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Thyroid Autoantibodies Display both "Original Antigenic Sin" and Epitope Spreading
Sandra M McLachlan1, Basil Rapoport1
1Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States.
Frontiers in Immunology
|January 13, 2018
Summary
Original antigenic sin drives thyroid autoimmunity by autoantibodies targeting specific regions of thyroglobulin, thyroid peroxidase, and TSHR. This phenomenon, where initial immune responses shape future reactions, offers targets for blocking autoimmune development.
Area of Science:
- Immunology
- Endocrinology
- Autoimmunity
Background:
- Spontaneous thyroid autoimmunity involves autoantibodies against thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit.
- Original antigenic sin (OAS) describes how initial immune responses influence subsequent antibody production, potentially impacting autoimmune disease progression.
Purpose of the Study:
- To investigate evidence of original antigenic sin in spontaneous thyroid autoimmunity.
- To explore the phenomenon of epitope spreading in the development of thyroid autoantibodies.
- To identify potential targets for antigen-specific immunotherapy to prevent thyroid autoimmunity.
Main Methods:
- Analysis of autoantibody interactions with immunodominant regions of Tg, TPO, and TSHR A-subunit.
- Studies in transgenic mice (TSHR A-subunit/NOD.H2) to assess the impact of non-pathogenic TSHR A-subunit on pathogenic TSHR antibodies.
- Observation of autoantibody development patterns (Tg, TPO, TSHR A-subunit) in humans and autoimmune mice.
Main Results:
- Autoantibodies in spontaneous thyroid autoimmunity preferentially recognize immunodominant regions on Tg, TPO, and TSHR A-subunit, consistent with OAS.
- Recognition of these specific epitopes persists despite fluctuations in autoantibody levels.
- Experimental enhancement of pathogenic TSHR antibodies by non-pathogenic TSHR A-subunit further supports OAS.
- Epitope spreading observed, with autoantibodies developing sequentially against Tg, then TPO and TSHR A-subunit.
Conclusions:
- Original antigenic sin plays a significant role in shaping the autoantibody response in spontaneous thyroid autoimmunity.
- The pattern of epitope spreading suggests a cascade initiated by thyroglobulin.
- Targeting thyroglobulin (Tg) for antigen-specific immunotherapy could potentially prevent the development of pathogenic antibodies against TPO and TSHR, offering a novel therapeutic strategy.