiolitis that included children in an intensive care unit. DATA EXTRACTION Two reviewers independently extracted data and assessed methodologic quality. DATA SYNTHESIS A total of 2,319 citations were screened, and 16 randomized, controlled trials were included. There were three trials of surfactant, three of ribavirin, three of immune globulin, three of systemic corticosteroids, and one each of vitamin A, interferon, erythropoietin, and heliox. A meta-analysis of the three surfactant studies showed a strong trend toward a decrease in duration of mechanical ventilation of 2.58 days (95% confidence interval, -5.34 to 0.18 days; p =.07) and a significant decrease of 3.3 intensive care unit days (95% confidence interval, -6.38 to -0.23 days; p =.04). A meta-analysis of the three systemic corticosteroid studies showed no overall effect on duration of mechanical ventilation when all three trials were combined (-0.62 day; 95% confidence interval, -2.78 to 1.53 days; p =.57). We identified one published meta-analysis of three ribavirin studies showing a significant decrease in ventilator days with ribavirin (-1.2 days; 95% confidence interval, -0.2 to -3.4 days; p =.2). CONCLUSIONS Currently, there are no clearly effective interventions available to improve the outcome of critically ill infants with bronchiolitis. Surfactant seems to be a promising intervention, and corticosteroids or ribavirin may also be beneficial.