Antigenome Signatures as Biomarkers for Subtyping Disease Heterogeneity in Lupus Patients
Abstract
Rationale, Objective and Aims: Lupus patients cannot receive the care they need without accurate diagnostics and some understanding of the diseases cause. Presently, one of the major clinical tests for lupus looks for molecules in patients blood (antibodies) that specifically bind target molecules (antigens). Specifically, doctors look for antibodies generated by the immune system that target molecules of the human body in an antinuclear antibody test (ANA). These ANA antibodies are found in many, but not all, lupus patients and may come and go throughout the course of disease. These antibodies can also be found in people who have other autoimmune diseases and in up to 20% of people who are healthy. The immune system makes quadrillions of antibody molecules that bind millions of different antigens. The proposed studies will examine ANA antibodies and identify the human proteins they recognize to determine whether these antibodies contribute to disease. Despite ANA tests being the most commonly prescribed immunology assay, a single patient sample may yield conflicting results when measured by different manufacturers test kits. Such inconsistencies are particularly detrimental to patients, as new therapies and eligibility for clinical trials are increasingly restricted to patients with positive ANA test results. Thus, better understanding how these clinical tests work at a molecular level and identifying the self-antigens that antibodies bind will enable better patient diagnosis, treatment, and care. The goal of these studies is to revolutionize how lupus is both diagnosed and understood by systematically defining the antigens that antibodies target in individual patients, enabling personalized medicine. The most advanced techniques generally available are capable of assessing only a few antibody-targeted antigens at a time. However, a newly developed cutting-edge technology enables the simultaneous assessment of the ~20,000 proteins found in the human body. This technology can enable the correlation of exactly which proteins are targeted by antibodies in patients with certain shared symptoms or disease features. Moreover, the antibodies that lead to positive or negative results in clinical test kits can be identified comprehensively, enabling the development of better diagnostics. A definitive means of classifying lupus patients as truly ANA-positive or ANA-negative may also allow the discovery of protein targets that identify ANA-negative lupus patients. Lupus-specific antibodies may also be identified in all or subsets of lupus patients that are not found in patients with other autoimmune diseases or healthy individuals. This analysis could reveal antibodies that either predict or cause lupus specifically, empowering the development of better tests to conclusively diagnose lupus and guide the treatment of disease specifically in each patient. Projects Relationship to Lupus Research Program Focus Areas: These studies will use a novel technology to identify markers for progressive stages of lupus, map lupus heterogeneity among patients, subtype patients, and may enable personalized medicine-based treatments through a better understanding of disease mechanisms. Research Applicability: The proposed research is imminently applicable to lupus patients at every phase of disease, from diagnosis to effective treatment. For instance, this study may identify antibody targets that allow patients at early stages of diagnosis to know definitively whether they have lupus or another autoimmune disease. Antibody targets may be identified that enable doctors to predict disease course or anticipate relapse in established lupus patients. Furthermore, the data produced may reveal antibody markers that indicate which patient subsets are likely to respond to specific therapies, advancing personalized medicine. Importantly, our results may also lead to the development of improved test kits so that patients interested in entering
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910639
Entities
People
- Thomas Tedder
Organizations
- Duke University
- United States Army