Document Detail


T-cell and B-cell signaling biomarkers and treatment targets in lupus.
MedLine Citation:
PMID:  19550330     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE OF REVIEW: Systemic lupus erythematosus is characterized by the production of antinuclear autoantibodies and dysfunction of T-cells, B-cells, and dendritic cells. Here, we review newly recognized genetic factors and mechanisms that underlie abnormal intracellular signal processing and intercellular communication within the immune system in systemic lupus erythematosus. RECENT FINDINGS: Activation of the mammalian target of rapamycin plays a pivotal role in abnormal activation of T and B-cells in systemic lupus erythematosus. In T-cells, increased production of nitric oxide and mitochondrial hyperpolarization were identified as metabolic checkpoints upstream of mammalian target of rapamycin activation. Mammalian target of rapamycin controls the expression T-cell receptor-associated signaling proteins CD4 and CD3zeta through increased expression of the endosome recycling regulator HRES-1/Rab4 gene, mediates enhanced Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B-cells, and blocks the expression of Foxp3 and the expansion of regulatory T-cells. Mitochondrial hyperpolarization and the resultant ATP depletion predispose T-cells to necrosis, thus promoting the dendritic cell activation, antinuclear autoantibody production, and inflammation. SUMMARY: Mitochondrial hyperpolarization, increased activity of mammalian target of rapamycin and Syk kinases, enhanced receptor recycling and Ca2+ flux have emerged as common T and B-cell biomarkers and targets for treatment in systemic lupus erythematosus.
Authors:
Andras Perl; David R Fernandez; Tiffany Telarico; Edward Doherty; Lisa Francis; Paul E Phillips
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Current opinion in rheumatology     Volume:  21     ISSN:  1531-6963     ISO Abbreviation:  Curr Opin Rheumatol     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-08-13     Completed Date:  2009-11-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9000851     Medline TA:  Curr Opin Rheumatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  454-64     Citation Subset:  IM    
Affiliation:
Division of Rheumatology, Department of Medicine, State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York 13210, USA. perla@upstate.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
B-Lymphocytes / immunology*,  metabolism
Biological Markers / metabolism
Calcium Signaling
Endocytosis
Humans
Lupus Erythematosus, Systemic / immunology*,  metabolism,  therapy
Mitochondria / metabolism
Models, Biological
Oxidative Stress
Protein Kinases / metabolism
Receptors, Antigen, B-Cell / metabolism
Signal Transduction
T-Lymphocytes / immunology*,  metabolism
rab4 GTP-Binding Proteins / metabolism
Grant Support
ID/Acronym/Agency:
AI 048079/AI/NIAID NIH HHS; AI 061066/AI/NIAID NIH HHS; AI 072648/AI/NIAID NIH HHS; AR056957/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Receptors, Antigen, B-Cell; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein; EC 3.6.5.2/rab4 GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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