Association of stress proteins with autoantigens

A possible mechanism for triggering autoimmunity?

Anthony W. Purcell, A. Todd, G. Kinoshita, T. A. Lynch, C. L. Keech, M. J. Gething, T. P. Gordon

Research output: Contribution to journalArticleResearchpeer-review

45 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)193-200
Number of pages8
JournalClinical and Experimental Immunology
Volume132
Issue number2
DOIs
Publication statusPublished - 1 May 2003
Externally publishedYes

Keywords

  • Autoantibody
  • Epitope spreading
  • Grp78
  • Ro (SS-A)

Cite this

Purcell, Anthony W. ; Todd, A. ; Kinoshita, G. ; Lynch, T. A. ; Keech, C. L. ; Gething, M. J. ; Gordon, T. P. / Association of stress proteins with autoantigens : A possible mechanism for triggering autoimmunity?. In: Clinical and Experimental Immunology. 2003 ; Vol. 132, No. 2. pp. 193-200.
@article{530e56aec89d43eb81ab07cc87f3ab62,
title = "Association of stress proteins with autoantigens: A possible mechanism for triggering autoimmunity?",
abstract = "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.",
keywords = "Autoantibody, Epitope spreading, Grp78, Ro (SS-A)",
author = "Purcell, {Anthony W.} and A. Todd and G. Kinoshita and Lynch, {T. A.} and Keech, {C. L.} and Gething, {M. J.} and Gordon, {T. P.}",
year = "2003",
month = "5",
day = "1",
doi = "10.1046/j.1365-2249.2003.02153.x",
language = "English",
volume = "132",
pages = "193--200",
journal = "Clinical and Experimental Immunology",
issn = "0009-9104",
publisher = "Blackwell Science Ltd Oxford BSL",
number = "2",

}

Association of stress proteins with autoantigens : A possible mechanism for triggering autoimmunity? / Purcell, Anthony W.; Todd, A.; Kinoshita, G.; Lynch, T. A.; Keech, C. L.; Gething, M. J.; Gordon, T. P.

In: Clinical and Experimental Immunology, Vol. 132, No. 2, 01.05.2003, p. 193-200.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Association of stress proteins with autoantigens

T2 - A possible mechanism for triggering autoimmunity?

AU - Purcell, Anthony W.

AU - Todd, A.

AU - Kinoshita, G.

AU - Lynch, T. A.

AU - Keech, C. L.

AU - Gething, M. J.

AU - Gordon, T. P.

PY - 2003/5/1

Y1 - 2003/5/1

N2 - 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.

AB - 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.

KW - Autoantibody

KW - Epitope spreading

KW - Grp78

KW - Ro (SS-A)

UR - http://www.scopus.com/inward/record.url?scp=0038555742&partnerID=8YFLogxK

U2 - 10.1046/j.1365-2249.2003.02153.x

DO - 10.1046/j.1365-2249.2003.02153.x

M3 - Article

VL - 132

SP - 193

EP - 200

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

SN - 0009-9104

IS - 2

ER -