Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis

Abstract

A few patients with Hashimoto's thyroiditis or Graves' disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto's encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis. Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases. Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.

Keywords: AChR, acetylcholine receptors; AD, Alzheimer disease; AKRIAI, aldehyde reductase-I; ALS, amyotrophic lateral sclerosis; AT, autoimmune thyroiditis; BBB, blood-brain barrier; BLAST, Basic Local Alignment Search Tool; Bioinformatics; CCP, complement control protein; DDAHI, dimethylargininase-I; EGF, epidermal growth factor; GD, Graves' disease; GPCR, G protein-coupled receptors; Graves’ disease; HE, Hashimoto’s encephalopathy; HT, Hashimoto’s thyroiditis; Hashimoto’s encephalopathy; LRR, leucine-rich repeats; MG, myasthenia gravis; MuSK, muscular tyrosin kinase receptors; NMJ, neuromuscular junction; SREAT, steroid-responsive encephalopathy associated with autoimmune thyroiditis; TAb, anti-thyroid antibodies; Thyroglobulin; Thyroperoxidase; Thyrotropin receptors.

Fig. 1

Illustrative examples of amino acid sequence homologies between CNS proteins and TSH-R, Tg and TPO (top, middle and bottom panel, respectively). Epitopes of the three thyroid autoantigens are underlined.

Fig. 2

Homologies between CNS-expressed proteins and TSH-R. Segments in black represent single homologous sequences, segments in gray represent the cumulative span of multiple, overlapping homologous sequences of the same protein.

Fig. 3

Homologies between CNS-expressed proteins and Tg. Segments in black represent single homologous sequences, segments in gray represent the cumulative span of multiple, overlapping homologous sequences of the same protein.

Fig. 4

Homologies between CNS-expressed proteins and TPO. Segments in black represent single homologous sequences, segments in gray represent the cumulative span of multiple, overlapping homologous sequences of the same protein.