A novel role of peptidyl-prolyl isomerase-1 as inducer of IL-6 expression in systemic lupus erythematosus

2015 ◽  
Vol 3 (2) ◽  
pp. 439-450
Author(s):  
Michael R Takeno ◽  
Jacob B Gunn ◽  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Stat3 Phosphorylation ◽  
Pin1 Inhibitor

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. Pro-inflammatory cytokines, such as interleukin 1β, IL-6 and IFN-g are associated with the SLE progression; however, the precise molecular mechanisms that in occurs improper cytokines production in SLE remain unknown. Autoantibody production and renal disease were evaluated in NZB/W F1 mice treated with a specific Pin1 inhibitor, Juglone. Inhibition of Pin1 activity significantly suppressed the IL-6 expression in NZB/W F1 mice and developed milder renal lesions than the lesions developing in non Juglone-treated mice. We further found that Pin1 inhibitor treatment suppresses B-cell differentiation and T-cell activation in NZB/W F1 lupus mice. Finally, stat3 phosphorylation was decreased in T cells from Pin1inhibitor-treated mice at 40 weeks of age as compared to that from the saline and isotype control mAb treatment groups. This is the first study to demonstrate that Pin1 plays critical roles in SLE development. Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy target for future SLE therapies.

A novel role of peptidyl-prolyl isomerase-1 as inducer of IL-6 expression in systemic lupus erythematosus

2015 ◽  
Vol 3 (2) ◽  
pp. 139-152
Author(s):  
Michael R Takeno ◽  
Jacob B Gunn
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Stat3 Phosphorylation ◽  
Pin1 Inhibitor

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. Pro-inflammatory cytokines, such as interleukin 1β, IL-6 and IFN-g are associated with the SLE progression; however, the precise molecular mechanisms that in occurs improper cytokines production in SLE remain unknown. Autoantibody production and renal disease were evaluated in NZB/W F1 mice treated with a specific Pin1 inhibitor, Juglone. Inhibition of Pin1 activity significantly suppressed the IL-6 expression in NZB/W F1 mice and developed milder renal lesions than the lesions developing in non Juglone-treated mice. We further found that Pin1 inhibitor treatment suppresses B-cell differentiation and T-cell activation in NZB/W F1 lupus mice. Finally, stat3 phosphorylation was decreased in T cells from Pin1inhibitor-treated mice at 40 weeks of age as compared to that from the saline and isotype control mAb treatment groups. This is the first study to demonstrate that Pin1 plays critical roles in SLE development. Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy target for future SLE therapies.

scholarly journals Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1641
Author(s):  
Chang-Youh Tsai ◽  
Chieh-Yu Shen ◽  
Chih-Wei Liu ◽  
Song-Chou Hsieh ◽  
Hsien-Tzung Liao ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Tissue Damage ◽  
Immune Modulation ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Circular Rnas ◽  
Contributing Factors ◽  
Systemic Lupus ◽  
Non Coding Rnas

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future.

scholarly journals The Homogeneous Multiplexed System-a New Method for Autoantibody Profile in Systemic Lupus Erythematosus

2005 ◽  
Vol 12 (2) ◽  
pp. 107-111 ◽  
Author(s):  
Gisele Zandman-Goddard ◽  
Boris Gilburd ◽  
Ora Shovman ◽  
Miri Blank ◽  
Svetlana Berdichevski ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Sledai Score ◽  
Autoantibody Profile ◽  
Multiplex System

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method.We analyzed the presence of elevated titers of anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Jo1, anti-centromere, anti-Scl-70, anti-histone, and anti-dsDNA antibodies in 199 serum samples (113 SLE patients, 86 healthy donors). We compared the type, level and number of autoantibodies and the correlation between the autoantibody profile and disease severity utilizing the SLEDAI score.Elevated titers of at least one autoantibody were detected in 48% of 42 SLE patients. Elevated titers of anti-Ro antibodies were most commonly detected. The distribution of specific autoantibodies was: anti-Ro- 23.8%, anti-dsDNA- 19%, anti-histone- 19%, anti-RNP- 14.2%, anti-La antibodies- 11.9%, anti-Sm- 7.1%, anti-Scl 70-4.7%, and anti-centromere- 2.4%. Utilizing ROC analysis, the sensitivity and specificity of anti-DNA antibodies at a cutoff value of 34 IU/ml were 87.1% and 79.4% respectively. Elevated titers of anti-Jo1 antibody were not detected. There was a correlation with the titer of anti-Ro antibodies and disease activity by the SLEDAI score. Seven patients harbored one autoantibody only, 15 patients harbored 2-3 autoantibodies, 3 patients harbored 4-5 autoantibodies, and one patient harbored 6 autoantibodies. A correlation between the number of autoantibodies per patient and disease severity was found. One patient with a multitude of autoantibodies had severe lupus and a myriad of clinical manifestations.In conclusion, the multiplex system is specific and sensitive, provides an autoantibody profile in a single test, and may be useful as a diagnostic test for SLE. Elevated anti-Ro antibodies are associated with severe disease. An autoantibody load may be indicative of more severe disease.

scholarly journals Transcription Factor Activity Inference in Systemic Lupus Erythematosus

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 299
Author(s):  
Raul Lopez-Dominguez ◽  
Daniel Toro-Dominguez ◽  
Jordi Martorell-Marugan ◽  
Adrian Garcia-Moreno ◽  
Christian H. Holland ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Transcription Factor ◽  
Lupus Erythematosus ◽  
Activity Patterns ◽  
Clinical Manifestations ◽  
Systemic Autoimmune Disease ◽  
Transcription Factor Activity ◽  
Factor Activity ◽  
Systemic Lupus ◽  
Almost All

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE. Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples. Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets—one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE. Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.

scholarly journals Case of a Сombination of Lupus Erythematosus, Antiphospholipid Syndrome and Myocardial Infarction

Kardiologiia ◽  
2019 ◽  
Vol 59 (12) ◽  
pp. 92-96
Author(s):  
N. A. Kosheleva ◽  
N. M. Nikitina ◽  
E. U. Andreeva
Keyword(s):  
Myocardial Infarction ◽  
Systemic Lupus Erythematosus ◽  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
The Body ◽  
Systemic Autoimmune Disease ◽  
Unknown Etiology ◽  
Systemic Lupus ◽  
Wide Range

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology characterized by a wide range of clinical manifestations with damage to various organs and systems of the body. There are bad prognostic factors for SLE: damage to the heart, kidney, central nervous system, the development of hematological crises and secondary antiphospholipid syndrome. A number of authors consider systemic lupus erythematosus a “new” risk factor for atherosclerosis. The overall risk of myocardial infarction (MI) in patients with SLE is 10 times higher than in the general population. The article presents clinical case report of the development of myocardial infarction in a woman with SLE, receiving therapy for secondary antiphospholipid syndrome.

Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus

Lupus ◽  
2016 ◽  
Vol 26 (7) ◽  
pp. 746-755 ◽  
Author(s):  
N Glesse ◽  
P Vianna ◽  
L M G Paim ◽  
M C C Matte ◽  
A K K Aguiar ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Protective Factor ◽  
Clinical Manifestations ◽  
Immunological Tolerance ◽  
Control Group ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Wide Range ◽  
Polymorphic Variants

Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL –844CC genotype and –844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL –844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX –248GA genotype and the –248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3+Annexin V+ 7-AAD+) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.

scholarly journals Respiratory Manifestations in Systemic Lupus Erythematosus

2021 ◽  
Vol 14 (3) ◽  
pp. 276
Author(s):  
Salvatore Di Bartolomeo ◽  
Alessia Alunno ◽  
Francesco Carubbi
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Specific Pattern ◽  
Systemic Autoimmune Disease ◽  
Therapeutic Approaches ◽  
Systemic Lupus ◽  
Respiratory Involvement ◽  
Life Threatening

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by a wide spectrum of clinical manifestations. The respiratory system can be involved in up to 50–70% of patients and be the presenting manifestation of the disease in 4–5% of cases. Every part of the respiratory part can be involved, and the severity can vary from mild self-limiting to life threatening forms. Respiratory involvement can be primary (caused by SLE itself) or secondary (e.g., infections or drug toxicity), acute or chronic. The course, treatment and prognosis vary greatly depending on the specific pattern of the disease. This review article aims at providing an overview of respiratory manifestations in SLE along with an update about therapeutic approaches including novel biologic therapies.

scholarly journals Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

2021 ◽  
Vol 13 (600) ◽  
pp. eabi4994
Author(s):  
Marc Scherlinger ◽  
Vivien Guillotin ◽  
Isabelle Douchet ◽  
Pierre Vacher ◽  
Andréa Boizard-Moracchini ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Transforming Growth Factor Β ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Systemic Lupus Erythematosus Pathogenesis ◽  
Dsdna Antibody

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin–dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.

scholarly journals FRI0602-HPR PERSISTENT HYPOCOMPLEMENTEMIA IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 907.2-907
Author(s):  
M. L. Leguizamón ◽  
Y. Soria Curi ◽  
S. M. Mazza ◽  
G. V. Espasa ◽  
F. J. Hüttmann ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Evolution Time ◽  
Accumulated Damage ◽  
Clinical Records

Background:Systemic lupus erythematosus (SLE) is a systemic, chronic, autoimmune disease of unknown cause characterized by a wide variety of clinical manifestations and autoantibody production. The complement is useful in the initial diagnosis, as an activity marker and for the follow-up of patients with SLE. Individual components may fluctuate only slightly with disease activity and C4 may even remain low during remission. Hypocomplementemia is associated with renal involvement, cutaneous vasculitis, diffuse alveolar hemorrhage, however, patients with persistent hypocomplementemia are not characterized yet.Objectives:1) Determine the prevalence of persistent hypocomplementemia in patients with SLE.2) Identify clinical characteristics, disease activity and accumulated damage in these patients.Methods:A longitudinal study was conducted with a review of the medical records of patients diagnosed with SLE (ACR criteria 82/97) who attended the Rheumatology Service between January 2000 and December 2015. Patients with a minimum evolution time of 6 months from the diagnosis of SLE with quarterly controls and monitoring for 2 years. Persistent Hypocomplementemia (PHC) was defined at C3 and / or C4 values below the normal range of the reference laboratory in a sustained form for at least 24 months. Demographic variables, clinical manifestations, disease activity by SLEDAI 2k, flare by SELENA SLEDAI and accumulated damage by SLICC / SDI were analyzed.Results:Clinical records of 254 patients with SLE were reviewed and 144 were included; 96% were women, with a mean age at diagnosis of SLE of 30.5 ± 11.2 years and a time of evolution of the disease at the last control 11.85 ± 7.8 years. Forty-one patients had PHC (28.5%; 95% CI 21.1, 35.8). The median of evolution time disease at the moment of PHC was 1 year (0-24) and the mean time of persistence of hypocomplementemia was 56 ± 46 months. In the univariate analysis, PHC was associated with hematological involvement during the course of the disease (p=0.01). Patients with PHC had a higher frequency of severe flare during follow-up (p=0.02). PHC was not associated with age of onset of SLE, disease activity (maximum SLEDAI reached), accumulated damage or death. Applying Logistic Regression Model with dependent variables with a level of significance <0.25, PHC was associated independently with hematological compromise (OR 3.2).Conclusion:In this cohort of patients, the prevalence of PHC was 28.5%. PHC was associated with severe flare and hematological compromise.Disclosure of Interests:None declared

Clinical case of lung lesions in patient with newly diagnosed systemic lupus erythematosus

2019 ◽  
Vol 1 (9) ◽  
pp. 53-57
Author(s):  
T. N. Gavva ◽  
L. V. Kuzmenkova ◽  
Yu. N. Fedulaev ◽  
T. V. Pinchuk ◽  
D. D. Kaminer ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Clinical Case ◽  
Clinical Manifestations ◽  
Lung Damage ◽  
Newly Diagnosed ◽  
Systemic Lupus ◽  
Lung Lesions ◽  
Laboratory Parameters ◽  
Clinical Interest

A case of lung damage in systemic lupus erythematosus (SLE) in a 33-year-old woman is described. This case is of clinical interest due to the complexity of diagnosis due to the fact that SLE is a disease with diverse clinical manifestations involving many organs and systems, which often makes it difficult to timely recognize the onset of the disease. SLE still remains a challenge and requires special attention to the patient s history, clinical and laboratory parameters of the patient, as well as specific immunological examinations.

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