Maribel Aranda Guillen’s research while affiliated with Karolinska Institutet and other places

The immune response to SARS-CoV-2 is highly heterogeneous, with interferon (IFN)-stimulated gene (ISG) expression playing a dual role in antiviral defense and immune dysregulation. To understand the broader implications of IFN-driven immune responses, we analyzed whole-blood transcriptomics, plasma proteomics, metabolomics, and immune cell profiling in COVID-19 patients and uninfected controls. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG expression clusters, independent of acute disease severity. HIS patients exhibited elevated inflammatory mediators (S100A8/A9, Neopterin) and altered metabolic profiles, yet immune activation patterns varied. Plasma from HIS cases induced differential activation in healthy neutrophils and monocytes, with severe HIS plasma showing reduced activation, suggesting the presence of suppressive soluble factors. Metabolomic analysis revealed widespread lipid metabolism dysregulation, including reductions in phospholipids, sphingolipids, and plasmalogens, which correlated with impaired immune activation. Branched-chain lipids and tryptophan metabolism products correlated strongly with monocyte and neutrophil activation, linking metabolic shifts to immune regulation. Despite IFN autoantibody detection in a subset of patients, no direct association with ISG expression was observed. These findings suggest that IFN-driven immune-metabolic dysregulation may persist beyond acute infection, contributing to post-viral inflammation, immune dysfunction, and susceptibility to long COVID or autoimmune-like sequelae. The interplay between IFN signaling, mitochondrial function, and lipid metabolism highlights novel therapeutic targets for immune modulation in viral infections and chronic inflammatory conditions. Understanding these immune signatures may inform precision medicine approaches in post-viral syndromes and immunometabolic disorders.

Severe COVID-19 is characterized by immune dysregulation and coagulation abnormalities, leading to complications such as thromboembolism and multi-organ failure. This study explores the relationship between autoantibodies targeting coagulation-related factors and gene expression in severe COVID-19. Whole-blood transcriptomics revealed upregulation of coagulation-related genes, including VWF and Factor V, in severe patients compared to mild cases and healthy controls. Autoantibody profiling against seven coagulation-related proteins (ADAMTS13, Factor V, Protein S, SERPINC1, Apo-H, PROC1, and Prothrombin) showed reactivities below established positivity thresholds, but mean-fluorescent intensities were elevated numerically in severe (Protein S) and convalescent (SERPINC1) patients. Correlation analysis revealed trends of negative associations between autoantibody reactivities and coagulation gene expression in severe cases, suggesting a potential role for autoantibodies in modulating immune-coagulation interactions warranting further orthogonal validation. Furthermore, age-dependent increases in subthreshold autoantibody reactivities were observed in severe cases, highlighting the potential impact of immunosenescence on disease severity. These findings do not exclude the possibility that subthreshold autoantibodies may contribute indirectly to immune-coagulation dynamics in severe COVID-19 through mechanisms beyond direct transcriptional regulation. This study highlights the complexity of immune-coagulation interactions and provides foundation for future research into their biological and clinical relevance, particularly for identifying biomarkers and therapeutic targets in thromboinflammatory diseases.

Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

Autoimmune Addison’s disease is the predominant cause of primary adrenal failure, and is highly heritable. The genetic background has remained poorly understood due to the low prevalence and complex inheritance of the disease. We performed a genome-wide association study, which identified nine independent risk loci (P < 5 × 10–8). In addition to novel and previous risk loci involved in lymphocyte functionality, we further associated autoimmune Addison’s disease with two independent protein-coding alterations in the gene Autoimmune Regulator (AIRE). The most striking is the amino-acid substitution p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10–25), which introduces an additional cysteine residue in the zinc-finger motif of the PHD2 domain of AIRE. This unbiased elucidation of the genetic contribution to development of autoimmune Addison’s disease points to the importance of central immunological tolerance, and explains 35–41 percent of heritability.