ANALYSIS OF INTERFERON-I SIGNALING ACTIVITY IN CHILDREN WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS OF A PILOT PROSPECTIVE STUDY

2021 ◽  
Vol 100 (3) ◽  
pp. 77-88
Author(s):  
R.K. Raupov ◽  
◽  
E.N. Suspitsyn ◽  
E.M. Kalashnikova ◽  
R.C. Mulkidzhan ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Age Of Onset ◽  
Negative Relationship ◽  
Clinical Manifestations ◽  
Type I ◽  
Systemic Lupus ◽  
Cold Urticaria ◽  
Pediatric Department ◽  
Interferon System

The interferon system (IFN) is a group of signaling molecules with antiviral, antitumor and antiproliferative effects. The most studied signaling pathway is mediated by IFN type I. Mutations of IFN-I-regulated genes are involved in the pathogenesis of systemic lupus erythematosus (SLE). Interferon index (IFN-I-index) – a quantitative indicator of the level of expression of IFN-Iregulated genes – is used to assess the activity of the interferon system. Objective of the study: to assess the level of the IFN-I index in children with SLE, as well as to compare the clinical and laboratory characteristics of patients with high and normal levels of the IFN-I-index. Materials and methods of research: 40 patients (girls – 83%, boys – 17%) under 18 years of age with SLE diagnosed in accordance to the SLICC 2012 criteria were included in a multicenter prospective open uncontrolled nonrandomized continuous study. The age of the patients was 15,2 (12,5 ; 16,7) years. All of them underwent examination and treatment in the Pediatric department № 3 at the clinic of the St. Petersburg State Pediatric Medical University and in the Pediatric department of the Almazov National Medical Research Center. The IFN-I index was determined by real-time PCR with a quantitative assessment of the expression of 5 genes induced by IFN-α and β. Results: aggravated family history of rheumatic diseases was noted in 8 patients: SLE – in 3 (8%), rheumatoid arthritis – in 3 (8%), cold urticaria – in 2 (5%). The average age of onset of the disease is 12 years. The most common clinical manifestations were lesions of the skin, joints, mucous membranes, central nervous system, kidney and fever. 31 patients (78%) had an increased IFN-I index. All cases of kidney failure were observed only in patients with a high IFN index (36% vs 0%, p=0,036). Patients with increased IFN-I-index had statistically significant increased levels of antinuclear (87% vs 56%, p=0,043) and rheumatoid factors (36% vs 0%, p=0,036), higher ECLAM index values (3,0 vs 1.0, p=0,048), ferritin levels (p=0,0008) and, as a consequence, the need for more intensive immunosuppressive therapy (using rituximab and cyclophosphamide) compared with patients with normal IFN-Iindex. A positive statistically significant correlation of the IFN-I index with male sex (r=0,41, p=0,008), nephritis (r=0,35, p=0,026), livedoid rash (r=0,38, p=0,017 ), Raynaud's phenomenon (r=0,37, p=0,018), high antinuclear factor (r=0,82, p=0,001), rheumatoid factor (r=0,654, p=0,011), antibodies to Sm antigen (r=0,57, p=0,034), as well as a negative relationship with anemia (r=–0,67, p=0,009). Conclusion: IFN-I-index can be considered as a surrogate biomarker of activity and prognosis of SLE. Further research is required to validate its diagnostic role.

Adult systemic lupus erythematosus in Egypt: The nation-wide spectrum of 3661 patients and world-wide standpoint

Lupus ◽  
2021 ◽  
pp. 096120332110142
Author(s):  
Tamer A Gheita ◽  
Rasha Abdel Noor ◽  
Esam Abualfadl ◽  
Osama S Abousehly ◽  
Iman I El-Gazzar ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Age Of Onset ◽  
Wide Spectrum ◽  
Age At Onset ◽  
Disease Onset ◽  
Clinical Manifestations ◽  
Population Based ◽  
Systemic Lupus ◽  
Cross Sectional

Objective The aim of this study was to present the epidemiology, clinical manifestations and treatment pattern of systemic lupus erythematosus (SLE) in Egyptian patients over the country and compare the findings to large cohorts worldwide. Objectives were extended to focus on the age at onset and gender driven influence on the disease characteristics. Patients and method This population-based, multicenter, cross-sectional study included 3661 adult SLE patients from Egyptian rheumatology departments across the nation. Demographic, clinical, and therapeutic data were assessed for all patients. Results The study included 3661 patients; 3296 females and 365 males (9.03:1) and the median age was 30 years (17–79 years), disease duration 4 years (0–75 years) while the median age at disease onset was 25 years (4–75 years). The overall estimated prevalence of adult SLE in Egypt was 6.1/100,000 population (1.2/100,000 males and 11.3/100,000 females).There were 316 (8.6%) juvenile-onset (Jo-SLE) and 3345 adult-onset (Ao-SLE). Age at onset was highest in South and lowest in Cairo (p < 0.0001). Conclusion SLE in Egypt had a wide variety of clinical and immunological manifestations, with some similarities with that in other nations and differences within the same country. The clinical characteristics, autoantibodies and comorbidities are comparable between Ao-SLE and Jo-SLE. The frequency of various clinical and immunological manifestations varied between gender. Additional studies are needed to determine the underlying factors contributing to gender and age of onset differences.

The Potential Role of Interferon-regulatory Factor 7 Among Taiwanese Patients with Systemic Lupus Erythematosus

2011 ◽  
Vol 38 (9) ◽  
pp. 1914-1919 ◽  
Author(s):  
LI-HSIN LIN ◽  
PIN LING ◽  
MING-FEI LIU
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Control Group ◽  
Type I ◽  
Mrna Levels ◽  
Regulatory Factor ◽  
Systemic Lupus ◽  
Increased Risk

Objective.Type I interferons (IFN), especially IFN-α, have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Members of the IFN regulatory factor (IRF) family, which regulate IFN expression, have been implicated as risk factors for SLE. Our aims were to investigate the expression of IRF7 and its correlation with disease activity and to explore the association in Taiwanese patients between 2 genetic single-nucleotide polymorphisms (SNP) of IRF7 and SLE.Methods.IRF7 messenger RNA (mRNA) levels were measured in peripheral blood mononuclear cells by real-time reverse transcription polymerase chain reaction in 51 adult patients with SLE and 65 age-matched and sex-matched controls. Their serum IFN-α levels were determined by ELISA and the clinical manifestations were recorded at the same time. Two IRF7 SNP, rs1061501 and rs1061502, were examined by genotyping across 92 patients with SLE and 92 age and sex-matched healthy control subjects.Results.Compared with controls, the expression of IRF7 mRNA was significantly increased in patients with SLE and was positively correlated with both the serum level of IFN-α and lupus disease activity. The distribution of SNP rs1061501 by genotype (CC, CT, and TT) and by allele (C, T) was significantly different between the SLE and the control group (p = 0.028 for genotype and p = 0.009 for allele). There were no significant differences for SNP rs1061502.Conclusion.The results suggest that dysregulation of IRF7 might mediate an excessive production of IFN-α, which then exerts a crucial effect on the pathogenesis of human SLE. The IRF7 SNP rs1061501 TT genotype and T allele are enriched in Taiwanese patients with SLE and thus would seem to be associated with an increased risk of developing SLE.

scholarly journals The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus

2015 ◽  
Vol 74 (7) ◽  
pp. 1474-1478 ◽  
Author(s):  
Tobias Alexander ◽  
Ramona Sarfert ◽  
Jens Klotsche ◽  
Anja A Kühl ◽  
Andrea Rubbert-Roth ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Therapeutic Option ◽  
Serum Antibody ◽  
Clinical Manifestations ◽  
Surrogate Marker ◽  
Type I ◽  
Systemic Lupus

ObjectivesTo investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE).MethodsTwelve patients received a median of two (range 1–4) 21-day cycles of intravenous bortezomib (1.3 mg/m2) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti–double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity.ResultsUpon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined.ConclusionsThese findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.

scholarly journals The type I interferon system in systemic lupus erythematosus

2006 ◽  
Vol 54 (2) ◽  
pp. 408-420 ◽  
Author(s):  
Lars Rönnblom ◽  
Maija-Leena Eloranta ◽  
Gunnar V. Alm
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I ◽  
Systemic Lupus ◽  
Interferon System

scholarly journals Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus

RMD Open ◽  
2017 ◽  
Vol 3 (2) ◽  
pp. e000508 ◽  
Author(s):  
Helena Tydén ◽  
Christian Lood ◽  
Birgitta Gullstrand ◽  
Christoffer Tandrup Nielsen ◽  
Niels H H Heegaard ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Endothelial Dysfunction ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Type I ◽  
Systemic Lupus ◽  
Interferon System

scholarly journals Role of Hsp90 in Systemic Lupus Erythematosus and Its Clinical Relevance

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Hem D. Shukla ◽  
Paula M. Pitha
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Heat Shock ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Heat Shock Protein 90 ◽  
Type I ◽  
Systemic Lupus ◽  
Conformational Regulation ◽  
Shock Proteins ◽  
Hsp 90

Heat shock proteins (HSP) are a family of ubiquitous and phylogenically highly conserved proteins which play an essential role as molecular chaperones in protein folding and transport. Heat Shock Protein 90 (Hsp90) is not mandatory for the biogenesis of most proteins, rather it participate in structural maturation and conformational regulation of a number of signaling molecules and transcription factors. Hsp90 has been shown to play an important role in antigen presentation, activation of lymphocytes, macrophages, maturation of dendritic cells, and in the enhanceosome mediated induction of inflammation. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Dysregulated expression of Type I interferonα, activation of B cells and production of autoantibodies are hallmarks of SLE. The enhanced levels of Hsp90 were detected in the serum of SLE patients. The elevated level of Hsp90 in SLE has also been correlated with increased levels of IL-6 and presence of autoantibodies to Hsp90. This suggests that Hsp90 may contribute to the inflammation and disease progression and that targeting of Hsp 90 expression may be a potential treatment of SLE. The pharmacologic inhibition of Hsp90 was successfully applied in mouse models of autoimmune encephalomyelitis and SLE—like autoimmune diseases. Thus targeting Hsp90 may be an effective treatment for SLE, especially if combined with other targeted therapeutic approaches.

scholarly journals Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Role of Proinflammatory Cytokines and Therapeutic Approaches

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Chary López-Pedrera ◽  
Maria Ángeles Aguirre ◽  
Nuria Barbarroja ◽  
Maria José Cuadrado
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Combined Therapy ◽  
Clinical Manifestations ◽  
New Drugs ◽  
Type I ◽  
Systemic Lupus ◽  
Accelerated Atherosclerosis ◽  
Increased Risk

Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a broad range of clinical manifestations, is associated with accelerated atherosclerosis (AT) and increased risk of cardiovascular complications. Relevant factors directly influencing the development of AT comprise immune complex generation, complement activation, and changes in the production and activity of a complex network of cytokines, including type I and II interferons, B lymphocyte stimulator (BLyS), TNFα, IL-6, IL-17 and migration macrophage inhibitor (MIF). Autoantibodies, also responsible for cytokine expression and activation, play a supplementary key role in the development of AT. Genomic and proteomic studies have contributed to the discovery of genes and proteins involved in AT, including some that may be suitable to be used as biomarkers. All that data has allowed the development of new drugs, most of them evaluated in clinical trials: inhibitors of IFN and TNFα, B cell directed therapies, synthetic oligodeoxynucleotides, intravenous immunoglobulin, or statins. The focus of the present paper is to summarize recent evidence showing the role of cytokines in the development of AT in SLE and the rationale, and safety concerns, in the use of combined therapy to prevent AT and cardiovascular disease.

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