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.

Public Health Relevance

The Mamula laboratory has focused on understanding the biochemistry of posttranslational modifications of proteins and their effect on immune function, the topic of the present proposal. The goal of the proposal is to both identify and understand the interactions of novel protein modifications (PTMs) with NOD-like receptors (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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048120-14
Application #
9388938
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2000-09-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Harvey, Bohdan P; Raycroft, Maurice T; Quan, Timothy E et al. (2014) Transfer of antigen from human B cells to dendritic cells. Mol Immunol 58:56-65
Mamula, Mark J (2014) Editorial: B cells: not just making immunoglobulin anymore. Arthritis Rheumatol 66:2-5
Doyle, Hester A; Yang, Mei-Ling; Raycroft, Maurice T et al. (2014) Autoantigens: novel forms and presentation to the immune system. Autoimmunity 47:220-33
Yang, Mei-Ling; Gee, Alaric J P; Gee, Renelle J et al. (2013) Lupus autoimmunity altered by cellular methylation metabolism. Autoimmunity 46:21-31
Doyle, Hester A; Aswad, Dana W; Mamula, Mark J (2013) Autoimmunity to isomerized histone H2B in systemic lupus erythematosus. Autoimmunity 46:6-13
Doyle, Hester A; Mamula, Mark J (2012) Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr Opin Immunol 24:112-8
Harvey, Bohdan P; Quan, Timothy E; Rudenga, Benjamin J et al. (2008) Editing antigen presentation: antigen transfer between human B lymphocytes and macrophages mediated by class A scavenger receptors. J Immunol 181:4043-51