Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?
Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.
Purcell
A W
AW
Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia. apurcell@unimelb.edu.au
Todd
A
A
Kinoshita
G
G
Lynch
T A
TA
Keech
C L
CL
Gething
M-J
MJ
Gordon
T P
TP
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000378:metabolism*; D015551:Autoimmunity / Q000502:physiology*; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D019084:Fluorescent Antibody Technique, Indirect; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D018832:Molecular Chaperones / Q000378:metabolism; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D000099207:SS-A Antigen
D001323:Autoantibodies; D001324:Autoantigens; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D020733:RNA, Small Cytoplasmic; D012261:Ribonucleoproteins; D000099207:SS-A Antigen; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C116006:RO60 protein, human; C492050:Ssa2 protein, mouse