Considerable experience has been accumulated in my laboratory to use immunological approaches to study the chemical composition of neurofibrillary tangles, a major lesion in senile dementia of Alzheimer type (SDAT). Recently, we have established 563 B cell lines by Epstein Barr Virus (EBV) transformation from the blood of four patients with a clinical diagnosis of SDAT. Preliminary studies by immunofluorescence and ABC immunocytochemistry show that some of these cell lines secrete autoantibodies reactive with neurofibrillary tangles and other neuronal components. These represent the first autoantibodies which have been shown to be reactive with neurofibrillary tangles. We wish to test the hypothesis that autoimmunity plays a certain role in the pathogenesis of SDAT and to utilize the autoantibodies to explore further the composition of neurofibrillary tangles.
Five specific aims are proposed. (1) Establish EBV transformed B cell lines from patients with SDAT, age-matched normal controls, post-stroke patients and normal young individuals. These experiments intend to ascertain frequencies of autoantibodies specific for selective groups of neurons, neurofibrillary tangles and related structures in these four groups. Autoantibodies unique to SDAT patients will also be determined. (2) Clone interesting cell lines which secrete autoantibodies and identify their reactive antigens with established immunocytochemical and serological approaches. (3) Make mouse or rat monoclonal antibodies to isolated neurofibrillary tangles. Those specific for tangles will be identified and used for comparison with studies with the human autoantibodies derived from SDAT patients. (4) Establish EBV transformed B cell lines from spouses of SDAT patients and from unaffected members of selected families with a history of familial SDAT. The demonstration of autoantibodies of interest in family members will provide clues to the relative importance of environmental vs genetic factors in SDAT. (5) Make mouse or rat monoclonal anti-idiotypic antibodies against human autoantibodies specific for or preferentially reactive with neurofibrillary tangles and related structures. These monoclonal anti-V region antibodies will be used to stain autopsied brain from SDAT patients in an attempt to demonstrate specific Ig depositation in the lesions, i.e. senile plaques. This approach will provide direct evidence for the role of these autoantibodies in the pathogenesis of SDAT. The proposed studies will provide information regarding the pathogenesis and diagnosis of SDAT as well as a rationale for significant possible new therapeutic approaches.
