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Results: 11 to 20 of 35

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Role of the adaptive immune system in hypertension.
Harrison DG, Vinh A, Lob H, Madhur MS
(2010) Curr Opin Pharmacol 10: 203-7
MeSH Terms: Adaptive Immunity, Animals, Antigens, Humans, Hypertension, Models, Immunological, T-Lymphocytes
Show Abstract · Added December 10, 2013
Recent studies have shown that both innate and adaptive immunity contribute to hypertension. Inflammatory cells, including macrophages and T cells accumulate in the vessel wall, particularly in the perivascular fat, and in the kidney of hypertensive animals. Mice lacking lymphocytes are resistant to the development of hypertension, and adoptive transfer of T cells restores hypertensive responses to angiotensin II and DOCA-salt challenge. Immune modulating agents have variable, but often-beneficial effects in ameliorating end-organ damage and blood pressure elevation in experimental hypertension. The mechanisms by which hypertension stimulates an immune response remain unclear, but might involve the formation of neoantigens that activate adaptive immunity. Identification of these neoantigens and understanding how they form might prove useful in the prevention and treatment of this widespread and devastating disease.
Copyright 2010 Elsevier Ltd. All rights reserved.
2 Communities
1 Members
0 Resources
7 MeSH Terms
Accounting for chance in the calculus of autoimmune disease.
Moore DJ
(2010) Med Hypotheses 74: 289-93
MeSH Terms: Autoimmune Diseases, Humans, Immunity, Innate, Models, Immunological, Models, Statistical, Stochastic Processes
Show Abstract · Added October 24, 2013
Discussions around the etiology of autoimmune disease routinely focus on the interplay between genes and the environment. In turn, efforts to ameliorate these diseases seek to modify genetic and environmental factors. However, there may be a third element that also accounts for the progression of autoimmunity. This article explores the role of chance, exemplified by the stochastic process of immune repertoire generation, in the evolution of autoimmunity. The presented modeling studies and concepts suggest that chance plays as significant a role as genes or environment. This hypothesis implies that a full understanding of the role of genes and environment will also require investigators to account for stochastic processes in building comprehensive disease models.
0 Communities
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6 MeSH Terms
A spatial model of tumor-host interaction: application of chemotherapy.
Hinow P, Gerlee P, McCawley LJ, Quaranta V, Ciobanu M, Wang S, Graham JM, Ayati BP, Claridge J, Swanson KR, Loveless M, Anderson AR
(2009) Math Biosci Eng 6: 521-46
MeSH Terms: Antineoplastic Agents, Computer Simulation, Docetaxel, Endothelial Cells, Humans, Models, Immunological, Neoplasms, Neovascularization, Pathologic, Taxoids, Vascular Endothelial Growth Factor A
Show Abstract · Added February 18, 2013
In this paper we consider chemotherapy in a spatial model of tumor growth. The model, which is of reaction-diffusion type, takes into account the complex interactions between the tumor and surrounding stromal cells by including densities of endothelial cells and the extra-cellular matrix. When no treatment is applied the model reproduces the typical dynamics of early tumor growth. The initially avascular tumor reaches a diffusion limited size of the order of millimeters and initiates angiogenesis through the release of vascular endothelial growth factor (VEGF) secreted by hypoxic cells in the core of the tumor. This stimulates endothelial cells to migrate towards the tumor and establishes a nutrient supply sufficient for sustained invasion. To this model we apply cytostatic treatment in the form of a VEGF-inhibitor, which reduces the proliferation and chemotaxis of endothelial cells. This treatment has the capability to reduce tumor mass, but more importantly, we were able to determine that inhibition of endothelial cell proliferation is the more important of the two cellular functions targeted by the drug. Further, we considered the application of a cytotoxic drug that targets proliferating tumor cells. The drug was treated as a diffusible substance entering the tissue from the blood vessels. Our results show that depending on the characteristics of the drug it can either reduce the tumor mass significantly or in fact accelerate the growth rate of the tumor. This result seems to be due to complicated interplay between the stromal and tumor cell types and highlights the importance of considering chemotherapy in a spatial context.
3 Communities
1 Members
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10 MeSH Terms
Infectious antigens may play a role in the pathogenesis of sarcoidosis.
Drake W
(2008) Medscape J Med 10: 288
MeSH Terms: Antigens, Fungal, Humans, Models, Immunological, Mycobacterium, Sarcoidosis
Added May 27, 2014
0 Communities
1 Members
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5 MeSH Terms
The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.
Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE
(2008) Nat Med 14: 748-55
MeSH Terms: Animals, Boronic Acids, Bortezomib, Lupus Erythematosus, Systemic, Mice, Mice, Inbred BALB C, Mice, Inbred MRL lpr, Mice, Inbred NZB, Models, Immunological, Nephritis, Ovalbumin, Plasma Cells, Protease Inhibitors, Proteasome Inhibitors, Pyrazines, Time Factors
Show Abstract · Added September 17, 2013
Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.
0 Communities
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16 MeSH Terms
Autoepitopes and alloepitopes of type IV collagen: role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis.
Borza DB
(2007) Nephron Exp Nephrol 106: e37-43
MeSH Terms: Anti-Glomerular Basement Membrane Disease, Autoantibodies, Collagen Type IV, Epitope Mapping, Glomerular Basement Membrane, Glomerulonephritis, Humans, Immunity, Innate, Isoantibodies, Models, Immunological
Show Abstract · Added August 21, 2013
Anti-glomerular basement membrane (anti-GBM) antibodies elicited by autoimmune or alloimmune mechanisms are associated with aggressive forms of rapid progressive glomerulonephritis. Pathogenic anti-GBM autoantibodies and alloantibodies target the noncollagenous (NC1) domains of the alpha3alpha4alpha5(IV) collagen, a major GBM component. In autoimmune anti-GBM glomerulonephritis, a breakdown of immune self-tolerance leads to the activation of autoreactive B and T cells recognizing epitopes within the alpha3NC1 subunit. In the GBM, the conformational epitopes targeted by anti-GBM autoantibodies are structurally sequestered within the alpha3alpha4alpha5NC1 hexamer complex formed upon assembly of collagen IV chains into trimeric molecules and networks. Autoantibodies selectively bind to and dissociate a subset of alpha3alpha4alpha5NC1 hexamers composed of monomer subunits, whereas hexamers containing NC1 dimer subunits are resistant to dissociation by autoantibodies. The crypticity of alpha3NC1 autoepitopes suggests that self-tolerance to alpha3(IV) collagen is broken by structural alterations of the native alpha3alpha4alpha5NC1 hexamer that unmask normally sequestered epitopes, triggering an autoimmune reaction. Post-transplant anti-GBM nephritis in the renal allograft of transplanted Alport patients is mediated by an alloimmune reaction to the NC1 domains of alpha3alpha4alpha5(IV) collagen, present in the allograft GBM but absent from Alport basement membranes. Alloantibodies from patients with autosomal-recessive Alport syndrome predominantly bind to the alpha3NC1 domain, whereas alloantibodies from X-linked Alport patients target preferentially, though not exclusively, epitopes within the alpha5NC1 subunit. The accessibility of the alloantigenic sites within the alpha3alpha4alpha5NC1 hexamers, contrasting with the crypticity of autoantigenic sites, suggest that different molecular forms of alpha3alpha4alpha5(IV) collagen initiate the immunopathogenic responses in the two forms of anti-GBM disease. Advances in elucidating the structure of the GBM antigen and the identification of the pathogenic B and T cell epitopes, along with new insights into the pathogenic mechanisms at cellular and molecular level will facilitate the development of targeted strategies for prevention, detection, and treatment of human anti-GBM antibody glomerulonephritis.
Copyright 2007 S. Karger AG, Basel.
0 Communities
1 Members
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10 MeSH Terms
NKT cells: T lymphocytes with innate effector functions.
Van Kaer L
(2007) Curr Opin Immunol 19: 354-64
MeSH Terms: Animals, Antigen Presentation, Antigens, CD1, Antigens, CD1d, Cell Differentiation, Cytotoxicity, Immunologic, Humans, Killer Cells, Natural, Lymphocyte Activation, Models, Immunological, T-Lymphocytes, Cytotoxic
Show Abstract · Added December 10, 2013
Natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens in the context of the MHC class I-related glycoprotein CD1d. Recent studies have identified multiple ways in which NKT cells can become activated during microbial infection. Mechanisms of CD1d-restricted antigen presentation are being unraveled, and a surprising connection has been made to proteins that control lipid metabolism and atherosclerosis. It appears that several microorganisms have developed strategies to interfere with the CD1d antigen-presentation pathway. New studies have also provided important insight into the mechanisms that control effector cell differentiation of NKT cells and have revealed specialized functions of distinct NKT cell subsets. Finally, there is continued enthusiasm for the development of NKT cell-based therapies of human diseases.
0 Communities
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11 MeSH Terms
Reciprocal regulation between natural killer cells and autoreactive T cells.
Shi FD, Van Kaer L
(2006) Nat Rev Immunol 6: 751-60
MeSH Terms: Animals, Autoimmunity, Cell Communication, Cytotoxicity, Immunologic, Humans, Killer Cells, Natural, Lymphocyte Activation, Models, Immunological, T-Lymphocytes
Show Abstract · Added December 10, 2013
The initiation and the progression of autoimmune diseases stem from complex interactions that involve cells of both the innate and the adaptive immune system. As we discuss here, natural killer (NK) cells, which are components of the innate immune system, can inhibit or promote the activation of autoreactive T cells during the initiation of autoimmunity. After they have been activated, autoreactive T cells contribute to the homeostatic contraction of NK-cell populations. The dynamic interaction between NK cells and autoreactive T cells might indicate the transition from the innate immune triggering of autoimmunity to the progressive phase of the disease. Understanding the mechanisms and signals that control the reciprocal regulation of NK cells and autoreactive T cells could have important implications for treatment in the clinic.
0 Communities
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9 MeSH Terms
Altered CXCR2 signaling in beta-arrestin-2-deficient mouse models.
Su Y, Raghuwanshi SK, Yu Y, Nanney LB, Richardson RM, Richmond A
(2005) J Immunol 175: 5396-402
MeSH Terms: Animals, Arrestins, Cell Movement, Epithelium, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Immunological, Neutrophils, Receptors, Interleukin-8B, Signal Transduction, Wound Healing, Wounds and Injuries, beta-Arrestin 2, beta-Arrestins
Show Abstract · Added May 30, 2013
CXCR2 is a G-protein-coupled receptor (GPCR) that binds the CXC chemokines, CXCL1-3 and CXCL5-8, and induces intracellular signals associated with chemotaxis. Many adaptor proteins are actively involved in the sequestration, internalization, and trafficking of CXCR2 and transduction of agonist-induced intracellular signaling. We have previously shown that adaptor protein beta-arrestin-2 (betaarr2) plays a crucial role in transducing signals mediated through CXCR2. To further investigate the role of betaarr2 on CXCR2-mediated signaling during acute inflammation, zymosan-induced neutrophils were isolated from peritoneal cavities of betaarr2-deficient (betaarr2(-/-)) and their wild-type (betaarr2(+/+)) littermate mice, and neutrophil CXCR2 signaling activities were determined by measurement of Ca(2+) mobilization, receptor internalization, GTPase activity, and superoxide anion production. The results showed that the deletion of betaarr2 resulted in increased Ca(2+) mobilization, superoxide anion production, and GTPase activity in neutrophils, but decreased receptor internalization relative to wild-type mice. Two animal models, the dorsal air pouch model and the excisional wound healing model, were used to further study the in vivo effects of betaarr2 on CXCR2-mediated neutrophil chemotaxis and on cutaneous wound healing. Surprisingly, the recruitment of neutrophils was increased in response to CXCL1 in the air pouch model and in the excisional wound beds of betaarr2(-/-) mice. Wound re-epithelialization was also significantly faster in betaarr2(-/-) mice than in betaarr2(+/+) mice. Taken together, the data indicate that betaarr2 is a negative regulator for CXCR2 in vivo signaling.
2 Communities
1 Members
0 Resources
16 MeSH Terms
NK cells promote islet allograft tolerance via a perforin-dependent mechanism.
Beilke JN, Kuhl NR, Van Kaer L, Gill RG
(2005) Nat Med 11: 1059-65
MeSH Terms: Animals, Antibodies, Monoclonal, CD11a Antigen, CD40 Antigens, CD40 Ligand, CD8-Positive T-Lymphocytes, Graft Survival, Histocompatibility Antigens Class I, Immune Tolerance, Immunotherapy, Intercellular Adhesion Molecule-1, Islets of Langerhans Transplantation, Killer Cells, Natural, Major Histocompatibility Complex, Membrane Glycoproteins, Mice, Mice, Knockout, Models, Animal, Models, Immunological, Perforin, Phenotype, Pore Forming Cytotoxic Proteins, Transplantation, Homologous
Show Abstract · Added December 10, 2013
Although major histocompatibility complex (MHC) class II-restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I-dependent reactivity in this process. Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell-dependent immunity. Rather, tolerance required innate immunity involving NK1.1(+) cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.
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23 MeSH Terms