Characterization of Antigen-Specific Immune Response in ALS

Project Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) in the brain and spinal cord. The resulting clinical presentation is heterogeneous and exists on a spectrum ranging from pure motor involvement (ALS) to pure cognitive involvement (frontotemporal dementia; FTD) referred to as the ALS/FTD spectrum. Over the past decade, increasing lines of evidence have revealed a potential role for immunity in ALS pathophysiology; however, this association in the human system remains not well described. Mislocalization of TAR DNA-binding protein of 43kDa (TDP-43) in 97% of ALS cases, is a hallmark of ALS/FTD and leads to the generation of de novo peptides/proteins in the central nervous system (CNS). We posit that these de novo proteins, in addition to post-translationally modified ALS-specific aggregates, may be immunogenic and contribute to underlying disease pathophysiology. Furthermore, aberrant clonal T cell responses have been implicated in ALS pathogenesis, and ALS microglia are pro-inflammatory and have toxic effects on MNs. Here, we will leverage an unbiased approach to identify self- and non-self peptides/antigens presented to brain-infiltrated T cell responses in ALS/FTD. Our overall goal is to decode the immune landscape in the brain of sporadic and familial ALS patients and control subjects through the identification of the immunogenic proteins presented by major histocompatibility complex (MHC) class I molecule expressed on microglia, mapping of their recognition by cognate T cell receptors (TCRs) in ALS/FTD. While prior efforts in other diseases (e.g., type 1 diabetes) have spanned decades to link antigens to TCRs, this proposed studies in ALS/FTD will be catalyzed by the multi-disciplinary expertise of our interdisciplinary team. We have access to postmortem tissue from ALS patients and control subjects (n=30) as well as blood cells from living ALS patients and healthy controls (n=40). We will use these specimens to identify MHC-bound peptides/antigens in the ALS/FTD brain to characterize the phenotype and clonality of brain-recruited T cells in the blood of ALS patients. To decode the immune landscape in ALS, we will address the following questions: (i) which antigens are priming T cells in the ALS/FTD brain, (ii) what are the ALS-relevant antigen-TCR pairs, (iii) what is the phenotype of clonally-expanded T cells, and (iv) how can these ALS/FTD-specific antigen-TCR pairs inform our understanding of the disease pathogenesis and progression. Leveraging the immune system to halt and/or reduce the progression of ALS/FTD holds great promise. Our lack of precision in knowing which antigens and which TCRs are relevant for ALS/FTD is a key barrier to advancing precision immunotherapies, alongside those targeting cell-autonomous mechanisms of neurodegeneration.