The Broad, Long Term Objective of the Stanford ACE is to serve as the leader within the ACE network in the development, implementation, and dissemination of multiplexed mechanistic assays for ACE trials. This proposal will develop 4 creative and novel techniques for mechanistic studies that can be transferred to our Human Immune Monitoring Center (HIMC, ACE Core B). As proof-of-principle, we propose to study B cells and antibodies in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Systemic Juvenile Idiopathic Arthritis (SJIA). Nevertheless, our new techniques can be used to study any autoimmune disease, and many cell types including monocytes and T lymphocytes. This flexibility should set the Stanford ACE apart from all other ACE sites. Most autoimmune diseases are associated with serum autoantibodies used to assist with diagnosis and prognostication. Critical questions remain in the field regarding the nature of the response to self. Do autoreactive B and T cells cause disease? Are autoantibodies and immune complexes (ICs) directly pathogenic, and if so which antigens drive disease? The overarching goal of the Stanford ACE proposal is to test the hypothesis that a subset of ICs are pathogenic in adult and pediatric rheumatic diseases, and that the mechanism(s) underlying their pathogenicity include cytokines, innate immune receptors (Fc receptors, Toll Like Receptors, TLRs), and signaling pathways mediated by JAK/STAT, NFKB, RORs, NFAT, IRFs, and other transcriptional regulators. We will take advantage of a rich repository of well characterized blood samples derived from patients with SLE, RA, and SJIA. We will test the hypothesis through further development of creative new technologies including protein and peptide arrays, B cell receptor sequencing, CyTOF, and an epigenomic assay called ATAC-Seq. We will disseminate assays to HIMC (ACE Core B) and other ACE sites, and will (i.) expand application of the technologies to additional human autoimmune diseases during the ACE funding period, (ii.) collaborate with other ACE investigators on their basic science projects, and (iii.) incorporate all 4 assays and Cores into the ACE Shared Research Agenda as mechanistic core assays for clinical trials.
Understanding the mechanistic underpinnings and pathogenesis of autoimmunity will improve the diagnosis and treatment of such diseases, facilitated by novel multiplexed assays developed by the Stanford ACE.
|Lee, Jung-Rok; Sato, Noriyuki; Bechstein, Daniel J B et al. (2016) Experimental and theoretical investigation of the precise transduction mechanism in giant magnetoresistive biosensors. Sci Rep 6:18692|
|Rosenberg, Jacob M; Price, Jordan V; Barcenas-Morales, Gabriela et al. (2016) Protein microarrays identify disease-specific anti-cytokine autoantibody profiles in the landscape of immunodeficiency. J Allergy Clin Immunol 137:204-13.e3|
|Lee, Jung-Rok; Bechstein, Daniel J B; Ooi, Chin Chun et al. (2016) Magneto-nanosensor platform for probing low-affinity protein-protein interactions and identification of a low-affinity PD-L1/PD-L2 interaction. Nat Commun 7:12220|
|Lee, Jung-Rok; Haddon, D James; Wand, Hannah E et al. (2016) Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus. Sci Rep 6:27623|
|Robinson, William H; Mao, Rong (2016) Biomarkers to guide clinical therapeutics in rheumatology? Curr Opin Rheumatol 28:168-75|
|Slight-Webb, Samantha; Lu, Rufei; Ritterhouse, Lauren L et al. (2016) Autoantibody-Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity. Arthritis Rheumatol :|
|Rasmussen, Tue Kruse; Andersen, Thomas; Bak, Rasmus OtkjÃ¦r et al. (2015) Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 production in systemic lupus erythematosus. Arthritis Res Ther 17:154|
|Robinson, William H; Mao, Rong (2015) Decade in review-technology: Technological advances transforming rheumatology. Nat Rev Rheumatol 11:626-8|
|Robinson, William H (2015) Sequencing the functional antibody repertoire--diagnostic and therapeutic discovery. Nat Rev Rheumatol 11:171-82|
|Kattah, Nicole H; Newell, Evan W; Jarrell, Justin Ansel et al. (2015) Tetramers reveal IL-17-secreting CD4+ T cells that are specific for U1-70 in lupus and mixed connective tissue disease. Proc Natl Acad Sci U S A 112:3044-9|
Showing the most recent 10 out of 17 publications