scholarly journals AB0082 PERSISTENT LOW COMPLEMENT LEVELS AND INTERFERON GENE UPREGULATION ARE PREDICTIVE FOR DISEASE PROGRESSION IN PATIENTS WITH INCOMPLETE SYSTEMIC LUPUS ERYTHEMATOSUS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1071.1-1071
Author(s):  
W. Lambers ◽  
J. Westra ◽  
S. Arends ◽  
B. Doornbos- van der Meer ◽  
B. Horvath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Protein A ◽  
Type I ◽  
Type Ii ◽  
Systemic Lupus ◽  
B Cell Activating Factor ◽  
Resistance Protein

Background:A subgroup of lupus patients present with mild symptoms and immunologic features, while they do not meet classification criteria for SLE. This disease state can be referred to as “incomplete systemic lupus erythematosus” (iSLE). Up to 55% of iSLE patients progress to SLE. Furthermore, previous research has shown that iSLE might overlap with early primary Sjögren’s disease (pSS).(1) Unfortunately, there are no predictive markers available for progression to classifiable disease. Type-I interferon (IFN) plays an important role in disease initiation of both SLE and pSS.(2,3) Myxovirus-resistance protein A (MxA) is a GTP-ase that has previously be demonstrated to correlate strongly with IFN-type I expression. Furthermore, interferon-inducible chemokines IFN-γ induced protein 10 (IP-10), and B-cell activating factor (BAFF), that are both inducible by IFN, are of interest, because it is demonstrated that these proteins are increased prior to the diagnosis of SLE.(4)Objectives:To find predictive markers that identify patients with incomplete systemic lupus erythematosus (iSLE) who are at the highest risk to progress to classifiable systemic lupus erythematosus (SLE) or primary Sjögren’s syndrome (pSS).Methods:Patients with iSLE (ANA ≥ 1:80, ≥ 1 clinical SLICC criterion, but not fulfilling the criteria, and disease manifestation <5 years) were included in a longitudinal observational study. Every half year, clinical status was evaluated and regular immunological serologic assessment was performed. Annually, interferon (IFN)-gene expression was determined by RT-PCR in whole blood using 14 genes. These genes represented 3 IFN-related modules. Some genes were mainly inducible by IFN-type I, others by IFN-type II. Furthermore, IFN-related mediators Myxovirus resistance protein A (MxA), interferon-gamma-induced protein 10 (IP-10) and B-cell activating factor (BAFF) were measured.Results:Of 38 included iSLE patients, 6 had developed SLE and 1 develop pSS (18%) after median follow up of 36 months. The 7 patients who developed SLE/pSS were all women, and were younger at baseline than those who remained having iSLE (median 26 years, IQR 20-29 vs. median 42 years, IQR 30-56, p=0.0009). Over time, these patients had significantly lower complement 3 (p<0.0001) and complement 4 levels (p=0.005), higher IFN-gene expression (p=0.007), and lower neutrophil counts (p=0.033) (see Figure 1.). No difference was found between IFN-type I and IFN-type II inducible genes. Levels of MxA, IP-10 and BAFF did not differ between patients who remained iSLE and who progressed to SLE/pSS.Figure 1.Conclusion:Gender, age at diagnosis, persistent low complement levels, and high IFN-gene expression can help to identify iSLE patients at the highest risk of progressing to classifiable disease.References:[1]Md Yusof MY, et al. Prediction of autoimmune connective tissue disease in an at-risk cohort: Prognostic value of a novel two-score system for interferon status. Ann Rheum Dis. 2018;1–8.[2]Yao Y, et al. Type I interferons in Sjögren’s syndrome. Autoimmun Rev. 2013;12(5):558–66.[3]Crow MK. Type I Interferon in the Pathogenesis of Lupus. J Immunol [Internet]. 2014;192(12):5459–68.[4]Lu R, et al. Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun. 2016;74:182–93.Disclosure of Interests:None declared

scholarly journals Interferon score is increased in incomplete systemic lupus erythematosus and correlates with myxovirus-resistance protein A in blood and skin

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Wietske M. Lambers ◽  
Karina de Leeuw ◽  
Berber Doornbos-van der Meer ◽  
Gilles F.H. Diercks ◽  
Hendrika Bootsma ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Protein A ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Skin Symptoms ◽  
Skin Biopsies ◽  
Resistance Protein ◽  
Unaffected Skin

Abstract Objectives Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. Methods Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators myxovirus-resistance protein A (MxA), IFN-γ-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. Results IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). Conclusions IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.

Type I interferon gene signature test–low and –high patients with systemic lupus erythematosus have distinct gene expression signatures

Lupus ◽  
2019 ◽  
Vol 28 (13) ◽  
pp. 1524-1533 ◽  
Author(s):  
PZ Brohawn ◽  
K Streicher ◽  
B W Higgs ◽  
C Morehouse ◽  
H Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Gene Signature ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Blood Samples ◽  
Ifn Γ

Objectives Type I interferon (IFN) is implicated in systemic lupus erythematosus (SLE) pathogenesis. We aimed to identify type I IFN signaling-dependent and -independent molecular pathways in a large population of patients with SLE. Methods Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were profiled using whole transcriptome array analyses. Type I IFN gene signature (IFNGS) test status (high or low) was determined using a validated qualitative polymerase chain reaction–based test. IFN-type-specific signatures were developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or pooled IFN-α. These, and multiple literature-derived cell type and cytokine pathway signatures, were evaluated in individual and pooled study populations. A Fisher’s exact test was used for associations, adjusted for false discovery rate. Results Whole blood samples from IFNGS test–high patients were enriched versus IFNGS test–low patients for CD40L signaling ( Q < 0.001), CXC cytokine ( Q < 0.001), TLR8-mediated monocyte activation ( Q < 0.001), IgG ( Q < 0.001), major histocompatibility complex class I ( Q < 0.001), and plasma cell ( Q < 0.001) gene expression signatures. IFNGS test–low patients had significant enrichment of eosinophil ( Q < 0.001), IFN-γ-specific ( Q = 0.005), and T-cell or B-cell ( Q < 0.001) signatures. Similar enrichment profiles were demonstrated in patients with primary Sjögren’s syndrome, systemic sclerosis, and dermatomyositis. Conclusions IFNGS test–high patients overexpressed many gene signatures associated with SLE pathogenesis compared with IFNGS test–low patients, reflecting broad immune activation. These results provide new insights into the molecular heterogeneity underlying SLE pathogenesis, highlighting shared mechanisms beyond type I IFN, across several autoimmune diseases. Trial registration Clinicaltrials.gov: NCT01438489 and NCT01283139.

scholarly journals Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification

2016 ◽  
Vol 75 (11) ◽  
pp. 2014-2021 ◽  
Author(s):  
Melissa E Munroe ◽  
Rufei Lu ◽  
Yan D Zhao ◽  
Dustin A Fife ◽  
Julie M Robertson ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Random Forest ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I ◽  
Type Ii ◽  
Systemic Lupus ◽  
Forest Models ◽  
Random Forest Models ◽  
Α Activity

ObjectivesThe relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE.MethodsSerial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models.ResultsIn cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification).ConclusionsYears before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.

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

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

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

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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