Associated TP22: Detection of novel neuronal autoantigens in Stiff-Person-Syndrome

Auto-antibodies (AAbs) to glutamic acid decarboxylases(GADs), the rate-limiting enzymes in the synthesis of the inhibitory neurotransmitter gamma-amino butyric acid (GABA), are reported to be presenting approximately 60–80% of patients with Stiff person syndrome (SPS). To this date, the pathogenic significance of these AAbs remains controversial; primarily because GADs are intracellular antigens and GAD65-antibody (GAD65-Ab)-positive patients  do not respond well to immunotherapy compared to those with antibodies against neuronal surface antigens. Additionally the antibodytiters do not directly correlate with the disease severity. Finally, no convincing animal model has been developed for SPS.

My project aims to identify a novel neuronal antigen that might play a pathogenic role in a cohort of SPS patients who may or may not respond to treatment with immunomodulatory regimes. In this study, recognized targets such as GAD-65 and -67 would be neutralized and characteristic signals from other novel AAbs would be studied using brain tissue from GAD-KO animals. Detection of such novel neuronal surface binding antibodies and their targets in SPS might provide a more favorable outcome, since such pathogenic targets might be amenable to immunotherapy (e.g., removal by plasma exchange). Early diagnosis and appropriate treatment might confer better prognosis compared to delayed therapy. Neural antibody testing on serum and CSF samples would help classify patients both prognostically (immunotherapy responsive or poor prognosis) and diagnostically (neurological / oncological).

In conclusion, GAD immunity plays an integral role in the development of SPS but it is vital to recognize novel cell-surface antibody targets and their effects on GABAergic neuronal functions, which might perhaps provide a basis for the phenotypic diversity.