GG-01 Hypomethylation of STAT1 and HLA-DRB1 in CD8+ T cells is associated with type-I interferon-dependent HLA-DRB1 overexpression and activation of autologous CD4+ T cells in systemic lupus erythematosus

Background:Neutrophils have been described as potent antigen-presenting cells able to activate T cells by MHC/TCR interaction and costimulatory molecules in tumor immunity. However, little is known about the direct interaction between neutrophils and CD4 T cells with respect to systemic lupus erythematosus (SLE). We have previously shown that OX40L expressed by monocytes from SLE patients promote the differentiation of naïve and memory cells into IL21 secreting T cells that are able to help B cells1,2.Objectives:In this study, we investigate OX40L expression on neutrophils from SLE patients and contribution of these OX40L+neutrophils in SLE pathogenesis to modulation of the B cell helper role of CD4 T cells.Methods:Surface expression of co-stimulatory molecules (OX40L, ICOSL, GITRL, 4-1BBL) on neutrophils from SLE patients and healthy donors (HD) was measured by flow cytometry (FC). Neutrophils from HD were stimulated with TLR7 or TLR8 agonists and IFNα after 5 hours of culture, OX40L expression was measured by FC and Western Blotting. CD4 T cells were cultured with the stimulated neutrophils for 3 days. At the end of the co-culture, percentages of IL21-expressing T follicular (Tfh) and peripheral helper (Tph) cells measured by FC. These generated T cells were also cultured in the presence of memory B cells. After 5 days of co-culture, plasmablast generation and Ig levels were assessed by FC and ELISA, respectively. Inhibition of OX40-OX40L interaction in vitro was achieved using ISB 830, a novel anti-OX40 mAb currently used in clinical trials.Results:Among the co-stimulatory molecules tested, percentages of OX40L+neutrophils in SLE (n=54) were increased compared to HD (n=25)(mean + SD: HD = 1,34%±1.62 vs SLE = 4,53%±8.1; p=0.29). OX40L expression positively correlated with SLE disease activity score (SLEDAI) (p = 0,04; r = 0,31) and with anti-DNA antibodies (p= 0,04, r = 0,33). Of note, the percentage of OX40L+neutrophils was higher in anti-sm-RNP+patients (n=16, mean= 9%±9.8), compared to anti-sm-RNP-patients (n=27, mean = 1,4%±2.5; p = 0,02). The percentage of OX40L+neutrophils was higher in patients with class III or IV lupus nephritis, and inflammatory infiltrate within the kidney biopsy disclosed OX40L+neutrophils, in close contact with T cells. Neutrophils from HD express OX40L with TLR8 agonist, or IFNα priming followed by TLR7 agonist. When memory CD4 T cells were cultured in the presence of TLR8-stimulated neutrophils, the proportion of IL21-expressing Tfh (CXCR5+PD1+) and Tph (CXCR5-PD1hi) were increased, compared to culture with unstimulated neutrophils. This process was dependent on OX40-OX40L interactions, since in vitro treatment with the anti-OX40 blocking antibody ISB 830, inhibited the differentiation of memory T cells into Tfh and Tph. Both generated Tfh and Tph were able to promote the differentiation of memory B cells into Ig-secreting plasmablasts.Conclusion:Our results disclose an unprecedented phenomenon where cross-talk between TLR7/8-activated neutrophils and CD4 lymphocytes operates through OX40L-OX40 costimulation, and neutrophils promote the differentiation of pro-inflammatory Tfh and Tph, as well as IL21 production. Therefore, OX40L/OX40 should be considered as a potentially therapeutic axis in SLE patients.References:[1]Jacquemin et al. Immunity 2015;[2]Jacquemin et al. JCI Insight 2018Disclosure of Interests:Angela Pappalardo Grant/research support from: Ichnos Sciences, Elodie Wojciechowski: None declared, Itsaso Odriozola: None declared, Isabelle Douchet: None declared, Nathalie Merillon: None declared, Andrea Boizard-Moracchini: None declared, Pierre Duffau: None declared, Estibaliz Lazaro: None declared, Marie-Agnes Doucey Employee of: Ichnos Sciences, Lamine Mbow Employee of: Ichnos Sciences, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Patrick Blanco Grant/research support from: Ichnos Sciences

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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

Nature Communications ◽

10.1038/s41467-021-22312-y ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Norzawani Buang ◽

Lunnathaya Tapeng ◽

Victor Gray ◽

Alessandro Sardini ◽

Chad Whilding ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Lupus Erythematosus ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Systemic Lupus ◽

Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

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Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus

Arthritis & Rheumatology ◽

10.1002/art.41518 ◽

2020 ◽

Author(s):

Kerry A Casey ◽

Michael A Smith ◽

Dominic Sinibaldi ◽

Nickie L Seto ◽

Martin P Playford ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Cardiometabolic Disease ◽

Type I ◽

Systemic Lupus ◽

Disease Markers

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B cells require “nurturing” by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus

Clinical Immunology ◽

10.1016/j.clim.2010.03.003 ◽

2010 ◽

Vol 136 (1) ◽

pp. 105-115 ◽

Cited By ~ 11

Author(s):

Arpita Choudhury ◽

Philip L. Cohen ◽

Robert A. Eisenberg

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

B Cells ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Systemic Lupus ◽

Graft Versus Host

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Targeting type I interferon in systemic lupus erythematosus

Nature Reviews Rheumatology ◽

10.1038/nrrheum.2016.83 ◽

2016 ◽

Vol 12 (7) ◽

pp. 377-378 ◽

Cited By ~ 9

Author(s):

Timothy B. Niewold

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Type I ◽

Systemic Lupus

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Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus

10.1101/2020.10.29.20222000 ◽

2020 ◽

Author(s):

Sarthak Gupta ◽

Shuichiro Nakabo ◽

Jun Chu ◽

Sarfaraz Hasni ◽

Mariana J. Kaplan

Keyword(s):

Systemic Lupus Erythematosus ◽

General Population ◽

Lupus Erythematosus ◽

Preventive Measures ◽

Type I Interferon ◽

Type I ◽

List Type ◽

Signal Transducer ◽

Systemic Lupus

AbstractObjectivesAnti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFNα autoantibodies was associated with COVID-19 infection in SLE patients.MethodsPatients with SLE who developed COVID-19 between April 1st to October 1st, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFNα IgG autoantibodies by ELISA. The ability of plasma anti-IFNα autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFNα in vitro was assessed by flow cytometry.ResultsTen SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFNα for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFNα induced STAT1 phosphorylation.None of the other SLE samples blocked IFNα signaling.ConclusionsWe noted an increased prevalence of pre-existing anti-IFNα autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFNα in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19.Key MessagesWhat is already known about this subject?-Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE) and have recently been associated with severe COVID-19 in the general population.What does this study add?-SLE subjects with COVID-19 had an increased prevalence of pre-existing anti-IFNα autoantibodies compared to the reported prevalence in lupus patients and the general population with severe COVID-19.-Plasma from 50% of subjects with these autoantibodies were able to block in vitro activity of IFNα.-SLE patients with pre-existing anti-IFNα autoantibodies had more severe COVID-19 manifestations.How might this impact on clinical practice or future developments?-Anti-IFNα autoantibodies may be pathogenic and could prove to be a helpful prognostic marker to predict which SLE patient may develop COVID-19 and inform preventive measures and management of this subset of patients.

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