Sera of elderly bullous pemphigoid patients with associated neurological diseases recognize bullous pemphigoid antigens in the human brain

Background: Bullous pemphigoid (BP) is an acquired autoimmune dermatosis that is often associated with various neurological diseases (ND) in the elderly. Previously, we reported that BP antigen 1 (BPAG1) of the mouse brain can be recognized by serum samples of BP patients with ND (BP+ND), indicating the possibility that BPAG1 could act as a shared autoantigen of the skin and brain. However, it is not known whether the serum of BP+ND patients could recognize BPAG1 in the human brain. Objectives: The aim of this study is to determine whether sera of BP+ND patients could recognize BP antigens in human brain tissue. Methods: Serum samples of BP+ND patients and those of age- and sex-matched BP patients without ND, ND patients without BP, and normal controls were obtained. Serum samples were examined by immunoblotting against protein extracts of human skin and brain. Results: A 230-kDa protein of human epidermal extract was recognized by 16 of 22 (72.7%) serum samples of elderly BP+ND patients, whereas it was recognized by 50, 0, and 0% of serum samples of BP, ND, and controls, respectively. A 230-kDa protein of human brain extract was recognized by 12 of 22 (54.5%) serum samples of BP+ND patients, whereas it was recognized by 9.1, 9.1, and 4.5% of serum samples of BP, ND, and controls, respectively. A 180- and a 165-kDa protein could also be recognized by a proportion of serum samples of BP and BP+ND patients. Conclusion: This study demonstrated that both human skin and brain contain immunogenic BPAG1 in BP+ND patients. We speculate that alterations of the central nervous system in the course of pathological changes of elderly ND patients could expose the neural isoforms of BPAG1 or other BP antigens. Autoantibodies against these antigens in the brain may cross-react with antigen in the skin, which may underlie the pathological development of BP.