TY - JOUR
T1 - High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis
AU - Iwamoto, Taro
AU - Dorschner, Jessica M.
AU - Selvaraj, Shanmugapriya
AU - Mezzano, Valeria
AU - Jensen, Mark A.
AU - Vsetecka, Danielle
AU - Amin, Shreyasee
AU - Makol, Ashima
AU - Osborn, Thomas
AU - Moder, Kevin
AU - Chowdhary, Vaidehi R.
AU - Izmirly, Peter
AU - Belmont, H. Michael
AU - Clancy, Robert M.
AU - Buyon, Jill P.
AU - Wu, Ming
AU - Loomis, Cynthia A.
AU - Niewold, Timothy B.
N1 - Funding Information:
This study was supported by grants to TBN from the Colton Center for Autoimmunity, National Institutes of Health (AR060861, AR057781, AR065964), the Lupus Research Foundation, and the Lupus Research Alliance. 1T. Iwamoto, MD, PhD, Colton Center for Autoimmunity, New York University, New York, New York, USA, and Allergy and Clinical Immunology, Chiba University, Japan; 2J.M. Dorschner, BS, D. Vsetecka, MPH, S. Amin, MD, A. Makol, MD, T. Osborn, MD, K. Moder, MD, V.R. Chowdhary, MD, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 3S. Selvaraj, MS, V. Mezzano, MD, PhD, M. Wu, MD, C.A. Loomis, MD, PhD, Department of Pathology, New York University, New York, New York, USA; 4M.A. Jensen, PhD, R.M. Clancy, PhD, J.P. Buyon, MD, T.B. Niewold, MD, Colton Center for Autoimmunity, New York University, New York, New York, USA; 5P. Izmirly, MD, H.M. Belmont, MD, Division of Rheumatology, New York University, New York, New York, USA. TBN has received research grants from EMD Serono and Janssen, and has consulted for Thermo Fisher, Progentec, and Inova, all unrelated to the current manuscript. The remaining authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. T.B. Niewold, Colton Center for Autoimmunity, NYU Grossman School of Medicine, 550 1st Ave., New York, NY 10016, USA. Email: Timothy.Niewold@nyulangone.org. Accepted for publication November 3, 2021.
Publisher Copyright:
© 2022 The Journal of Rheumatology
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Objective. Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. Methods. Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. Results. Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. Conclusion. Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.
AB - Objective. Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. Methods. Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. Results. Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. Conclusion. Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.
KW - interferon signature gene
KW - lupus nephritis
KW - podocyte injury type I interferon
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U2 - 10.3899/jrheum.210391
DO - 10.3899/jrheum.210391
M3 - Article
C2 - 34782453
AN - SCOPUS:85128161079
SN - 0315-162X
VL - 49
SP - 388
EP - 397
JO - Journal of Rheumatology
JF - Journal of Rheumatology
IS - 4
ER -