Acquired immune-mediated polyneuropathies, both the acute form (Guillain Barre Syndrome; GBS) and the chronic form (Chronic Inflammatory Demyelinating Polyneuropathy; CIDP) represent a diagnostic challenge for two reasons. Recent advances in treatment strategies offer significant benefit to such patients. The hypothesis underlying this research is that identification of specific targets of autoantibodies in CIDP and GBS will provide a better understanding of the immune pathogenesis of these diseases and a useful serum marker for diagnosis, prognosis, and treatment. While both the humoral and cellular immune systems have been implicated in the pathogenesis of these diseases, recent research supports the primary role of humoral immune system in the pathogenesis. We have recently identified human beta-tubulin as a potential antigenic target in CIDP and GBS. We plan to define the target epitope/s on beta-tubulin in serum of patients with CIDP and GBS. Serums will be tested for antibody binding against peptide fragments of human beta-tubulin using ELISA methodology. Next, the epitopes on beta-tubulin that react with induced antibodies arising after immunization with beta-tubulin will be studied using the same methodology.
The third aim i s to study a large cohort of clinically well characterized CIDP and GBS patients and correlated clinical features of the patients with anti beta-tubulin antibodies. Both a retrospective study and prospective study will address presence and degree of antibody binding to beta-tubulin and correlate this with age, sex, duration of illness, modalities involved, degree of weakness, and response to treatment.
The final aim will ask if natural anti beta-tubulin antibodies are pathogenic. Patient IgM or IgG will be passively transferred systemically to mice. In a second model, patient sera will be injected locally into rat sciatic nerve. Animals will be studied electrophysiologically and nerves evaluated morphologically.
| Connolly, A M; Chez, M G; Pestronk, A et al. (1999) Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr 134:607-13 |
| Connolly, A M; Pestronk, A; Mehta, S et al. (1998) Primary alpha-sarcoglycan deficiency responsive to immunosuppression over three years. Muscle Nerve 21:1549-53 |
| Connolly, A M; Pestronk, A; Mehta, S et al. (1997) Serum IgM monoclonal autoantibody binding to the 301 to 314 amino acid epitope of beta-tubulin: clinical association with slowly progressive demyelinating polyneuropathy. Neurology 48:243-8 |
| Connolly, A M; Pestronk, A; Planer, G J et al. (1996) Congenital muscular dystrophy syndromes distinguished by alkaline and acid phosphatase, merosin, and dystrophin staining. Neurology 46:810-14 |
