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

Salvatore Benvenga; Alessandro Antonelli; Poupak Fallahi; Carmen Bonanno; Carmelo Rodolico; Fabrizio Guarneri

doi:10.1016/j.jcte.2021.100274

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

J Clin Transl Endocrinol. 2021 Nov 6:26:100274. doi: 10.1016/j.jcte.2021.100274. eCollection 2021 Dec.

Authors

Salvatore Benvenga^{1

2

3}, Alessandro Antonelli⁴, Poupak Fallahi⁴, Carmen Bonanno⁵, Carmelo Rodolico⁵, Fabrizio Guarneri⁶

Affiliations

¹ Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.
² Interdepartmental Program on Molecular and Clinical Endocrinology and Women's Endocrine Health, AOU Policlinico "G. Martino", Via Consolare Valeria 1, 98125 Messina, Italy.
³ Master Program on Childhood, Adolescent and Women's Endocrine Health, Via Consolare Valeria 1, 98125 Messina, Italy.
⁴ Department of Clinical and Experimental Medicine, University of Pisa, Via Paolo Savi 10, 56126 Pisa, Italy.
⁵ Neurology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.
⁶ Dermatology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.

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.