Document Detail


Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens.
MedLine Citation:
PMID:  21537078     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Apoptotic cells must be rapidly cleared, as defects in this process can lead to autoimmunity. Milk fat globule EGF factor 8 (MFG-E8) binds to apoptotic cells and facilitates their removal through interaction with phagocytes. Mice deficient in MFG-E8 develop lupus-like autoimmunity associated with accumulation of apoptotic cells in vivo. Here, we have shown that MFG-E8 controls phagocytic ingestion of cell fragments as well as their intracellular processing into MHC-antigen complexes. Older Mfge8-/- mice spontaneously developed dermatitis associated with CD8+ T cell infiltration and striking activation of effector memory CD8+ T cells. CD8+ T cell responses to both exogenous and endogenous apoptotic cell-associated antigens were enhanced in Mfge8-/- mice. MFG-E8 deficiency accelerated the onset of disease in a mouse model of autoimmune diabetes. Enhanced CD8+ T cell responses were attributed to increased cross-presentation by DCs along with increased detection of antigen-MHCI complexes. Intracellular trafficking analysis revealed that intact apoptotic cells ingested by wild-type DCs rapidly fused with lysosomes, whereas smaller fragments persisted in Mfge8-/- DC endosomal compartments for 24 hours. These observations suggest that MFG-E8 deficiency promotes immune responses to self antigens not only by delaying the clearance of dying cells but also by altering intracellular processing, leading to enhanced self-antigen presentation.
Authors:
YuFeng Peng; Keith B Elkon
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-02
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  121     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-02     Completed Date:  2011-08-17     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2221-41     Citation Subset:  AIM; IM    
Affiliation:
Division of Rheumatology, University of Washington, Seattle, Washington 98195, USA. pengyf@u.washington.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigen Presentation / immunology*
Antigens, Surface / genetics,  immunology,  physiology*
Apoptosis / immunology*
Autoantibodies / biosynthesis
Autoantigens / immunology*,  metabolism
Autoimmune Diseases / etiology,  genetics,  immunology,  pathology
Autoimmunity / genetics,  immunology*
Cells, Cultured / immunology
Dendritic Cells / immunology
Dermatitis / immunology,  pathology
Diabetes Mellitus, Type 1 / immunology,  pathology
Disease Models, Animal
Female
Immunoglobulin Class Switching
Immunoglobulin G / immunology
Immunologic Memory / immunology
Lupus Erythematosus, Systemic / immunology,  pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Milk Proteins / genetics,  immunology
Phagocytosis
Protein Transport / immunology*
T-Lymphocyte Subsets / immunology
Grant Support
ID/Acronym/Agency:
AR48796/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, Surface; 0/Autoantibodies; 0/Autoantigens; 0/Immunoglobulin G; 0/Mfge8 protein, mouse; 0/Milk Proteins
Comments/Corrections
Erratum In:
J Clin Invest. 2012 Feb 1;122(2):782

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


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