We propose a collaborative effort to identify epitopes presented by MHC-I and MHC-II proteins in the Alzheimer?s disease (AD) brain, and to determine whether or not these are targeted by infiltrating T cells. Comprehensive MHC immunopeptidomes will be determined for AD brains using fresh autopsy tissue, and the resulting peptide lists scanned for microbial antigens. Brain regions typically infiltrated by T cells in AD will be compared to unaffected regions, to identify microbial antigens possibly driving expansion and activation of inflammatory T cells. The overall goal of the proposed supplemental work is to characterize the MHC-presented peptidome of the brain during Alzheimer?s disease. This work fits within the two aims of the active research project ?Dynamics and tuning of MHCII-presented peptidomes? (R01-AI137198-02).
Specific Aim 1 of the active award is to identify qualitative and quantitative differences in the MHC II self-peptidome presented by local dendritic cells in different anatomical sites. High-density immunopeptidomes will be characterized by LC/MS/MS using methods that currently are being optimized in work underway in the active grant. We will isolate MHC-I and MHC-II bound peptides from diseased and healthy tissue from Alzheimer?s patients, searching for differences in antigen presentation in regions expected to be more affected in AD as compared to another region with minimal T cell infiltration. We will use a mouse model to test the immunogenicity of any identified antigens expressed specifically or preferentially in brain regions relevant to AD.
Specific Aim 2 of the active award is to understand the consequences of infection and inflammation on the self and foreign MHCII peptidome. We will search for epitopes derived from HHV-6A, HHV-7, and other microbial agents implicated in AD among the peptidomes identified in Alzheimer?s brain tissue samples. We will focus on HHV-6A, because of its known tropism for CD4 T cells, glia, and neurons, but other viral and bacterial pathogens also will be considered. Thus the proposed research will generate tools for a critical and rigorous look at potential linkages between AD, brain immunity, and microbial infection, and will help to validate the linkage between AD and HHV-6/7 established by bioinformatics approaches.
MHC II proteins bind peptides and present them to T cells as part of the system by which the immune system surveys the body for infection or malignancy. The major long term goal of our study is to determine how the set of MHC II-presented peptides help to maintaining tolerance to self and prevent autoimmunity.
|Santambrogio, Laura; Rammensee, Hans-Georg (2018) Contribution of the plasma and lymph Degradome and Peptidome to the MHC Ligandome. Immunogenetics :|