Post Translational Modifications in Tolerance and Autoimmunity

Yale University, New Haven CT

Investigators

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Abstract

DESCRIPTION (provided by applicant): One major function of the immune system is to discriminate between self and non-self tissues, cells, and proteins. Our laboratory has focused on understanding the biochemistry of posttranslational modifications (PTMs) of proteins and their effect on immune function, the topic of the present proposal. It is known that between 50 and 90% of the proteins in the human body acquire posttranslational modification (PTMs). PTMs alter many aspects of protein chemistry, including primary and tertiary structure, biological (and/or enzymatic) functions, and proteolytic degradation that may be critical in generating immunogenic or tolerogenic self-peptides. Studies from the Mamula lab illustrate that PTMs can create new self-antigens by altering immunologic processing and presentation. While many protein modifications exist, the present work will focus on those created, amplified, or altered in the context of inflammation in models of SLE. These observations are superimposed on recent studies showing that innate immune receptors are critical in the development of lupus autoimmunity. For example, both foreign pathogen components (PAMPS) as well as modified self-proteins (Damage Associated Molecular Patterns; DAMPS) will activate both Toll Like Receptor (TLR) and NOD Like Receptor (NLR) pathways. Moreover, the pathogenesis in lupus creates an inflammatory milieu that favors the generation of posttranslational modifications that may become DAMPS. The goal of the proposal is to both identify and understand the interactions of novel protein modifications with NLRs and in inflammatory pathways of SLE in both murine models and in human disease. Overall, we will identify and examine the effects of inflammation-mediated PTMs on immunogenicity, intracellular signaling pathways, and the development of lupus autoimmunity. A clear goal of the present work is to not only identify unique markers of inflammation, but also to identify potential therapeutic pathways, including PTM repair pathways, that may alter the course of disease.