Autoimmune rheumatologic diseases

No Preference

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
6:15 PM - 7:30 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.


Kristen Demoruelle


University of Colorado School of Medicine

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    Monica Purmalek

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

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      Nickie Seto

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

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        Emily Bowers

        University of Colorado School of Medicine

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          Jill M. Norris

          Colorado School of Public Health

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            Michael Holers

            University of Colorado School of Medicine

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              William H. Robinson

              Stanford University; VA Palo Alto Health Care System

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                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.

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                  Kevin Deane

                  University of Colorado School of Medicine

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                    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



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