BACKGROUND: The simultaneous occurrence of bullous pemphigoid (BP) and multiple sclerosis (MS), two autoimmune diseases involving the skin and the central nervous system (CNS), respectively, has been described. OBJECTIVES: As the BPAG1 gene encodes the epithelial isoform of BP antigen 1 (BPAG1-e), a major autoantigen of BP, as well as additional variants expressed in the neurones of the CNS and peripheral nervous system and in Schwann cells, we tested the hypothesis that products of the BPAG1 gene act as shared autoantigens in both BP and MS. METHODS: The reactivity of cerebrospinal fluid (CSF) obtained from 18 patients with MS, 10 patients with other inflammatory CNS diseases and 20 normal controls was assayed by immunoblotting against two recombinant fragments of BPAG1-e encompassing regions that are also found in the neuronal variants BPAG1-n and BPAG1-a. RESULTS: The recombinant protein glutathione-S-transferase (GST)-BPAG1-e1-887 was recognized by five of 18 (27%) CSF samples obtained from patients with MS, two of 10 (20%) samples from patients with other inflammatory neurological diseases and five of 20 (25%) samples from normal controls. Furthermore, two of 18 (11%) CSF samples from patients with MS bound to GST-BPAG1-e1880-2649, whereas none of the samples obtained from patients with other inflammatory neurological diseases or from control subjects showed reactivity. CONCLUSIONS: These results raise the possibility that a subset of patients with MS develops an autoantibody response to the neuronal variants of BPAG1. These findings potentially open the avenue of neuronal BPAG1 variants being novel targets of autoantibodies in neurological diseases.