Reactivity to Novel Autoantigens in Patients with Coexisting Central Nervous System Demyelinating Disease and Autoimmune Thyroid Disease

Abstract

Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with coexistent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with coexisting CNS demyelinating disease and AITD were identified and their clinical and radiological features were recorded. Blood and DNA were collected and tested for HLA type and for the response of T cells and antibodies to a variety of antigens. Patients with multiple sclerosis (MS) without AITD and healthy individuals were included as controls. Patients with coexisting AITD and CNS demyelinating disease were almost exclusively female (43/44) and had prominent spinal cord involvement as the main neurological finding. The HLA molecules carried by individuals with CNS demyelinating disease and AITD differed from both other MS patients and healthy individuals. Furthermore, patients with both CNS disease and AITD showed less T cell reactivity than patients with MS alone to myelin proteolipid protein, but, compared to other groups, showed elevated levels of T cell reactivity to the calcitonin gene-related peptide, which is present in both the CNS and the thyroid, and elevated levels of T cell and antibody to the leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a molecule that is expressed in the brainstem and spinal cord, and which is a homolog of the thyroid-stimulating hormone receptor. We suggest that reactivity of autoreactive immune cells in these patients against antigens present in both the thyroid and the spinal cord is a potential mechanism underlying the pattern of lesion development in the CNS in patients with coexisting AITD and MS and might indicate a novel mechanism of disease pathogenesis in these patients.

Alemtuzumab-related thyroid disease in people with multiple sclerosis is associated with age and brainstem phenotype at disease onset

“…We hypothesise that use of alemtuzumab in pwMS induces immune reconstitution that can manifest with increased T-cell cross-reactivity between antigens or epitopes common to both the brainstem and the thyroid. 18 This concept of ‘spreading’ autoimmunity between the central nervous system (CNS) and extra-CNS locations is not new, 18 and may be seen in other clinical settings, the best example of which is the pathogenicity of anti-glutamic acid decarboxylase (GAD) antibodies in the development of type 1 diabetes and stiff person syndrome, due to recognition of different epitopes of the GAD65 isoform between patients with these two clinically distinct diseases. 19 Immune-mediated links between other pairings of neurological and thyroid disease have been reported.…”

“…However, 57.1% of MS patients with early brainstem involvement did not develop symptomatic GD with alemtuzumab therapy, likely because a strategic combination of additional contributory factors 6,8 is necessary for its manifestation. Furthermore, both MS and GD are associated with HLA-DRB*03, 18 and polymorphisms in T-cell-related genes CD226 and IL2RA. 26 Notably, timing of MS brainstem involvement may be an important contributory factor: while almost all alemtuzumab-treated pwMS in our cohort eventually developed brainstem lesions with subsequent MS relapses, only pwMS with early brainstem involvement, specifically at first clinical attack of MS, developed symptomatic GD.…”

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

“…As explained under Materials and Methods, we probed the literature for articles on the presence of serum autoantibodies against each of the thyroid autoantigen-homologous proteins in autoimmune diseases, including thyroid autoimmune diseases, by performing a PubMed search with the string “(autoanti* OR autoimm* OR autoreact*) AND” followed by the name of each protein and manually selecting relevant original papers [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] , [90] , [91] , [92] , [93] . As summarized in Table 4 , of the 46 CNS proteins homologous to TSH-R, 5 (11%; LGR4, chondroadherin, alpha-1A adrenergic receptor, Mu opioid receptor, and melanin-concentrating hormone receptor 1) were reported to stimulate autoAb, and in the following con...…”

“… Protein No. of articles Citations Results Leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) 1 Greer JM et al 2017 [38] Patients with both CNS disease and AITD have elevated levels of T cells and antibodies to LGR4, which is expressed in brainstem and spinal cord Chondroadherin 1 Mazzara S et al 2015 [39] Autoantibodies to chondroadherin are present in autoimmune hepatitis patients and could be used as diagnostic/prognostic markers Alpha-1A adrenergic receptor 2 Wenzel K et al 2008 [40] Agonistic autoantibodies to alpha-1A adrenergic receptor are present in patients with hypertension and are a possible cause of hypertension. Wenzel K et al 2010 [41] In a rat model, autoantibodies to alpha-1A adrenergic receptor may contribute to cardiovascular damage.…”

Migraine and thyroid dysfunction: Co‐occurrence, shared genes and biological mechanisms

“…A major calcitonin gene superfamily includes calcitonin, amylin, katacalcin, adrenomedullin and CGRP. CGRP levels have been reported to be upregulated in the diseased thyroid gland (hypothyroidism and hyperthyroidism) [103]. Also, CGRP is known to play an important role during migraine pain where an increase in its levels induces migraine attacks [104,105].…”