Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jun 20:9:100246.
doi: 10.1016/j.jtauto.2024.100246. eCollection 2024 Dec.

Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus

Affiliations

Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus

Ellen D Kaan et al. J Transl Autoimmun. .

Abstract

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.

Methods: We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.

Results: We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = -0.530; p = 0.007) and anti-PmScl100 (r = -0.445; p = 0.03).

Conclusion: We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.

Keywords: Autoantibodies; Interferon signature; NETosis; Patient stratification; Systemic lupus erythematosus.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Flowchart representing the patient selection process. IFN: interferon; NET: neutrophil extracellular traps.
Fig. 2
Fig. 2
(A) Principal component analysis of 24 patients with SLE visualized in a 3D plot. (B) Heatmap of Z-scores for 57 autoantibodies in patients with high and low IFN signature, and high or low NET inducing capacity. Vertical axis shows clustering of patients based on IFN status (blue) and NET inducing capacity (orange/pink). Horizontal axis represents clustering based on autoantibody profiles. (C) SELENA-SLEDAI score, anti-dsDNA, and thrombocyte concentration in cluster 1 and 2 from Fig. 2A. Lines represent median. Differences between clusters were tested with a Mann-Whitney-U test. (D) Representation of individual SELENA-SLEDAI items in patients in cluster 1 and cluster 2 from Fig. 2A. Darker area represents % of patients positive for this item. Only items present in patients from our cohort are shown. *χ2(=1, N = 24) = 8.00, p = 0.005. IFN: interferon signature; NET: neutrophil extracellular trap. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
(A) Immunofluorescence (IF) intensity in IFN positive and IFN negative patiënts for EphB2, RipP1, and RNP70. Line represents mean IF intensity. (B) Correlation of EphB2, RipP1, and RNP70 IF intensity with IFN score.IF:immunofluorescence; IFN:interferon. *not significant after Bonferroni correction.
Fig. 4
Fig. 4
(A) Immunofluorescence (IF) intensity of autoantibodies against FcER and PmScl100 in patients with a low and high NET inducing capacity; Line represents mean IF intensity. (B) Correlation of FcER and PmScl100 IF intensity with NET inducing capacity. IF: immunofluorescence; NET: NETosis. *Not significant after Bonferroni correction for multiple testing.

Similar articles

Cited by

References

    1. Stojan G., Petri M. Epidemiology of systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 2018;30:144–150. - PMC - PubMed
    1. Gatto M., Zen M., Iaccarino L., Doria A. New therapeutic strategies in systemic lupus erythematosus management. Nat. Rev. Rheumatol. 2019;15:30–48. - PubMed
    1. Rodriguez-Almaraz E., Gutierrez-Solis E., Rabadan E., Rodriguez P., Carmona L., Morales E., Galindo M. Something new about prognostic factors for lupus nephritis? A systematic review. Lupus. 2021;30:2256–2267. - PubMed
    1. Toro-Dominguez D., Martorell-Marugan J., Goldman D., Petri M., Carmona-Saez P., Alarcon-Riquelme M.E. Stratification of systemic lupus erythematosus patients into three groups of disease activity progression according to longitudinal gene expression. Arthritis Rheumatol. 2018;70:2025–2035. - PMC - PubMed
    1. Kariuki S.N., Franek B.S., Kumar A.A., Arrington J., Mikolaitis R.A., Utset T.O., et al. Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. Arthritis Res. Ther. 2010;12 - PMC - PubMed

LinkOut - more resources