Class III/IV Lupus Nephritis Shows an Association with High Serum Type 1 Interferon Levels

The role of type 1 interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE) has been extensively studied. Mechanistically, it has a broad effect on several cell lines which leads to a breakdown of immune tolerance and resulting autoimmunity. The interferon-blocking drug anifrolumab has an expanding role in lupus nephritis management, having recently demonstrated some encouraging results in the TULIP-LN lupus nephritis trial.¹ The utility of calculating interferon scores in SLE has generated considerable discourse amongst rheumatologists. This study from Iwamoto et al investigated a possible correlation between high levels of type 1 interferon within serum samples and lupus nephritis activity.²

Jack Arnold, MBBS, MRCP

In total, 221 lupus patients were recruited for this study, all of which met ≥4 American College of Rheumatology (ACR) revised criteria for SLE diagnosis. Type 1 IFN activity in sera was measured using an established bioassay and type 1 IFN-induced transcripts were measured using reverse transcriptase polymerase chain reaction (PCR). Interestingly, the authors carried out this study in a cohort of patients with a single ancestral background (European-American). It is important to note that a previous international multiracial cohort study has demonstrated higher rates of lupus nephritis in younger male patients of African, Asian, or Hispanic ethnicity.³

Investigators found that the prevalence of class III/IV nephritis was significantly higher in those with high levels of serum interferon (OR 5.4, P=0.009). Double-stranded DNA positivity and low C3 complement levels also correlated with an increased prevalence of class III/VI nephritis. Subsequent multivariate analysis showed that high type 1 IFN activity was a better predictor of class III/IV nephritis than serum complement or double-stranded DNA titres. The mean age of disease onset was also found to be significantly younger in those with high levels of serum type 1 IFN. High type 1 IFN patients also demonstrated higher concurrent Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores than those with lower levels of type 1 IFN. IFN was shown to promote chemokine secretion and the production of proapoptotic molecules within immortalized podocyte cell lines.

The source of IFN production within these patients remains a controversial issue. It has been suggested that plasmacytoid dendritic cells (pDCs) play a pivotal role in IFN production and degradation of immune tolerance in SLE.⁴ Additionally, inhibition of a pDC-specific receptor with the humanised monoclonal BIIBO59 demonstrated encouraging results, even in cutaneous disease.⁶ Conversely, previous work from Psarras et al at Leeds has demonstrated an enriched interferon signature in the skin without the presence of infiltrating immune cells.⁵ Interestingly, Iwamoto’s study did not demonstrate colocalization of plasmacytoid dendritic cells pDCs within the renal tissue. Podocyte damage appeared to occur independently of their presence which should prompt further investigation.

In summary, this work suggests an association between high levels of systemic interferon and class III/IV lupus nephritis. The use of a single ancestry cohort does limit the generalisability of this data. TULIP-LN has already hinted at the utility of interferon blockade in lupus nephritis and further clinical trials will provide a greater body of evidence going forward.

References:

1. Jayne D, Rovin B, Mysler EF, Furie RA, Houssiau FA, Trasieva T, et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis [Internet]. 2022 Apr 1 [cited 2022 Apr 27];81(4):496–506. Available from: https://ard.bmj.com/content/81/4/496

2. Iwamoto T, Dorschner JM, Selvaraj S, Mezzano V, Jensen MA, Vsetecka D, et al. High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis. J Rheumatol. 2022;49(4):388–97.

3. Hanly JG, O’Keeffe AG, Su L, Urowitz MB, Romero-Diaz J, Gordon C, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford) [Internet]. 2016 Oct 5 [cited 2022 Jun 14];55(2):252–62. Available from: https://pubmed.ncbi.nlm.nih.gov/26342222/

4. Eloranta ML, Rönnblom L. Cause and consequences of the activated type I interferon system in SLE. J Mol Med [Internet]. 2016 Oct 1 [cited 2022 Jun 14];94(10):1103–10. Available from: https://link.springer.com/article/10.1007/s00109-016-1421-4

5. Psarras A, Alase A, Antanaviciute A, Carr IM, Md Yusof MY, Wittmann M, et al. Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity. Nat Commun 2020 111 [Internet]. 2020 Dec 1 [cited 2022 May 31];11(1):1–18. Available from: https://www.nature.com/articles/s41467-020-19918-z

6. Furie R, Werth VP, Merola JF, Stevenson L, Reynolds TL, Naik H, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Invest [Internet]. 2019 Mar 1 [cited 2022 Jun 14];129(3):1359–71. Available from: https://pubmed.ncbi.nlm.nih.gov/30645203/