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Abstract Number: 2420

Blood Transcriptome Analysis Reveals Enhanced B Cell and Complement Cascade Signatures in Patients with Major Neuropsychiatric Systemic Lupus Erythematosus

Dionysis Nikolopoulos1, George Sentis2, Jason Kitsos2, Panagiotis Garantziotis3, Noemin Kapsala2, antigoni Pieta2, Myrto Nikoloudaki4, Theodora Manolakou5, Sofia Flouda2, Ioannis Parodis6, Anastasia Filia2, George Bertsias7, Antonis Fanouriakis2 and Dimitrios Boumpas8, 1Karolinska Institutet and Karolinska University Hospital, Division of Rheumatology, Department of Medicine Solna, Stockholm, Sweden, 2National and Kapodistrian University of Athens, Athens, Greece, 3Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany, Erlangen, Germany, 4Rheumatology and Clinical Immunology, University of Crete School of Medicine, Heraklion, Greece, Heraklion, Greece, 5Karolinska Institutet, Stockholm, Sweden, 6Karolinska Institutet, Karolinska University Hospital; Örebro University, Solna, Sweden, 7Laboratory of Rheumatology, Autoimmunity and Inflammation. University Hospital, Rheumatology, Clinical Immunology, Heraklion, Greece, 84th Department of Internal Medicine, "Attikon" University Hospital, Athens, Greece, Athens, Greece

Meeting: ACR Convergence 2024

Keywords: Gene Expression, immunology, neurology, neuropsychiatric disorders, Systemic lupus erythematosus (SLE)

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Session Information

Date: Monday, November 18, 2024

Title: SLE – Diagnosis, Manifestations, & Outcomes Poster III

Session Type: Poster Session C

Session Time: 10:30AM-12:30PM

Background/Purpose: The molecular basis of neuropsychiatric systemic lupus erythematosus (NPSLE) remains elusive because of clinical heterogenicity, the complexity of pathophysiologic mechanisms involved and limited access to tissue.

Methods: We performed whole-blood RNA sequencing from 308 SLE [119 with at least one major neuropsychiatric event treated intensive immunosuppressive therapy (NPSLE) and 189 SLE patients with no history of NPSLE (non-NPSLE)] and matched 72 healthy controls (HC). Pathway enrichment analysis, unsupervised weighted gene co-expression network analysis (WGCNA) and deconvolution were applied to reveal NPSLE-specific signatures and distinguish NPSLE endotypes.

Results: Comparison between NPSLE and HC revealed 1292 differentially expressed genes, indicating dysregulation of adaptive immune response, immunoglobulin mediated immune response and classical autoantibody-mediated complement activation along with upregulation of IL-1, IL-6, IL-17, and IL-12/IL-23 signaling. Monocyte, memory B cell and activated memory CD4 T cell proportions were significantly increased in NPSLE compared to HC. The comparison between NPSLE and non-NPSLE revealed a robust upregulation of immunoglobulin complex, complement cascade, DNA damage response (DDR), B cell signatures coupled with increased IL-1 and IL-6 signaling. More importantly, upregulation of B cell and complement activation were more pronounced in active NPSLE compared to inactive NPSLE. Next, we performed unsupervised analysis of SLE transcriptome identifying 16 gene modules of co-expressed genes. Within NPSLE, diffuse NPSLE positively correlated with “oxidative phosphorylation” module. Active NPSLE was characterized by enhanced activity of “autophagy” module compared to inactive NPSLE, while NPSLE with distinct aPL profiles were not associated with specific signatures. Finally, we explored whether specific NPSLE manifestations are associated with distinct transcriptomic signatures. “DDR” and “DNA metabolism” modules correlated with seizures, while the later correlated with acute confusional state. Psychosis was positively associated with the “Inflammation” module. The “Innate immunity” module was positively linked to impaired cognition and the “Chromatin organization” was associated with both impaired cognition and myelitis. Moreover, the “Protein metabolism” was negatively associated with impaired cognition and peripheral neuropathies, while the “Interferon” module significantly correlated with optic neuritis. 

Conclusion: Our findings demonstrate that the clinical heterogeneity of NPSLE is mirrored by molecular diversity, with each NPSLE endotype characterized by distinct molecular signatures. Upregulation of the adaptive immune response and complement activation is strongly associated with neuropsychiatric involvement in SLE. This suggests that inhibitors of the complement cascade, such as avacopan, and B cell-targeted therapies, like CD19 CAR T cell therapy—which may counteract the transcriptomic abnormalities in NPSLE—have been tested for the treatment of autoimmune diseases and could be further explored for major NPSLE.


Disclosures: D. Nikolopoulos: None; G. Sentis: None; J. Kitsos: None; P. Garantziotis: None; N. Kapsala: None; a. Pieta: None; M. Nikoloudaki: None; T. Manolakou: None; S. Flouda: None; I. Parodis: Amgen, 5, 6, AstraZeneca, 1, 2, 6, Aurinia, 1, 5, 6, Bristol-Myers Squibb(BMS), 2, 5, Eli Lilly, 5, GlaxoSmithKlein(GSK), 1, 2, 5, 6, Janssen, 2, 6, Novartis, 1, 2, Otsuka Pharma, 1, 2, 5, 6, Roche, 2, 5, 6; A. Filia: None; G. Bertsias: None; A. Fanouriakis: None; D. Boumpas: None.

To cite this abstract in AMA style:

Nikolopoulos D, Sentis G, Kitsos J, Garantziotis P, Kapsala N, Pieta a, Nikoloudaki M, Manolakou T, Flouda S, Parodis I, Filia A, Bertsias G, Fanouriakis A, Boumpas D. Blood Transcriptome Analysis Reveals Enhanced B Cell and Complement Cascade Signatures in Patients with Major Neuropsychiatric Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/blood-transcriptome-analysis-reveals-enhanced-b-cell-and-complement-cascade-signatures-in-patients-with-major-neuropsychiatric-systemic-lupus-erythematosus/. Accessed .
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