Objectives The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE.
Methods Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models.
Results In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification).
Conclusions Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.
- Systemic Lupus Erythematosus
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Handling editor Tore K Kvien
Contributors MEM, TBN, GCT, MPK, JBH and JAJ designed the study. MEM, JRA, TG, JMR, BFB, TBN and JAJ participated in data acquisition. MEM, RL, JRA, DAF, JMR, YDZ, TBN, JBH and JAJ participated in data analysis. All authors assisted with the development of the manuscript and gave final approval for publication. MEM, RL, JMR and JAJ had full access to data for the study. JAJ had the final responsibility for the decision to submit for publication.
Funding Research reported in this publication was supported by the National Institute of Allergy, Immunology and Infectious Diseases, Office of Research on Women's Health, National Institute of General Medical Sciences and the National Institute of Arthritis, Musculoskeletal and Skin Diseases under award numbers U01AI101934, U19AI082714, U54GM104938, P30GM103510, P30AR053483 and S10RR026735. This material is also the result of work supported with resources and the use of facilities through the Department of Veterans Affairs. Additional support was provided by the National Institute of Allergy, Immunology and Infectious Diseases and National Institute of Arthritis, Musculoskeletal and Skin Diseases under award numbers AI071651 and AR060861 (TBN). JBH would like to acknowledge support from the US Department of Veterans Affairs and NIH grants U01HG006828, UL1TR000077, R37AI024717, R21AI103980, P01AI083194 and P01AI049084.
Disclaimer This publication is the sole responsibility of the authors and does not represent the views of the National Institutes of Health or the Department of Veterans Affairs. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of the Army, US Armed Forces Department of Defense, or the US Government.
Competing interests None declared.
Ethics approval Experiments were performed in accordance with the Helsinki Declaration and approved by the Institutional Review Boards of the Oklahoma Medical Research Foundation and the Walter Reed National Military Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The data resulting from this study are available upon written request submitted to the corresponding author, subject to (1) the Material Transfer Agreement and Materials and Data Usage Agreement of the Oklahoma Medical Research Foundation, (2) the approval of the Armed Forces Health Surveillance Center and (3) documentation of all appropriate research training, including but not limited to human subjects research training.