scholarly journals Stochastic models of receptor oligomerization by bivalent ligand

2006 ◽  
Vol 3 (9) ◽  
pp. 545-559 ◽  
Author(s):  
Tomás Alarcón ◽  
Karen M Page
Keyword(s):  
Stochastic Models ◽  
Cellular Response ◽  
Cell Activation ◽  
Design Principle ◽  
Ligand Concentration ◽  
Bivalent Ligand ◽  
Oligomer Formation ◽  
Receptor Oligomerization ◽  
Stochastic Fluctuations

In this paper, we develop stochastic models of receptor binding by a bivalent ligand. A detailed kinetic study allows us to analyse the role of cross-linking in cell activation by receptor oligomerization. We show how oligomer formation could act to buffer intracellular signalling against stochastic fluctuations. In addition, we put forward the hypothesis that formation of long linear oligomers increases the range of ligand concentration to which the cell is responsive, whereas formation of closed oligomers increases ligand concentration specificity. Thus, different physiological functions requiring different degrees of specificity to ligand concentration would favour formation of oligomers with different lengths and geometries. Furthermore, provided that ligand concentration specificity is taken as a design principle, our model enables us to estimate parameters, such as the minimum proportion of receptors, that must engage in oligomer formation in order to trigger a cellular response.

The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1507-1514 ◽  
Author(s):  
Nathalie Satta ◽  
Sylvie Dunoyer-Geindre ◽  
Guido Reber ◽  
Richard J. Fish ◽  
Francoise Boehlen ◽  
...  
Keyword(s):  
Antiphospholipid Antibodies ◽  
Cellular Response ◽  
Cell Activation ◽  
Inflammatory Marker ◽  
Wild Type Mouse ◽  
Mouse Fibroblast ◽  
Mrna Levels ◽  
Wild Type ◽  
Mediate Cell

Abstract Antiphospholipid antibodies (APLAs) promote inflammatory and procoagulant responses in endothelial cells and monocytes. Previous studies have shown that MyD88, TRAF6, and NF-κB mediate cell activation by APLAs. These intermediates are also used by toll-like receptors (TLRs). We investigated the role of TLRs in the cellular response to APLAs. IgGs were isolated from the plasma of 5 patients with antiphospholipid syndrome along with immunopurified anti–β2-glycoprotein 1 IgG from a sixth patient. Control IgG was obtained from a pool of healthy donor plasmas negative for APLAs. Wild-type mouse embryonic fibroblasts (EFs) and EFs deficient in TLR1, TLR2, TLR4, or TLR6 were incubated with APLAs, anti–β2-glycoprotein 1 IgG, or control IgG. On incubation with the patient IgG, but not control IgG, a significant increase in mRNA levels of the inflammatory marker proteins MCP-1, ICAM-1, and IL-6 as well as IL-6 secretion was observed in wild-type EFs, whereas TLR2-deficient EFs did not respond. Responses in TLR1- and TLR6-deficient EFs were decreased and those in TLR4-deficient EFs comparable to those in wild-type EFs. Overexpression of human TLR2 in the TLR2-deficient EFs restituted the response to patient IgG. Our results imply that TLR2 plays a role in mouse fibroblast activation by APLAs.

scholarly journals Fluctuations in TCR and pMHC interactions regulate T cell activation

2021 ◽  
Author(s):  
Joseph R. Egan ◽  
Tim Elliott ◽  
Ben D. MacArthur
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Information Theoretic ◽  
Histocompatibility Complex ◽  
Copy Numbers ◽  
Stochastic Fluctuations ◽  
Antigen Presenting

ABSTRACTAdaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major-histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs) respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR clustering. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell per se that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.

CD38 as an immunomodulator in cancer

2020 ◽  
Vol 16 (34) ◽  
pp. 2853-2861
Author(s):  
Yanli Li ◽  
Rui Yang ◽  
Limo Chen ◽  
Sufang Wu
Keyword(s):  
Multiple Myeloma ◽  
Cell Activation ◽  
Human Tissues ◽  
Transmembrane Glycoprotein ◽  
Cell Activation Marker ◽  
Research Findings ◽  
A Cell ◽  
And Function ◽  
Human Molecule

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

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 Oxidized LDLs as Signaling Molecules

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1184
Author(s):  
Jean-Marc Zingg ◽  
Adelina Vlad ◽  
Roberta Ricciarelli
Keyword(s):  
Free Radicals ◽  
Cellular Response ◽  
Vascular System ◽  
Signaling Molecules ◽  
Scavenger Receptors ◽  
Physiological Relevance ◽  
Reactive Radicals ◽  
Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

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