Autoimmune rheumatologic diseases

Thematic

Increased Levels of Sputum Antibodies to a Subset of Citrullinated Peptide Antigens Correlate with Sputum Neutrophil Extracellular Trap Levels in Subjects At-Risk for Future RA

Friday, June 16
2:05 PM - 2:20 PM

Background: Our previous studies have identified anti-citrullinated protein/peptide antibodies (ACPA) generated in the lung in individuals with established RA and individiuals who are at-risk for RA suggesting that the lung could be a site of initiation of RA-related autoimmunity. Neutrophil extracellular trap (NET) formation is one potential mechanism that could trigger ACPAs because NETs externalize citrullinated proteins and release peptidylarginine deiminase. Herein, we explored associations between NETs and individual ACPAs in the lungs from subjects At-Risk for RA.


Methods: We studied 24 subjects At-Risk for future RA based on familial or serologic risk factors. Blood and induced sputum were tested for ACPAs using a bead-based array with 29 individual citrullinated proteins/peptides. Levels of NET complexes were measured by a DNA-myeloperoxidase (MPO) and DNA-neutrophil elastase (NE) sandwich ELISA. Using Bonferonni's correction, results were significant if p < 0.002 for DNA-MPO and DNA-NE.


Results: In At-Risk subjecs, increasing sputum NET levels significantly correlated with 27/29 ACPA levels. The strongest associations (p≤0.001) were cit-H2A/a21-20, cit-vimentin58-77cyclic, cit-alpha-enolase5-21, cit-fibrinogen27-43, cit-fibrinogen211-230cyclic, cit-fibrinogen616-635cyclic, cit-fibrinogenB54-72, and cit-apolipoprotein E277-269cyclic. No significant correlation was seen between NET and individual ACPA levels in the blood.


Conclusions: In subjects At-Risk for RA, we identified a strong correlation between levels of sputum NET complexes and multiple ACPAs. Importantly, these associations were not present in serum. Therefore, these findings suggest that NET formation in the lung may be associated with the local mucosal production of multiple ACPA reactivities. Additional studies are needed to determine if NET-associated cit-proteins are an initial trigger or a self-perpetuating stimulus of sputum ACPA generation.


Send Email for Kristen Demoruelle

Monica Purmalek

National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health

Presentation(s):

Send Email for Monica Purmalek

Nickie Seto

National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health

Presentation(s):

Send Email for Nickie Seto

Send Email for Emily Bowers

Send Email for Jill Norris

Send Email for Michael Holers

William H. Robinson

Associate Professor
Stanford University

Dr. Robinson is an Associate Professor of Medicine at Stanford University, and a Staff Physician at VA Palo Alto. The Robinson laboratory works in the fields of B cell biology, autoimmunity and inflammation. Dr. Robinson pioneered development of protein arrays, lipid arrays, and most recently high-throughput sequencing approaches to identify the targets of antibody responses, investigate mechanisms underlying disease, and to develop novel therapeutic approaches. Dr. Robinson is the Director of the Stanford Osteoarthritis Initiative, PI of the NIH Stanford AMP Technology Center, and Co-Director of the Stanford-UCSF Arthritis Foundation Center of Excellence. He co-founded the Stanford Human Immune Monitoring Center, serves on the editorial boards of several journals, and serves on the Board of Directors of the American College of Rheumatology. He is an inventor on 23 patent applications, and technologies developed in his Stanford and VA laboratories have been licensed to nine companies in the biotechnology industry. Dr. Robinson was elected to the American Society for Clinical Investigation and the Henry Kunkel Society. Dr. Robinson received his MD and PhD degrees from Stanford University, and completed his clinical training in internal medicine at UCSF.

Presentation(s):

Send Email for William Robinson

Mariana J. Kaplan

Senior Investigator and Chief, Systemic Autoimmunity Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health

Mariana J. Kaplan, MD is Senior Investigator and Chief of the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Dr. Kaplan's research has focused on identifying mechanisms of organ damage and premature vascular disease in systemic autoimmunity. More specifically, she investigates how innate immunity promotes end-organ damage in systemic lupus erythematosus, rheumatoid arthritis and other systemic autoimmune diseases. Recently, her research has focused on identifying abnormalities of neutrophil subsets and the role of neutrophil extracellular traps (NETs) in lupus, vasculitis and rheumatoid arthritis, both of which may contribute to the development of autoimmune responses and to end-organ damage. Dr. Kaplan also has an interest in identifying novel therapeutic targets that may prevent premature vascular damage in systemic autoimmunity, as well as the role of environmental triggers in the induction of autoimmunity. Moreover, she has led clinical trials to identify mechanisms that reduce blood vessel dysfunction in autoimmune and chronic inflammatory disorders.

Presentation(s):

Send Email for Mariana Kaplan

Send Email for Kevin Deane


Assets

Increased Levels of Sputum Antibodies to a Subset of Citrullinated Peptide Antigens Correlate with Sputum Neutrophil Extracellular Trap Levels in Subjects At-Risk for Future RA



Attendees who have favorited this

Send Email for Increased Levels of Sputum Antibodies to a Subset of Citrullinated Peptide Antigens Correlate with Sputum Neutrophil Extracellular Trap Levels in Subjects At-Risk for Future RA