Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading

Kerry A. McLaughlin; Carolyn C. Richardson; Stefan Williams; Ezio Bonifacio; Diana Morgan; Richard G. Feltbower; Michael Powell; Bernard Rees Smith; Jadwiga Furmaniak; Michael R. Christie

doi:10.1016/j.clim.2015.06.002

Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading

Kerry A. McLaughlin, Carolyn C. Richardson, Stefan Williams, Ezio Bonifacio, Diana Morgan, Richard G. Feltbower, Michael Powell, Bernard Rees Smith, Jadwiga Furmaniak, Michael R. Christie^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Diversification of autoimmunity to islet autoantigens is critical for progression to Type 1 diabetes. B-cells participate in diversification by modifying antigen processing, thereby influencing which peptides are presented to T-cells. In Type 1 diabetes, JM antibodies are associated with T-cell responses to PTP domain peptides. We investigated whether this is the consequence of close structural alignment of JM and PTP domain determinants on IA-2. Fab fragments of IA-2 antibodies with epitopes mapped to the JM domain blocked IA-2 binding of antibodies that recognise epitopes in the IA-2 PTP domain. Peptides from both the JM and PTP domains were protected from degradation during proteolysis of JM antibody:IA-2 complexes and included those representing major T-cell determinants in Type 1 diabetes. The results demonstrate close structural relationships between JM and PTP domain epitopes on IA-2. Stabilisation of PTP domain peptides during proteolysis in JM-specific B-cells may explain determinant spreading in IA-2 autoimmunity.

Original language	English
Pages (from-to)	226-236
Number of pages	11
Journal	CLINICAL IMMUNOLOGY
Volume	160
Issue number	2
DOIs	https://doi.org/10.1016/j.clim.2015.06.002
Publication status	Published - 1 Oct 2015

Keywords

Autoantibody
Determinant spreading
Epitope
Monoclonal antibody
Type 1 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.clim.2015.06.002

Cite this

@article{8fce75fa0fbc4f35867aebc467cc0512,

title = "Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading",

abstract = "Diversification of autoimmunity to islet autoantigens is critical for progression to Type 1 diabetes. B-cells participate in diversification by modifying antigen processing, thereby influencing which peptides are presented to T-cells. In Type 1 diabetes, JM antibodies are associated with T-cell responses to PTP domain peptides. We investigated whether this is the consequence of close structural alignment of JM and PTP domain determinants on IA-2. Fab fragments of IA-2 antibodies with epitopes mapped to the JM domain blocked IA-2 binding of antibodies that recognise epitopes in the IA-2 PTP domain. Peptides from both the JM and PTP domains were protected from degradation during proteolysis of JM antibody:IA-2 complexes and included those representing major T-cell determinants in Type 1 diabetes. The results demonstrate close structural relationships between JM and PTP domain epitopes on IA-2. Stabilisation of PTP domain peptides during proteolysis in JM-specific B-cells may explain determinant spreading in IA-2 autoimmunity.",

keywords = "Autoantibody, Determinant spreading, Epitope, Monoclonal antibody, Type 1 diabetes",

author = "McLaughlin, {Kerry A.} and Richardson, {Carolyn C.} and Stefan Williams and Ezio Bonifacio and Diana Morgan and Feltbower, {Richard G.} and Michael Powell and {Rees Smith}, Bernard and Jadwiga Furmaniak and Christie, {Michael R.}",

year = "2015",

month = oct,

day = "1",

doi = "10.1016/j.clim.2015.06.002",

language = "English",

volume = "160",

pages = "226--236",

journal = "CLINICAL IMMUNOLOGY",

issn = "1521-6616",

publisher = "ACADEMIC PRESS INC",

number = "2",

}

TY - JOUR

T1 - Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes

T2 - Implications for determinant spreading

AU - McLaughlin, Kerry A.

AU - Richardson, Carolyn C.

AU - Williams, Stefan

AU - Bonifacio, Ezio

AU - Morgan, Diana

AU - Feltbower, Richard G.

AU - Powell, Michael

AU - Rees Smith, Bernard

AU - Furmaniak, Jadwiga

AU - Christie, Michael R.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Diversification of autoimmunity to islet autoantigens is critical for progression to Type 1 diabetes. B-cells participate in diversification by modifying antigen processing, thereby influencing which peptides are presented to T-cells. In Type 1 diabetes, JM antibodies are associated with T-cell responses to PTP domain peptides. We investigated whether this is the consequence of close structural alignment of JM and PTP domain determinants on IA-2. Fab fragments of IA-2 antibodies with epitopes mapped to the JM domain blocked IA-2 binding of antibodies that recognise epitopes in the IA-2 PTP domain. Peptides from both the JM and PTP domains were protected from degradation during proteolysis of JM antibody:IA-2 complexes and included those representing major T-cell determinants in Type 1 diabetes. The results demonstrate close structural relationships between JM and PTP domain epitopes on IA-2. Stabilisation of PTP domain peptides during proteolysis in JM-specific B-cells may explain determinant spreading in IA-2 autoimmunity.

AB - Diversification of autoimmunity to islet autoantigens is critical for progression to Type 1 diabetes. B-cells participate in diversification by modifying antigen processing, thereby influencing which peptides are presented to T-cells. In Type 1 diabetes, JM antibodies are associated with T-cell responses to PTP domain peptides. We investigated whether this is the consequence of close structural alignment of JM and PTP domain determinants on IA-2. Fab fragments of IA-2 antibodies with epitopes mapped to the JM domain blocked IA-2 binding of antibodies that recognise epitopes in the IA-2 PTP domain. Peptides from both the JM and PTP domains were protected from degradation during proteolysis of JM antibody:IA-2 complexes and included those representing major T-cell determinants in Type 1 diabetes. The results demonstrate close structural relationships between JM and PTP domain epitopes on IA-2. Stabilisation of PTP domain peptides during proteolysis in JM-specific B-cells may explain determinant spreading in IA-2 autoimmunity.

KW - Autoantibody

KW - Determinant spreading

KW - Epitope

KW - Monoclonal antibody

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=84938057757&partnerID=8YFLogxK

U2 - 10.1016/j.clim.2015.06.002

DO - 10.1016/j.clim.2015.06.002

M3 - Article

C2 - 26071317

AN - SCOPUS:84938057757

SN - 1521-6616

VL - 160

SP - 226

EP - 236

JO - CLINICAL IMMUNOLOGY

JF - CLINICAL IMMUNOLOGY

IS - 2

ER -

Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this