Immunoprofiling of Diabetic and Nondiabetic Lumbosacral Radiculoplexus Neuropathy
Abstract
Lumbosacral radiculoplexus neuropathy (LRPN) is a form of non-systemic vasculitis more commonly encountered among patients with type 2 diabetes mellitus. Among patients with diabetes mellitus, it is also referred to as diabetic lumbosacral radiculoplexus neuropathy (DLRPN) or diabetic amyotrophy. Epidemiology studies have demonstrated that incidence of diabetic and non-diabetic LRPN is more than twice the incidence of Guillain-Barré syndrome or chronic immune polyradiculoneuropathy, highlighting importance of early identification and management of this disease. The diagnosis of these neuropathies continues to be based on clinical evaluation, and many cases require nerve biopsy. As most patients initially presents with abrupt severe unilateral leg pain, many are misdiagnosed as nerve root compression due to disc herniation or degenerative spine disease, leading to unnecessary back surgeries. Even among patients who are correctly diagnosed, it is difficult to predict the disease course and identify a subset of individuals who are going to have disease relapse. There exists, therefore, a critical need to identify blood biomarkers that can be utilized for diagnosis as well as long-term outcome prediction. Without such biomarkers, LRPN/DLRPN diagnostics will continue to challenge many physicians, and many cases may end being misdiagnosed. We will use a library of bacteriophages expressing all known human proteins (phage display) to evaluate presence of disease-specific antibodies in patients. Careful analysis of autoantibody repertoires with this novel technique provides an opportunity to identify an antibody signature for LRPN/DLRPN detection (diagnosis) and a distinct antibody signature to inform disease outcome or treatment response (prognosis). We will compare these readouts across different neuropathy types in addition to comparisons with healthy individuals. The antibodies identified through phage display will be carefully evaluated through other techniques as well, to confirm their sensitivity and specificity. Based on the analysis of LRPN/DLRPN nerve biopsies, this autoimmune neuropathy appears to be mediated by inflammatory cells. Therefore, we will also evaluate autoantigen-specific cell-mediated immune responses among a subset of patients, by culturing the patients’ lymphocytes and antigen-presenting cells in the presence of the proteins targeted by their autoantibodies, as identified through phage display. Our studies of autoantibody signature identification and/or autoantigen specific T-cell response should also yield immediately translatable data with therapeutic significance. For example, data from our T-cell studies could also support the development of targeted therapeutic approaches such as CAR-T cells directed against specific autoreactive T-cell receptors. Our laboratory has a strong track record in antibody biomarker discovery over the past two decades including paraneoplastic neuropathy biomarkers such as CRMP5. We have utilized technologies such as phage display to identify novel antibody biomarkers associated with unique autoimmune or paraneoplastic syndromes such as kelch-like protein 11 KLHL11, leucine zipper 4 LUZP4, and neurofilament-light chain IgG. We have also successfully demonstrated autoantigen specific T-cell responses among a subset of these conditions such as KLHL11 and LUZP4. We have the necessary infrastructure, expertise, and patient samples to carry out this unique project. Our long-term goal is to develop an understanding of immune mechanisms that contribute to the development and progression of LRPN/DLRPN.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310100
Entities
People
- Divyanshu Dubey
Organizations
- Mayo Clinic
- United States Army