Interferon pathway in SLE: one key to unlocking the mystery of the disease

Rönnblom, Lars; Leonard, Dag

doi:10.1136/lupus-2018-000270

Cited by 240 publications

(238 citation statements)

References 124 publications

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“…These three cytokines (IFN-alpha, IFN-beta, IL-6) as well as IP-10 had a statistically significant difference between IFNpos and IFNneg SLE patients as well (Figure 1F; Supplementary Figure S1F). The role of IFNs as pro-inflammatory cytokines is well-studied in SLE 34,35 . Another cytokine with a significant difference between IFNpos and IFNneg is IL-6, which is also pro-inflammatory.…”

Section: Ifn Response Status Of Sle Patients Correlates With the Levementioning

confidence: 99%

Integrative transcriptomic analysis of SLE reveals IFN-driven cross-talk between immune cells

Panwar

Schmiedel

Liang

et al. 2020

Preprint

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The systemic lupus erythematosus (SLE) is an incurable autoimmune disease disproportionately affecting women and may lead to damage in multiple different organs. The marked heterogeneity in its clinical manifestations is a major obstacle in finding targeted treatments and involvement of multiple immune cell types further increases this complexity. Thus, identifying molecular subtypes that best correlate with disease heterogeneity and severity as well as deducing molecular cross-talk among major immune cell types that lead to disease progression are critical steps in the development of more informed therapies for SLE. Here we profile and analyze gene expression of six major circulating immune cell types from patients with well-characterized SLE (classical monocytes (n=64), T cells (n=24), neutrophils (n=24), B cells (n=20), conventional (n=20) and plasmacytoid (n=22) dendritic cells) and from healthy control subjects. Our results show that the interferon (IFN) response signature was the major molecular feature that classified SLE patients into two distinct groups: IFN-signature negative (IFNneg) and positive (IFNpos). We show that the gene expression signature of IFN response was consistent (i) across all immune cell types, (ii) all single cells profiled from three IFNpos donors using single-cell RNA-seq, and (iii) longitudinal samples of the same patient. For a better understanding of molecular differences of IFNpos versus IFNneg patients, we combined differential gene expression analysis with differential Weighted Gene Co-expression Network Analysis (WGCNA), which revealed a relatively small list of genes from classical monocytes including two known immune modulators, one the target of an approved therapeutic for SLE (TNFSF13B/BAFF: belimumab) and one itself a therapeutic for Rheumatoid Arthritis (IL1RN: anakinra). For a more integrative understanding of the cross-talk among different cell types and to identify potentially novel gene or pathway connections, we also developed a novel gene coexpression analysis method for joint analysis of multiple cell types named integrated WGNCA (iWGCNA). This method revealed an interesting cross-talk between T and B cells highlighted by a significant enrichment in the expression of known markers of T follicular helper cells (Tfh), which also correlate with disease severity in the context of IFNpos patients. Interestingly, higher expression of BAFF from all myeloid cells also shows a strong correlation with enrichment in the expression of genes in T cells that may mark circulating Tfh cells or related memory cell populations. These cell types have been shown to promote B cell class-switching and antibody production, which are well-characterized in SLE patients. In summary, we generated a large-scale gene expression dataset from sorted immune cell populations and present a novel computational approach to analyze such data in an integrative fashion in the context of an autoimmune disease. Our results reveal the power of a hypothesis-free and datadriven approach to discover drug t...

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Section: Ifn Response Status Of Sle Patients Correlates With the Levementioning

confidence: 99%

Integrative transcriptomic analysis of SLE reveals IFN-driven cross-talk between immune cells

Panwar

Schmiedel

Liang

et al. 2020

Preprint

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“…Systemic lupus erythematosus (SLE) is a chronic disease characterised by loss of tolerance to self-antigens, formation of immune complexes and an activated type I interferon system 1–3. Despite improved prognosis, the mortality rate stills exceeds that of the general population 4.…”

Section: Introductionmentioning

confidence: 99%

High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

et al. 2019

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ObjectivesTo investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).MethodsPatients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.ResultsSLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10–86 and OR 7.48 (6.73 to 8.32), p=2.2×10–304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10–5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10–2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10–5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10–3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10–2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10–3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10–2), anti-β2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10–3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10–2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10–2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10–2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10–7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10–3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10–2) in high to low quartile comparison.ConclusionsA high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

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“…Interferons are a natural component of the immune system that activate antiviral machinery in order to inhibit replication and increase immune response [134]. This process can be sped up via interferon injection [134]. Given its ability to stimulate active immunity, previous studies have tested alpha‐ and beta‐types of interferons against MERS and SARS [135].…”

Section: Drug Development For the Treatment Of Covid‐19mentioning

confidence: 99%

A Guide to COVID‐19: a global pandemic caused by the novel coronavirus SARS‐CoV‐2

et al. 2020

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The emergence of the SARS‐CoV‐2 strain of the human coronavirus has thrown the world into the midst of a new pandemic. In the human body, the virus causes COVID‐19, a disease characterized by shortness of breath, fever, and pneumonia, which can be fatal in vulnerable individuals. SARS‐CoV‐2 has characteristics of past human coronaviruses, with close genomic similarities to SARS‐CoV, the virus that causes the disease SARS. Like these related coronaviruses, SARS‐CoV‐2 is transmitted through the inhalation of droplets and interaction with contaminated surfaces. Across the world, laboratories are developing candidate vaccines for the virus – with vaccine trials underway in the United States and the United Kingdom – and considering various drugs for possible treatments and prophylaxis. Here, we provide an overview of SARS‐CoV‐2 by analyzing its virology, epidemiology, and modes of transmission while examining the current progress of testing procedures and possible treatments through drugs and vaccines.

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Interferon pathway in SLE: one key to unlocking the mystery of the disease

Cited by 240 publications

References 124 publications

Integrative transcriptomic analysis of SLE reveals IFN-driven cross-talk between immune cells

Integrative transcriptomic analysis of SLE reveals IFN-driven cross-talk between immune cells

High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

A Guide to COVID‐19: a global pandemic caused by the novel coronavirus SARS‐CoV‐2

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