COOH-terminal clustering of autoantibody and T-cell determinants on the structure of GAD65 provide insights into the molecular basis of autoreactivity

Diabetes
Gustavo FenaltiMerrill J Rowley

Abstract

To gain structural insights into the autoantigenic properties of GAD65 in type 1 diabetes, we analyzed experimental epitope mapping data in the context of the recently determined crystal structures of GAD65 and GAD67, to allow "molecular positioning" of epitope sites for B- and T-cell reactivity. Data were assembled from analysis of reported effects of mutagenesis of GAD65 on its reactivity with a panel of 11 human monoclonal antibodies (mAbs), supplemented by use of recombinant Fab to cross-inhibit reactivity with GAD65 by radioimmunoprecipitation of the same mAbs. The COOH-terminal region on GAD65 was the major autoantigenic site. B-cell epitopes were distributed within two separate clusters around different faces of the COOH-terminal domain. Inclusion of epitope sites in the pyridoxal phosphate-and NH(2)-terminal domains was attributed to the juxtaposition of all three domains in the crystal structure. Epitope preferences of different mAbs to GAD65 aligned with different clinical expressions of type 1 diabetes. Epitopes for four of five known reactive T-cell sequences restricted by HLA DRB1*0401 were aligned to solvent-exposed regions of the GAD65 structure and colocalized within the two B-cell epitope clusters. The continuo...Continue Reading

References

Sep 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·W RichterW A Scherbaum
Jan 1, 1985·Annual Review of Immunology·J A TainerR A Lerner
May 1, 1995·The Journal of Experimental Medicine·P Panina-BordignonF Sinigaglia
Nov 1, 1996·Journal of Internal Medicine·A Lernmark
Dec 30, 1996·Clinica Chimica Acta; International Journal of Clinical Chemistry·M PowellJ Furmaniak
Jul 22, 1997·Proceedings of the National Academy of Sciences of the United States of America·S D PatelG Sonderstrup-McDevitt
Feb 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·G T NepomB S Nepom
Feb 23, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Deepak T NairDinakar M Salunke
Jul 5, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Juan Carlos JaumeSteinunn Baekkeskov
Jan 4, 2003·Nature Reviews. Immunology·Paul H Plotz
Jul 17, 2003·Clinical Immunology : the Official Journal of the Clinical Immunology Society·M E PrimoM R Ermácora
Oct 15, 2003·The Journal of Clinical Endocrinology and Metabolism·Tetsuro KobayashiAke Lernmark
Sep 28, 2004·Diabetes·F Susan WongMark J Shlomchik
Nov 18, 2004·Autoimmunity Reviews·Ian R Mackay, Merrill J Rowley
Dec 22, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sonia QuaratinoMarco Londei
Nov 23, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Raghavanpillai RajuChristiane S Hampe
Jun 1, 2006·Proteins·Arun S KonagurthuArthur M Lesk
Jun 7, 2006·Proceedings of the National Academy of Sciences of the United States of America·Didrik Paus, Greg Winter
Sep 20, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jun YanMark J Mamula
Mar 27, 2007·Nature Structural & Molecular Biology·Gustavo FenaltiJames C Whisstock

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Citations

Feb 27, 2013·Applied Physiology, Nutrition, and Metabolism = Physiologie Appliquée, Nutrition Et Métabolisme·Joachim Nielsen, Niels Ørtenblad
Apr 16, 2011·PloS One·Bindu JayakrishnanMerrill J Rowley
Jun 2, 2009·Psychosomatic Medicine·Lisa L BarnesDenis A Evans
Jun 26, 2009·Psychosomatic Medicine·Anastasia GeorgiadesRichard S Surwit
Mar 28, 2008·Proceedings of the National Academy of Sciences of the United States of America·Shilpa OakChristiane S Hampe
Nov 28, 2012·La Presse médicale·Christian Boitard
Jun 14, 2015·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Kerry A McLaughlinMichael R Christie
Sep 29, 2009·Journal of Immunological Methods·Shilpa OakChristiane S Hampe
May 26, 2009·Autoimmunity Reviews·Gustavo Fenalti, Ashley M Buckle
Jun 3, 2008·Journal of Autoimmunity·Gustavo Fenalti, Merrill J Rowley
Jul 26, 2011·Clinical & Developmental Immunology·Roberto MalloneChristian Boitard
Sep 29, 2009·Molecular Immunology·Yasir ArafatAshley M Buckle
May 20, 2008·Diabetes Care·Taro MaruyamaChristiane S Hampe
May 29, 2015·F1000Research·Wei JiangElizabeth D Mellins
Nov 28, 2007·Immunology and Cell Biology·Ian R Mackay
Apr 8, 2017·Journal of Immunology Research·Hiroshi MitomaChristiane S Hampe
Sep 26, 2017·Cerebellum & Ataxias·Hiroshi MitomaChristiane S Hampe
Apr 16, 2021·Therapeutic Advances in Neurological Disorders·Popianna TsiortouMarinos C Dalakas

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