Key residues contributing to dominant conformational autoantigenic epitopes on thyroid peroxidase identified by mutagenesis

Biochemical and Biophysical Research Communications
Monika GoraJ P Banga

Abstract

Thyroid peroxidase (TPO) is a major autoantigen in thyroid autoimmune disease where pathogenic autoantibodies recognise conformational epitopes restricted to two overlapping immunodominant regions (IDR) termed IDR-A and -B. Based upon our structural model of TPO, we report on the localisation of the IDRs to specific amino acids important for autoantibody binding. Using a panel of recombinant human Fabs (rhFabs) from autoimmune patients, specific for the IDR-A or -B epitopes, in combination with eukaryotic expression of 14 single amino acid mutants of TPO, we identify R225 and K627 as key components of IDR-A and -B, respectively. Moreover, each mutant specifically led to the loss of binding of three different IDR-A- or -B-specific rhFabs, without affecting the binding of autoantibodies to the other determinant. Further supportive evidence for the role of amino acids R225 and K627 was obtained with murine monoclonal antibodies that first defined the IDRs. The identification of amino acids R225 and K627 as key residues for the IDR epitopes on TPO will advance our understanding of the molecular basis of autoreactivity and facilitate the design of novel therapeutic agents.

References

Nov 15, 1989·Biochemical and Biophysical Research Communications·J HataT Kotani
Jun 1, 1995·The Journal of Experimental Medicine·A Lanzavecchia
Mar 5, 1998·Clinical and Experimental Immunology·J GuoS M McLachlan
Oct 16, 1999·Autoimmunity·F Grennan JonesB Rees Smith
Sep 20, 2000·Redox Report : Communications in Free Radical Research·A GardasJ P Banga

❮ Previous
Next ❯

Citations

Apr 14, 2005·Best Practice & Research. Clinical Endocrinology & Metabolism·Mark F Prummel, Wilmar M Wiersinga
Mar 31, 2006·Thyroid : Official Journal of the American Thyroid Association·Salvatore BenvengaFabrizio Guarneri
Sep 8, 2007·Thyroid : Official Journal of the American Thyroid Association·Sandra M McLachlan, Basil Rapoport
Mar 17, 2005·Journal of Autoimmune Diseases·Damien BressonSylvie Péraldi-Roux
May 15, 2013·Thyroid : Official Journal of the American Thyroid Association·Marlena GodlewskaJ Paul Banga
Jun 1, 2006·International Immunology·Sandra A RebuffatSylvie Péraldi-Roux
Aug 16, 2005·Archives of Biochemistry and Biophysics·Jean Ruf, Pierre Carayon

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Thyroiditis

Autoimmune thyroiditis is an inflammatory disease of thyroid gland due to autoimmune responses leading to lymphocytic infiltration of the gland. It is characterized by the presence of circulating thyroid antigen-specific T-cells and thyroid autoantibodies. Discover the latest research on autoimmune thyroiditis here.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.