Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response

Londe, Ana Carolina; Fernández-Ruiz, Ruth; Julio, Paulo Rogério; Appenzeller, Simone; Niewold, Timothy B.

doi:10.3899/jrheum.2022-0827

Cited by 9 publications

(3 citation statements)

References 181 publications

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“…The elevated activity of type 1 interferon signaling is closely associated with the susceptibility to autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and rheumatoid arthritis 58 . Counterintuitively, we consistently observed an upregulation of type 1 interferon-associated genes in multiple blood cell populations of BP patients in the remission stage, including pDCs, B cells, CD8 + T cells, and NK cells (Figures S2D, S3C, 5G and 6F).…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid

Wang,

Liang,

Zhao

et al. 2024

Preprint

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Bullous Pemphigoid (BP) triggers profound functional changes in both non-immune and immune cells in the skin and circulation, yet the underlying mechanisms remain elusive. In this study, we conducted single-cell transcriptome analysis on donor-matched lesional and non-lesional skin, as well as blood samples from BP patients. Lesional skin non-immune cells coordinately upregulated metabolism, wound healing, immune activation, and cell migration associated pathways. Skin LAMP3+ DCs derived from cDC2 exhibited higher pro-inflammatory signatures than those from cDC1, and VEGFA+ mast cells driving BP progression, were predominantly from lesional skin. As BP patients transition from active to remission stages, blood B cell function shifts from differentiation and memory formation to heightened type 1 interferon signaling and reduced IL-4 response. Blood CX3CR1+ZNF683+ and LAG3+ exhausted T cells exhibited the highest TCR expansion among clones shared with skin CD8+T cells, suggesting they likely represent BP-reactive cells fueling skin CD8+T cell clonal expansion. Clinical parameters for BP severity correlated positively with blood NK cell IFN-gamma production, whereas correlated negatively with NK cell AREG production. In lesional skin, NK cell-keratinocyte interactions exhibited reduced AREG-EGFR and enhanced IFNG-IFNGR1/2 signaling. NK cell-derived AREG mitigates IFN-gamma-induced keratinocyte apoptosis, highlighting a crucial balance between AREG and IFN-gamma in BP progression. These results reveal significant functional shifts in BP pathology within skin and blood cells and suggest new therapeutic targets for disease management.

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Section: Discussionmentioning

confidence: 99%

Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid

Wang,

Liang,

Zhao

et al. 2024

Preprint

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“…Type I interferon (IFN-I) is known to perform a crucial function in the pathophysiology of autoimmune diseases, particularly in the progression of SjS ( 95 , 96 ). Interestingly, studies indicate that the most strongly linked differentially methylated positions and regions in SjS patients are situated within genes regulated by type I interferon ( 13 ).…”

Section: Role Of Dna Methylation In Sjsmentioning

confidence: 99%

Functional significance of DNA methylation: epigenetic insights into Sjögren’s syndrome

Wang,

Riaz,

Wang

et al. 2024

Front. Immunol.

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Sjögren’s syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.

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“…For type I IFNs, plasma proteomic analysis revealed that higher circulating levels of IFNA5 were associated with a higher relative wall thickness in women, but not in men ( 157 ). It may be that determination of a type I IFN signature, as has been done in SLE for instance ( 42 , 158 ), may offer greater prognostic value than measurement of individual IFNs. However, even amongst patients with SLE who often exhibit a strong type I IFN response, a type I IFN signature has not been robustly associated with CVD ( 44 ).…”

Section: Introductionmentioning

confidence: 99%

Interferons and interferon-related pathways in heart disease

Tran,

Batchu,

Advani

2024

Front. Cardiovasc. Med.

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Interferons (IFNs) and IFN-related pathways play key roles in the defence against microbial infection. However, these processes may also be activated during the pathogenesis of non-infectious diseases, where they may contribute to organ injury, or function in a compensatory manner. In this review, we explore the roles of IFNs and IFN-related pathways in heart disease. We consider the cardiac effects of type I IFNs and IFN-stimulated genes (ISGs); the emerging role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; the seemingly paradoxical effects of the type II IFN, IFN-γ; and the varied actions of the interferon regulatory factor (IRF) family of transcription factors. Recombinant IFNs and small molecule inhibitors of mediators of IFN receptor signaling are already employed in the clinic for the treatment of some autoimmune diseases, infections, and cancers. There has also been renewed interest in IFNs and IFN-related pathways because of their involvement in SARS-CoV-2 infection, and because of the relatively recent emergence of cGAS-STING as a pattern recognition receptor-activated pathway. Whether these advances will ultimately result in improvements in the care of those experiencing heart disease remains to be determined.

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Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response

Cited by 9 publications

References 181 publications

Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid

Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid

Functional significance of DNA methylation: epigenetic insights into Sjögren’s syndrome

Interferons and interferon-related pathways in heart disease

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