? ? Neuropathy is one of the most common and debilitating complications occurring in patients suffering from type 1 diabetes (TID). Diabetic neuropathy has been assumed to be a consequence of chronic hyperglycemia rather than an autoimmune manifestation. However, mounting evidence suggests that the neuropathy that develops in T1D patients could have an autoimmune basis. The applicant's group reported that under certain conditions spontaneously autoimmune non-obese diabetic (NOD) mice developed a spontaneous autoimmune neuropathy affecting the peripheral nervous system (PNS). In addition, T cell responses and auto-antibodies directed at neural cell antigens have been found in both T1D patients and the NOD mouse. Therefore, the applicant hypothesizes that diabetic neuropathy can have an autoimmune basis in many patients, and proposes to use proteomics to examine whether autoantibodies specific for neural auto-antigens are detected in the serum in mouse models and diabetic patients. The following specific aims are proposed to address this hypothesis:
Specific aim #1 : To develop and validate an autoantigen array for the detection of auto-antibodies against the nervous system. This will be carried out by a modification of the current """"""""myelin"""""""" array to include proteins specifically expressed in the PNS.
Specific aim #2 : To develop mouse models aimed at defining autoantigens and study the relationship between T1D and autoimmune neuropathy. The applicant proposes to probe the array developed above with sera from different mouse models in order to identify autoantigens targeted in the neuropathy and determine how the auto-antibody repertoire against the PNS is influenced by autoimmune diabetes.
Specific aim #3 : To determine if auto-antibodies against neural antigens are present in diabetic patients using autoantigen arrays. They will evaluate whether auto-antibodies specific for neural antigens are present in the serum of patients with type 1 diabetes who suffer from different types of neuropathy. This approach is expected to assess the autoimmune basis of diabetic neuropathy as well as to define potential autoantigens in the nerves. These studies are expected to provide insights into the cellular mechanisms underlying diabetic neuropathy and potentially result in diagnostic tools and new therapeutic avenues for this debilitating disease. ? ?
