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Abstract
Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of spontaneously arising pathogenic TSHR antibodies in transgenic human thyrotropin receptor/NOD.H2h4 mice by injecting a non-pathogenic form of TSHR A-subunit protein also provides evidence for original antigenic sin. From other studies, antigen presentation by B cells, not dendritic cells, is likely responsible for original antigenic sin. Recognition of restricted epitopes on the large glycosylated thyroid autoantigens (60-kDa A-subunit, 100-kDa TPO, and 600-kDa Tg) facilitates exploring the amino acid locations in the immunodominant regions. Epitope spreading has also been revealed by autoantibodies in thyroid autoimmunity. In humans, and in mice that spontaneously develop autoimmunity to all three thyroid autoantigens, autoantibodies develop first to Tg and later to TPO and the TSHR A-subunit. The pattern of intermolecular epitope spreading is related in part to the thyroidal content of Tg, TPO and TSHR A-subunit and to the molecular sizes of these proteins. Importantly, the epitope spreading pattern provides a rationale for future antigen-specific manipulation to block the development of all thyroid autoantibodies by inducing tolerance to Tg, first in the autoantigen cascade. Because of its abundance, Tg may be the autoantigen of choice to explore antigen-specific treatment, preventing the development of pathogenic TSHR antibodies.
Highlights
The concept of “original antigenic sin” arose from findings in humans and mice infected with influenza virus [1, 2] and in mice responding to Chlamydia proteins [3]
It should be noted that a restricted antibody response focused on the thyroid peroxidase (TPO) IMMUNODOMINANT REGION (IDR) occurs in AKR/J-mice injected with cells expressing human TPO but not in mice of the same strain immunized with human TPO protein and adjuvant [46]
The evidence for intermolecular epitope spreading in thyroid autoimmunity is focused on autoantibodies, unlike the emphasis on T cell epitope spreading in multiple sclerosis and IDDM type 1
Summary
The concept of “original antigenic sin” arose from findings in humans and mice infected with influenza virus [1, 2] and in mice responding to Chlamydia proteins [3]. We present contrary evidence supporting the concept of an original antigenic sin component occurring for autoantibodies in thyroid autoimmunity and perhaps for other autoantibody-mediated diseases. A phenomenon interlinked with original antigenic sin is epitope spreading, a well-recognized feature of some autoimmune conditions such as type 1 diabetes mellitus and multiple sclerosis, as well as for the animal models of these diseases, namely NOD mice and experimental autoimmune encephalomyelitis (EAE). In type 1 diabetes that develops spontaneously in NOD mice, T cell recognition of islet autoantigens spreads from proinsulin to other islet autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [for example, Ref. We examine evidence involving thyroid autoantibodies for both intramolecular original antigenic sin and intermolecular epitope spreading in autoimmune thyroid disease. AUTOANTIBODY RECOGNITION IN HUMANS OF AN IMMUNODOMINANT REGION (IDR)—A REFLECTION OF ORIGINAL ANTIGENIC SIN
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