Several lines of evidence suggest a definite and unique link between central nervous system (CNS) demyelinating diseases and autoimmune thyroid diseases (AITD). Some molecules targeted by the immune system in AITD have related family members expressed in the CNS. One example is the thyroid-stimulating hormone receptor (TSHR), the target of autoantibodies in Grave's (hyperthyroid) disease, which belongs to the same family as leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), which is highly expressed in the brainstem and spinal cord. In the current study we investigated immunoreactivity directed against TSHR and LGR4, and other features of disease in 44 patients with co-existing CNS demyelinating disease and AITD (28 hypothyroid and 16 hyperthyroid patients), compared to patients with CNS demyelinating disease alone or healthy individuals.
Patients with co-existing AITD and CNS demyelinating disease were almost exclusively female, and hyperthyroid patients were significantly more likely to have developed AITD prior to the onset of CNS disease than were patients with hypothyroidism. Blood and DNA were collected and tested for the HLA type and the response of T cells and antibodies to TSHR and LGR4. HLA molecules carried by patients with coexisting CNS demyelinating disease and AITD differed from both other CNS demyelinating disease patients and healthy individuals, with the most different group being patients with co-existing autoimmune hyperthyroidism preceding the onset of CNS demyelinating disease. Patients with co-existing CNS demyelinating disease and hyperthyroidism showed elevated levels of antibody and T cell reactivity to LGR4 and TSHR compared to the other groups.
We suggest that, in patients with co-existing CNS demyelinating disease and hyperthyroidism, CNS disease may develop as a direct consequence of spreading of disease from the thyroid to the CNS or vice-versa, due to cross-reactivity between TSHR and LGR4.