OspA and autoimmunity in chronic Lyme disease

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DESCRIPTION (provided by applicant): Infection with the Lyme disease spirochete Borrelia burgdorferi can involve multiple tissues. The neurologic complications target the central and peripheral nervous systems and usually respond to antibiotic treatment. Some patients, however, have persistent neurologic deficits despite treatment and in the absence of obvious infection, suggesting a possible role for autoimmunity in the pathogenesis of chronic Lyme disease. Recent reports of occurrence of similar neurologic syndromes following vaccination with the B. burgdorferi outer surface protein A (OspA) in some patients provide support for the autoimmune hypothesis, and point to OspA as a possible culprit. In our preliminary studies, we found that antibodies generated against an OspA peptide, corresponding to a human brain cDNA sequence, to strongly immunostain human brain pyramidal neurons, spinal cord motor neurons, and dorsal root ganglia sensory neurons. In addition, sera from 3 of 6 patients whose neurologic symptoms began shortly after vaccination with OspA, but not from 6 control subjects, were found to have elevated antibody titers against the same peptide. We now propose to identify the cross-reactive protein and to determine if immune reactivity to it is associated with the chronic neurologic sequelae in Lyme disease. The specific aims of this project are: 1) to identify and characterize the putative cross-reactive neural protein, 2) to determine whether the presence of antibodies to the cross-reactive neural antigen is associated with neurologic deficits in chronic Lyme disease, and 3) to determine whether patients with antibiotic resistant chronic Lyme disease and neurological deficits exhibit T-cell reactivity to the peptide or protein. If the findings of the study support a role for autoimmunity in chronic neuroborreliosis, it would shed new light on the pathogenesis of the neurological complications and provide a rationale for clinical trials using immunomodulatory agents in this group of patients. Identification of specific immune reactivity to an autoantigen might also be useful as a diagnostic marker and for monitoring of disease activity in affected patients.