scholarly journals FcγRIIB-I232T polymorphic change allosterically suppresses ligand binding

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wei Hu ◽  
Yong Zhang ◽  
Xiaolin Sun ◽  
Tongtong Zhang ◽  
Liling Xu ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Binding Affinities ◽  
Systemic Lupus ◽  
Single Nucleotide ◽  
Immune Cell Activation ◽  
Tm Domain ◽  
Dynamics Simulations

FcγRIIB binding to its ligand suppresses immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppressive function, which is clinically associated with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB’s TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further reveal that such tilting by I232T unexpectedly bends the FcγRIIB’s ectodomain toward plasma membrane to allosterically impede FcγRIIB’s ligand association. I232T substitution reduces in situ two-dimensional binding affinities and association rates of FcγRIIB to interact with its ligands, IgG1, IgG2 and IgG3 by three to four folds. This allosteric regulation by an SNP provides an intrinsic molecular mechanism for the functional loss of FcγRIIB-I232T in SLE patients.

scholarly journals FcγRIIB I232T polymorphic change allosterically suppresses ligand binding

2019 ◽  
Author(s):  
Wei Hu ◽  
Yong Zhang ◽  
Xiaolin Sun ◽  
Liling Xu ◽  
Hengyi Xie ◽  
...  
Keyword(s):  
Single Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Binding Affinities ◽  
Single Nucleotide ◽  
Immune Cell Activation ◽  
Tm Domain ◽  
Dynamics Simulations

AbstractFcγRIIB bindings to its ligand suppress immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppression function, which clinically associates with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB’s TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further revealed that such tilting by I232T unexpectedly bends the FcγRIIB’s ectodomain towards plasma membrane to allosterically impede FcγRIIB’s ligand association. We then used single-cell biomechanical assay to further find out that I232T also reduces two-dimensional in-situ binding affinities and association rates of FcγRIIB interacting with its ligands by three-folds. This allosteric regulation by a SNP provides an intrinsic molecular mechanism for functional loss of FcγRIIB-I232T in SLE patients.

Abstract MP41: A Role Of Isolevuglandins In Systemic Lupus Erythematosus Associated Autoimmunity And Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
David M Patrick ◽  
Nestor de la Visitacion ◽  
Michelle J Ormseth ◽  
Charles Stein ◽  
Sean S Davies ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Systemic Immune Activation

Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions that disproportionately affect women. SLE has heterogeneous manifestations and treatment is limited to the use of non-specific global immunosuppression. Importantly, there is an increased prevalence of hypertension in women with SLE compared to healthy controls. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation. Previous studies have shown an essential role of IsoLGs in immune cell activation and the development of hypertension in animal models. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE. We first examined isoLG adduct accumulation within monocytes of human subjects with SLE compared to healthy controls. By flow cytometry, we found marked accumulation of isoLG adducts within CD14 + monocytes (34.2% ± 12.4% vs 3.81% ± 2.1% of CD14 + , N = 10-11, P <0.05). We confirmed this increase in isoLG adducts by mass spectrometry. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the B6.SLE123 and NZBWF1 mouse models of SLE. Animals were treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks and were sacrificed at 32 weeks of age. C57BL/6 and NZW were used as controls. Importantly, treatment with 2-HOBA attenuated blood pressure in both mouse models (systolic BP 136.2 ± 5.6 mmHg for B6.SLE123 vs 120.9 ± 4.46 mmHg for B6.SLE123 +2HOBA; 164.7 ± 24.4 mmHg for NZBWF1 vs 136.9 ± 14.9 mmHg for NZBWF1 +2HOBA, N = 6-8, P < 0.05). Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the B6.SLE123 model (albumin/creatinine ratio 33.8 ± 2.0 x 10 -2 μg/mg for B6.SLE123 vs 5.5 ± 0.9 x 10 -2 μg/mg for B6.SLE123 +2HOBA, N = 7-9, P < 0.05). Finally, immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. These studies suggest a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE.

scholarly journals Deoxyribonuclease 1-Mediated Clearance of Circulating Chromatin Prevents From Immune Cell Activation and Pro-inflammatory Cytokine Production, a Phenomenon Amplified by Low Trap1 Activity: Consequences for Systemic Lupus Erythematosus

2021 ◽  
Vol 12 ◽  
Author(s):  
Jasmin Felux ◽  
Annika Erbacher ◽  
Magali Breckler ◽  
Roxane Hervé ◽  
Delphine Lemeiter ◽  
...  
Keyword(s):  
Immune Cells ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Wild Type ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Deficient Mice

Increased concentrations of circulating chromatin, especially oligo-nucleosomes, are observed in sepsis, cancer and some inflammatory autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, circulating nucleosomes mainly result from increased apoptosis and decreased clearance of apoptotic cells. Once released, nucleosomes behave both as an autoantigen and as a damage-associated molecular pattern (DAMP) by activating several immune cells, especially pro-inflammatory cells. Deoxyribonuclease 1 (DNase1) is a major serum nuclease whose activity is decreased in mouse and human lupus. Likewise, the mitochondrial chaperone tumor necrosis factor (TNF) receptor-associated protein-1 (Trap1) protects against oxidative stress, which is increased in SLE. Here, using wild type, DNase1-deficient and DNase1/Trap1-deficient mice, we demonstrate that DNase1 is a major serum nuclease involved in chromatin degradation, especially when the plasminogen system is activated. In vitro degradation assays show that chromatin digestion is strongly impaired in serum from DNase1/Trap1-deficient mice as compared to wild type mice. In vivo, after injection of purified chromatin, clearance of circulating chromatin is delayed in DNase1/Trap1-deficient mice in comparison to wild type mice. Since defective chromatin clearance may lead to chromatin deposition in tissues and subsequent immune cell activation, spleen cells were stimulated in vitro with chromatin. Splenocytes were activated by chromatin, as shown by interleukin (IL)-12 secretion and CD69 up-regulation. Moreover, cell activation was exacerbated when Trap1 is deficient. Importantly, we also show that cytokines involved in lupus pathogenesis down-regulate Trap1 expression in splenocytes. Therefore, combined low activities of both DNase1 and Trap1 lead to an impaired degradation of chromatin in vitro, delayed chromatin clearance in vivo and enhanced activation of immune cells. This situation may be encountered especially, but not exclusively, in SLE by the negative action of cytokines on Trap1 expression.

Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature

Lupus ◽  
2021 ◽  
pp. 096120332199010
Author(s):  
Vineeta Shobha ◽  
Anu Mohan ◽  
AV Malini ◽  
Puneet Chopra ◽  
Preethi Karunanithi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Time Course ◽  
Cell Activation ◽  
Immune Cell ◽  
Gene Signature ◽  
Systemic Lupus ◽  
Auto Antibody ◽  
Activation Status

Objective Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. Methods We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. Results Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. Conclusions Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

Oxidized Haemoglobin–Driven Endothelial Dysfunction and Immune Cell Activation: Novel Therapeutic Targets for Atherosclerosis

2013 ◽  
Vol 20 (37) ◽  
pp. 4806-4814 ◽  
Author(s):  
Brigitta Buttari ◽  
Elisabetta Profumo ◽  
Rita Businaro ◽  
Luciano Saso ◽  
Raffaele Capoano ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cell Activation ◽  
Immune Cell ◽  
Therapeutic Targets ◽  
Immune Cell Activation ◽  
Novel Therapeutic

scholarly journals Neuronal guidance proteins in cardiovascular inflammation

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Marius Keller ◽  
Valbona Mirakaj ◽  
Michael Koeppen ◽  
Peter Rosenberger
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Vascular Endothelial ◽  
Therapeutic Approaches ◽  
Immune Cell Activation ◽  
Cytokines And Chemokines ◽  
The Future ◽  
Cardiovascular Pathologies ◽  
Neuronal Guidance

AbstractCardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

scholarly journals Oxidative stress and immune cell activation quantification in sepsis and non-sepsis critical care patients by neopterin/7,8-dihydroneopterin analysis

Pteridines ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 68-82
Author(s):  
Gregory Baxter-Parker ◽  
Ravinder Reddy Gaddam ◽  
Elena Moltchanova ◽  
Anitra Carr ◽  
Geoff Shaw ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Function ◽  
Cell Activation ◽  
Immune Cell ◽  
Intensive Care Patients ◽  
Immune Cell Activation ◽  
Immune System Activation ◽  
System Activation ◽  
Urinary Neopterin ◽  
Critical Care Patients

AbstractIntroduction: Neopterin and 7,8-dihydroneopterin are used as biomarkers of oxidative stress and inflammation, but the effect of kidney function on these measurements has not been extensively explored. We examine the levels of oxidative stress, inflammation and kidney function in intensive patients and compare them to equivalent patients without sepsis.Methods: 34 Intensive care patients were selected for the study, 14 without sepsis and 20 with. Both groups had equivalent levels of trauma, assessed by SAPS II, SOFA, and APACHE II and III scores. Plasma and urinary neopterin and total neopterin (neopterin + 7,8-dihydroneopterin) values were measured.Results: Neopterin and total neopterin were significantly elevated in urine and plasma for multiple days in sepsis versus non-sepsis patients. Plasma neopterin and total neopterin have decreasing relationships with increased eGFR (p<0.008 and p<0.001, respectively). Plasma/urinary neopterin and total neopterin ratios demonstrate that total neopterin flux is more influenced by eGFR than neopterin, with significantce of p<0.02 and p<0.0002 respectively.Conclusion: Sepsis patients present with greater levels of oxidative stress and immune system activation than non-sepsis patients of equal levels of trauma, as measured by neopterin and total neopterin. eGFR may need to be taken into account when accessing the level of inflammation from urinary neopterin measurements.

scholarly journals AB0128 CXCL5 DAMPENS INFLAMMATION IN THE PRE-CLINICAL MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS VIA THE ORCHESTRAL EFFECT OF REGULATING NEUTROPHIL TRAFFICKING AND SUPPRESSING HELPER T CELL-MEDIATED IMMUNE RESPONSE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1365.2-1365
Author(s):  
X. Fan ◽  
D. Guo ◽  
C. T. Ng ◽  
A. Law ◽  
Z. Y. Poon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Systemic Lupus ◽  
Helper T Cell ◽  
Clinical Model ◽  
Cell Mediated Immune Response

Background:Patients with systemic lupus erythematosus (SLE) suffer from severe morbidity and mortality1-4, either from the disease itself or from side effects of immunosuppression5. Discovery of novel effective therapies with less toxicity is an urgent need.Objectives:The aim of this study is to elucidate the therapeutic potential and working mechanism of cytokine CXCL5 in lupus mice.Methods:Treatment with CXCL5, bone marrow (BM)-MSCs, standard of care (SOC) with combination of methylprednisolone and cyclophosphamide was given to 16-week-old Faslprmice. Mice were monitored for 10 weeks. Splenic immune cell subsets were measured by flow cytometry. Circulating cytokine and immunoglobulin were detected by Luminex technology. Renal function was evaluated by urinary spot albumin creatinine ratio. In situ renal immune cell infiltration and complement 3 deposition were detected by Haematoxylin and Eosin (H&E) staining and immunohistochemistry.Results:CXCL5 demonstrated consistent and potent immunosuppressive capacity in suppressing SLE with reduced autoantibody secretion, lymphoproliferation and preserved kidney function. With further exploration, we proved that CXCL5 reduced the proliferation of helper T cells (TH1 and TH2) in thein vitrofunctional assay. When we administrated CXCL5 to lupus mice, it promoted the proliferation of regulatory T cells and reduced the proliferation of TH17 cells, macrophages and neutrophils. Multiple proinflammatory cytokines including IL-2, IL-6, IL-12, IL-17A, KC/CXCL1, MIP-1β/CCL4 and TNF-α were also reduced. When combined with SOC, CXCL5 boosted its therapeutic effect and reduced the relevant indices of disease activity. When we correlated the effect of four different treatment groups (CXCL5, BM-MSCs, SOC, and CXCL5 plus SOC) on mice survival and target cell changes, we found that TH17 cells were the key effector cells involved in the pathogenesis of SLE.Conclusion:These findings demonstrated that CXCL5 dampens inflammation in the pre-clinical model of systemic lupus erythematosus via the orchestral effect of regulating neutrophil trafficking and suppressing helper T cell-mediated immune response. Administrating exogenous CXCL5 might be an attractive option to treat patients with lupus.References:[1]Ji S, Guo Q, Han Y, Tan G, Luo Y, Zeng F. Mesenchymal stem cell transplantation inhibits abnormal activation of Akt/GSK3beta signaling pathway in T cells from systemic lupus erythematosus mice.Cell Physiol Biochem.2012;29(5-6):705-712.[2]Peng SL. Altered T and B lymphocyte signaling pathways in lupus.Autoimmun Rev.2009;8(3):179-183.[3]Ferucci ED, Johnston JM, Gaddy JR, et al. Prevalence and incidence of systemic lupus erythematosus in a population-based registry of American Indian and Alaska Native people, 2007-2009.Arthritis Rheumatol.2014;66(9):2494-2502.[4]Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality.Arthritis Care Res (Hoboken).2012;64(2):159-168.[5]Sattwika PD, Mustafa R, Paramaiswari A, Herningtyas EH. Stem cells for lupus nephritis: a concise review of current knowledge.Lupus.2018;27(12):1881-1897.Acknowledgments:The work was supported by SMART II Centre Grant (NMRC/CG/M011/2017_SGH) and SingHealth Foundation (SHF/FG638P/2016).Disclosure of Interests:None declared

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