NOD Mice Exocrinopathy: Towards a Neuroimmune Link

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Abstract

Sjögren’s syndrome (SS) is a chronic autoimmune disorder of exocrine glands characterized as an autoimmune exocrinopathy and more specifically as an autoimmune epithelitis. An impaired balance of neuroimmune interactions mediated by vasoactive intestinal peptide (VIP) in the target organ at early stages of disease is explored by means of the nonobese diabetic (NOD) mouse model of SS. We have previously described a reduced salivary secretion and signaling upon VIP stimulation. The effect reflected a differential regulation of the neural isoform of nitric oxide synthase by calcium calmodulin kinase II and occurred prior to the appearance of detectable levels of cytokines in NOD glands. VIP acting on NOD macrophages treated with lipopolysaccharide promoted anti-inflammatory effects by inhibiting nitric oxide synthase induction as well as IL-12 and TNF-α production, while stimulating IL-10. Here we present evidence on the ability of apoptotic acinar cells from submandibular glands of NOD mice to stimulate nitric oxide in both peritoneal and glandular macrophage pools to a similar extent as lipopolysaccharide + IFN-γ. VIP was not effective to prevent nitrite accumulation and modestly increased IL-10 levels in macrophages coincubated with acinar cells. An enhanced nitrite response of NOD glandular macrophages in basal and stimulated conditions compared to peritoneal cells is also shown.

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The phosphatidylserine receptor: a crucial molecular switch?

V Fadok, Donna L. Bratton, Sian M Henson (2001)

The uptake and removal of necrotic or lysed cells involves inflammation and an immune response, due in part to processes that involve members of the collectin family, surface calreticulin and CD91. Clearance of apoptotic cells, by contrast, does not induce either inflammation or immunity. Could the phosphatidylserine receptor be the molecular switch that determines what the outcome will be?

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VIP-PACAP system in immunity: new insights for multitarget therapy.

A Arranz, C. Martinez Rivero, C. Abad … (2006)

Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti-inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti-inflammatory factors. These effects were reported both in vitro and in vivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection- and the autoimmunity-induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll-like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.

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Early pathogenic events associated with Sjögren's syndrome (SjS)-like disease of the NOD mouse using microarray analysis.

Jin-Xiong She, Richard A. McIndoe, Ken Nguyen … (2006)

Recently, we reported development of the C57BL/6.NOD-Aec1Aec2 mouse carrying two genetic intervals derived from the NOD mouse. These two genetic regions confer full Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. The current study was undertaken to apply microarray technology to define the molecular basis underlying onset of SjS-disease in C57BL/6.NOD-Aec1Aec2 mice. Using oligonucleotide microarrays, gene expression profiles of submandibular glands derived from 8- to 12-week-old C57BL/6.NOD-Aec1Aec2 mice and 8-week-old C57BL/6 mice were performed for comparison. Significant differential expressions were determined using the Mann-Whitney U test. Hybridizations using submandibular cDNA probes revealed 75 differentially expressed genes at 8 weeks and 105 differentially expressed genes at 12 weeks of age in C57BL/6.NOD-Aec1Aec2 mice compared to 8-week-old C57BL/6 mice. These genes were related generally to basic cellular activities such as transcription, translation, DNA replication, and protein folding. During the predisease phase, genes upregulated encode proteins associated with the IFN-gamma signal-transduction-pathway (Jak/Stat1), TLR-3 (Irf3 and Traf6) and apoptosis (casp11 and casp3), indicative of chronic proinflammatory stimuli, especially IL-1. Between 8 and 12 weeks of age, sets of clustered genes were upregulated that are associated with adaptive immune responses, especially B cell activation, proliferation and differentiation (Baffr, Taci, Bcma, Blys, April, CD70, CD40L, Traf1, Traf3, Pax5, c-Jun, Elk1 and Nf-kB), and neural receptors (Taj/Troy). Altered gene expressions of TLR3 and TNF-superfamily-receptors and ligands during this early phase of SjS suggest a possible viral etiology in the altered glandular homeostasis with an upregulated, possibly overstimulated, B-lymphocyte activation in the early autoimmune response present in the submandibular glands. The importance of NF-kappaB as a critical signal transduction pathway is also suggested but its link is not yet clear.

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Author and article information

Journal

Journal ID (publisher-id): NIM

Journal ID (nlm-ta): Neuroimmunomodulation

Journal ID (doi): 10.1159/issn.1021-7401

Title: Neuroimmunomodulation

Publisher: S. Karger AG

ISBN: 978-3-8055-8463-0

ISBN: 978-3-8055-8464-7

ISSN (Print): 1021-7401

ISSN (Electronic): 1423-0216

Publication date Subscription-year: 2007

Publication date (Print): December 2007

Publication date (Electronic): 05 December 2007

Volume: 14

Issue: 3-4

Pages: 175-181

Affiliations

Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina

Article

Publisher ID: 110643 Other ID: Neuroimmunomodulation 2007;14:175–181

DOI: 10.1159/000110643

PubMed ID: 18073511

SO-VID: 94348693-1154-4270-b33c-e94a6c9d892d

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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NOD Mice Exocrinopathy: Towards a Neuroimmune Link

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Most cited references 15

The phosphatidylserine receptor: a crucial molecular switch?

VIP-PACAP system in immunity: new insights for multitarget therapy.

Early pathogenic events associated with Sjögren's syndrome (SjS)-like disease of the NOD mouse using microarray analysis.

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