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Ann Rheum Dis. 2016 Nov;75(11):2014-2021. doi: 10.1136/annrheumdis-2015-208140. Epub 2016 Jan 25.

Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification.

Author information

1
Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
2
Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
3
Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
4
Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA.
5
Department of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Rheumatology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
7
Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.

Abstract

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.

KEYWORDS:

Autoantibodies; Autoimmunity; Chemokines; Cytokines; Systemic Lupus Erythematosus

PMID:
27088255
PMCID:
PMC4959992
DOI:
10.1136/annrheumdis-2015-208140
[Indexed for MEDLINE]
Free PMC Article

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