Human Lupus Nephritis

We do translational and clinical research on the autoimmune disease Systemic Lupus Erythematosus (SLE) aimed at identifying novel biomarkers and therapy targets

SLE is a systemic autoimmune chronic inflammatory disease that is characterized by prolonged morbidity and substantial mortality. It has a predominant occurrence in females compared to men (9:1), and over 80% of SLE cases occur in women in their childbearing age. Lupus nephritis is a chronic kidney disease and a serious manifestation of SLE. We aim to develop new therapeutic tools and ways to monitor the disease based on novel and precise knowledge of the disease initiation and development. Since the expression of both DNase I and neutrophil extracellular traps (NETs) are abnormal in SLE, we hypothesize that they can be utilized in therapy and as biomarkers. To explore this, we will investigate the expression pattern and regulation of DNase I and NETs.

Medlemmer:

Hege Lynum Pedersen (Principal investigator)

Premasany Kanapathippillai

Anita Ursvik

Aud-Malin Karlsson Hovd

Susannah von Hofsten

Kristin Andreassen Fenton

Studier:

DNase I

Reduction in clearance of chromatin is a major factor contributing to the pathogenesis of SLE. The occurrence of chromatin fragments in the kidney may be explained by malfunctioning clearance of apoptotic or necrotic chromatin due to reduced renal endonuclease activity. The main nuclease in the kidney is DNase I as it accounts for 80% of total renal endonuclease activity. Recent data from our research group have demonstrated an acquired error of renal chromatin degradation, possibly due to the loss of renal DNase I enzyme activity.

This translational project aims to get more detailed knowledge about the molecular mechanisms behind SLE and investigate the role and impact DNase I have in this disease. One of our hypotheses is that decreased urinary DNase I activity can predict kidney inflammation.

Publications:

Pedersen HL, Horvei KD, Thiyagarajan D, Norby GE, Seredkina N, Moroni G, Eilertsen GØ, Holdaas H, Strøm EH, Bakland G, Meroni PL, Rekvig OP. Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression. J Pathol Clin Res. 2018 Jul;4(3):193-203. doi: 10.1002/cjp2.99. Epub 2018 Apr 6. PMID: 29624903; PMCID: PMC6065113.

Thiyagarajan D, Pedersen HL, Seredkina N, Horvei KD, Arranz L, Sonneveld R, Nijenhuis T, van der Vlag J, Rekvig OP. IL-1β Promotes a New Function of DNase I as a Transcription Factor for the Fas Receptor Gene. Front Cell Dev Biol. 2018 Feb 6;6:7. doi: 10.3389/fcell.2018.00007. PMID: 29468159; PMCID: PMC5807897.

Horvei KD, Pedersen HL, Fismen S, Thiyagarajan D, Schneider A, Rekvig OP, Winkler TH, Seredkina N. Lupus nephritis progression in FcγRIIB-/-yaa mice is associated with early development of glomerular electron dense deposits and loss of renal DNase I in severe disease. PLoS One. 2017 Nov 30;12(11):e0188863. doi: 10.1371/journal.pone.0188863. PMID: 29190833; PMCID: PMC5708736.

Rekvig OP, Thiyagarajan D, Pedersen HL, Horvei KD, Seredkina N. Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities. Am J Pathol. 2016 Nov;186(11):2772-2782. doi: 10.1016/j.ajpath.2016.06.026. Epub 2016 Sep 21. PMID: 27664472.

Treatment and NETosis