scholarly journals Antinuclear Autoantibodies and Lupus Nephritis in Transgenic Mice Expressing Interferon γ in the Epidermis

1997 ◽  
Vol 186 (9) ◽  
pp. 1451-1459 ◽  
Author(s):  
John P. Seery ◽  
Joseph M. Carroll ◽  
Victoria Cattell ◽  
Fiona M. Watt
Keyword(s):  
Transgenic Mice ◽  
Lupus Erythematosus ◽  
Transgenic Animals ◽  
Organ Damage ◽  
Skin Lesions ◽  
Interferon Γ ◽  
Female Mice ◽  
Skin Immune System ◽  
Organ Specific ◽  
Ifn Γ

Systemic lupus erythematosus (SLE) is a potentially fatal non–organ-specific autoimmune disease that predominantly affects women. Features of the disease include inflammatory skin lesions and widespread organ damage caused by deposition of anti-dsDNA autoantibodies. The mechanism and site of production of these autoantibodies is unknown, but there is evidence that interferon (IFN) γ plays a key role. We have used the involucrin promoter to overexpress IFN-γ in the suprabasal layers of transgenic mouse epidermis. There was no evidence of organ-specific autoimmunity, but transgenic animals produced autoantibodies against dsDNA and histones. Autoantibody levels in female mice were significantly higher than in male transgenic mice. Furthermore, there was IgG deposition in the glomeruli of all female mice and histological evidence of severe proliferative glomerulonephritis in a proportion of these animals. Our findings are consistent with a central role for the skin immune system, acting under the influence of IFN-γ, in the pathogenesis of SLE.

scholarly journals Correlations of Expression Levels of a Panel of Genes (IRF5, STAT4, TNFSF4, MECP2, and TLR7) and Cytokine Levels (IL-2, IL-6, IL-10, IL-12, IFN-γ, and TNF-α) with Systemic Lupus Erythematosus Outcomes in Jordanian Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Amal H. Uzrail ◽  
Areej M. Assaf ◽  
Shtaywy S. Abdalla
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Renal Damage ◽  
Organ Damage ◽  
Systemic Lupus ◽  
Expression Levels ◽  
Cardiovascular Damage ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Ifn Γ

Systemic lupus erythematosus (SLE) is characterized by systemic end-organ damage. We investigated the involvement of IRF5, TLR-7, MECP2, STAT4, and TNFSF4 genes and TNF-α, IFN-γ, IL-2, IL-12, IL-6, and IL-10 cytokines in SLE pathogenesis and in organ damage in Jordanian patients. Blood was collected from 51 patients and 50 controls. Expression levels of SLE genes in PBMCs and cytokine levels were determined using RT-PCR and ELISA, respectively. Expression levels of all genes and levels of TNF-α, IL-12, IL-6, and IL-10 were higher in SLE patients than those in controls (p<0.05), whereas IL-2 level was lower. High STAT4 (α), TNFSF4, and IL-10 levels correlated with cardiovascular damage, and high MECP2 (α) and TNF-α correlated with renal damage. Pulmonary and musculoskeletal damages correlated with high levels of TNFSF4. We concluded that STAT4 and TNFSF4 genes with TNF-α and IL-10 cytokines could be used as biomarkers to assess SLE activity and manage treatment.

scholarly journals Development of Prediction Models for New Integrated Models and a Bioscore System to Identify Bacterial Infections in Systemic Lupus Erythematosus

2021 ◽  
Vol 11 ◽  
Author(s):  
Xvwen Zhai ◽  
Min Feng ◽  
Hui Guo ◽  
Zhaojun Liang ◽  
Yanlin Wang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Bacterial Infections ◽  
Prediction Models ◽  
Predictive Ability ◽  
Treg Cells ◽  
Interferon Γ ◽  
Systemic Lupus ◽  
Ifn Γ ◽  
Factor Α

ObjectivesDistinguishing flares from bacterial infections in systemic lupus erythematosus (SLE) patients remains a challenge. This study aimed to build a model, using multiple blood cells and plasma indicators, to improve the identification of bacterial infections in SLE.DesignBuilding PLS-DA/OPLS-DA models and a bioscore system to distinguish bacterial infections from lupus flares in SLE.SettingDepartment of Rheumatology of the Second Hospital of Shanxi Medical University.ParticipantsSLE patients with flares (n = 142) or bacterial infections (n = 106) were recruited in this retrospective study.OutcomeThe peripheral blood of these patients was collected by the experimenter to measure the levels of routine examination indicators, immune cells, and cytokines. PLS-DA/OPLS-DA models and a bioscore system were established.ResultsBoth PLS-DA (R2Y = 0.953, Q2 = 0.931) and OPLS-DA (R2Y = 0.953, Q2 = 0.942) models could clearly identify bacterial infections in SLE. The white blood cell (WBC), neutrophile granulocyte (NEUT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), IL-10, interferon-γ (IFN-γ), and tumor necrosis factor α (TNF-α) levels were significantly higher in bacteria-infected patients, while regulatory T (Treg) cells obviously decreased. A multivariate analysis using the above 10 dichotomized indicators, based on the cut-off value of their respective ROC curve, was established to screen out the independent predictors and calculate their weights to build a bioscore system, which exhibited a strong diagnosis ability (AUC = 0.842, 95% CI 0.794–0.891). The bioscore system showed that 0 and 100% of SLE patients with scores of 0 and 8–10, respectively, were infected with bacteria. The higher the score, the greater the likelihood of bacterial infections in SLE.ConclusionsThe PLS-DA/OPLS-DA models, including the above biomarkers, showed a strong predictive ability for bacterial infections in SLE. Combining WBC, NEUT, CRP, PCT, IL-6, and IFN-γ in a bioscore system may result in faster prediction of bacterial infections in SLE and may guide toward a more appropriate, timely treatment for SLE.

scholarly journals Bone Marrow and Thymus Expression of Interferon-γ Results in Severe B-Cell Lineage Reduction, T-Cell Lineage Alterations, and Hematopoietic Progenitor Deficiencies

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 583-595 ◽  
Author(s):  
Howard A. Young ◽  
Dennis M. Klinman ◽  
Della A. Reynolds ◽  
Krzysztof J. Grzegorzewski ◽  
Aisuke Nii ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Lineage ◽  
Interferon Γ ◽  
Ifn Γ ◽  
B Lineage ◽  
Spleen And Lymph Nodes

Abstract Interferon-γ (IFN-γ) is an immunoregulatory lymphokine that is primarily produced by T cells and natural killer cells. It has effects on T-cell, B-cell, and macrophage differentiation and maturation. We have developed transgenic mice that express elevated levels of IFN-γ mRNA and protein by inserting multiple copies of murine IFN-γ genomic DNA containing an Ig λ-chain enhancer in the first intron. The founder line carrying eight copies of this transgene has eightfold to 15-fold more IFN-γ–producing cells in the bone marrow and spleen than do nontransgenic littermates. Transgenic mice show a pronounced reduction in B-lineage cells in the bone marrow, spleen, and lymph nodes. In addition, single positive (CD4+,CD8− and CD4−,CD8+) thymocyte numbers are increased twofold, yet the number of splenic T cells is reduced by 50%. There is also a twofold to threefold decrease in the frequency and total number of myeloid progenitors in the bone marrow. Granulomatous lesions and residual degenerating cartilaginous masses are also present in the bones of these mice. Overall, our data show that the abnormal expression of IFN-γ in these transgenic mice results in multiple alterations in the immune system. These animals provide an important model to examine the role of IFN-γ expression on lymphoid and myeloid differentiation and function.

scholarly journals Sex-Dependent Effect of Melatonin on Systemic Erythematosus Lupus Developed in Mrl/Mpj-Faslpr Mice: It Ameliorates the Disease Course in Females, whereas It Exacerbates It in Males

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1717-1724 ◽  
Author(s):  
Antonio J. Jimenez-Caliani ◽  
Silvia Jimenez-Jorge ◽  
Patrocinio Molinero ◽  
Jose M. Fernandez-Santos ◽  
Ines Martin-Lacave ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Chronic Administration ◽  
Interferon Γ ◽  
Total Serum ◽  
Male Mice ◽  
Immunological Parameters ◽  
Female Mice ◽  
Spleen And Lymph Nodes ◽  
Nitrite Nitrate

In this study, the effect of chronic administration of melatonin on MRL/MpJ-Faslpr mice has been studied. These mice spontaneously develop an autoimmune disease that has many features resembling human systemic lupus erythematosus. In fact, histological studies showed that all female mice and most male mice exhibited glomerular abnormalities, arteritic lesions, and cellular interstitial inflammatory infiltrate ranging from mild to severe patterns. Treatment with melatonin improved the histological pattern in females and worsened it in males. Moreover, female mice treated with melatonin showed a diminution of titers of total serum IgG, IgM, and anti-double-stranded DNA and anti-CII autoantibodies; a decrease in proinflammatory cytokines (IL-2, IL-6, interferon-γ, TNF-α, and IL-1β), an increase in antiinflammatory cytokines (IL-10), and a decrease in nitrite/nitrate. In male mice, treatment with melatonin exhibited the opposite effect, worsening all the immunological parameters with an elevation of titers of autoantibodies and a prevalence of proinflammatory vs. antiinflammatory cytokines. Similar results were obtained when lymphocytes from spleen and lymph nodes were cultured. Again, melatonin treatment in females decreased proinflammatory cytokines and increased antiinflammatory cytokines produced by lymphocytes; in males, the effect was the opposite. These findings suggest that melatonin action in MRL/MpJ-Faslpr mice is gender dependent, probably through modulation and inhibition of sex hormones.

Overexpression of interferon-γ and indoleamine 2, 3-dioxygenase in systemic lupus erythematosus: relationship with the disease activity

2017 ◽  
Vol 41 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Saeed Mohammadi ◽  
Sima Sedighi ◽  
Ali Memarian ◽  
Yaghoub Yazdani
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Disease Activity Index ◽  
Interferon Γ ◽  
Systemic Lupus ◽  
Indoleamine 2 ◽  
Ifn Γ ◽  
Positive Correlations

AbstractBackground:Indoleamine 2, 3-dioxygenase (IDO) is a tryptophan catabolizing enzyme which is involved in immune regulation and autoimmune disorders such as systemic lupus erythematosus (SLE). Interferon-γ (IFN-γ) is an inflammatory cytokine which is the major inducer of IDO expression. Here, we evaluated the level of IFN-γ and IDO among SLE patients in correlation with the severity of SLE.Methods:Fifty-three SLE patients and 35 age matched healthy donors were enrolled in this study. Systemic lupus erythematosus disease activity index (SLEDAI) was used to calculate the disease activity. Real-time RT-PCR and ELISA were used to evaluate the gene expression of IDO and IFN-γ plasma concentration, respectively.Results:We showed that IDO-1, IDO-2 and IFN-γ were overexpressed among SLE patients significantly (p<0.0001). There were significant positive correlations between IFN-γ with the expression of IDO-1 (r=0.722, p<0.0001) and IDO-2 (r=0.682, p<0.0001). There were also positive correlations between SLEDAI scores with IDO-1 (r=0.675, p<0.0001), IDO-2 (r=0.727, p<0.0001) and IFN-γ (r=0.907, p<0.0001).Conclusions:IDO expression and IFN-γ level could be introduced as helpful biomarkers for the determination of disease severity in SLE patients.

scholarly journals Double-Edged Sword: Interleukin-2 Promotes T Regulatory Cell Differentiation but Also Expands Interleukin-13- and Interferon-γ-Producing CD8+ T Cells via STAT6-GATA-3 Axis in Systemic Lupus Erythematosus

2021 ◽  
Vol 12 ◽  
Author(s):  
Hiroshi Kato ◽  
Andras Perl
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Interleukin 2 ◽  
Inflammatory Cells ◽  
Interferon Γ ◽  
T Regulatory Cell ◽  
Systemic Lupus ◽  
Double Positive ◽  
Ifn Γ

Interleukin-2 (IL-2) expands the depleted T regulatory (Treg) cell population, and it has emerged as a potential therapy in systemic lupus erythematosus (SLE). However, IL-2 administration may involve the risk of expanding unwanted pro-inflammatory cells. We herein studied the effects of IL-2 on pro-inflammatory cytokine production by CD4+ and CD8+ T cells in parallel with Treg development following CD3/CD28 co-stimulation. While Treg cells are depleted in SLE patients, their CD4+ T cells were poised to receive and activate IL-2 signaling as evidenced by upregulation of CD25 and enhanced IL-2-incued STAT5 phosphorylation during Treg differentiation. In patients with SLE, however, IL-2 also expanded CD8+ T cells capable of producing interleukin-5, interkeukin-13 (IL-13), and interferon-γ (IFN-γ) that occurred with enhanced expression of GATA-3 and phosphorylation of STAT6 but not STAT5. Our data pinpoint a safety signal for systemic administration of IL-2 and challenges a long-held conceptual platform of type 1 and 2 cytokine antagonism by newly documenting the IL-2-dependent development of IL-13 and IFN-γ double-positive (IL-13+IFNγ+) CD8+ T cells in SLE.

scholarly journals Epidemiological, demographic, social, clinical features of manifestations of system red lupus in patients in Kazakhstan

2021 ◽  
Vol 59 (1) ◽  
pp. 75-83
Author(s):  
B. G. Issayeva ◽  
E. A. Aseeva ◽  
M. M. Saparbayeva ◽  
S. M. Issayeva ◽  
M. M. Kulshymanova ◽  
...  
Keyword(s):  
Nervous System ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Asian Population ◽  
Organ Damage ◽  
Skin Lesions ◽  
Asian Populations ◽  
Number Of Patients ◽  
The Republic ◽  
Significant Disease

Objective: to study and analyze the dynamics of prevalence, demographic, social, and clinical manifestations of systemic lupus erythematosus (SLE) in patients living in Kazakhstan.Materials and methods. Official materials of the Ministry of Health of the Republic of Kazakhstan (2009–2018): statistical compendiums, a consolidated reporting form for medical treatment (N 12). 102 patients (100 women and 2 men) were included in the register of SLE with reliable SLE according to SLICC (ACR, 2012). Assessment of the debut of the disease was carried out according to archival material (medical history, outpatient records) of patients. The activity of the process was evaluated according to SLEDAI-2K, organ damage according to SLICC/ACR (2000).Results. The total number of patients with SLE over 10 years (2009–2018) more than doubled, the growth rate was 101%. The overwhelming majority of patients with SLE are women (91%). In the study group, Asians (83.33%) predominated by race, of which Kazakhs (76.47%) were young (mean age – 33.85±10.58 years), with a disease duration of 5 (2; 9) years, time from the appearance of the first signs to verification of SLE – 4.5 (3; 12) years. The prevailing acute (49.0%), subacute (33.3%), rather than chronic (18.7%) variants of the course, with high activity according to SLEDAI-2K – 17.64±8.80. The most common clinical manifestations of the disease: skin lesions (98%), joints (79.4%), nervous system (49%), hematological (54.9%) and immunological (100%) disorders. The absence of organ damage (0 points) was detected in 10 (9.8%) cases, low (1 point) – in 21 (20.6%), medium (2–4) – in 61 (59.8%), high (over 4) – in 10 (9.8%) patients.Conclusion. SLE remains a socially significant disease in Kazakhstan, as evidenced by the dynamics of the increase in incidence (101%) over 10 years (2009–2018). The prevalence of SLE is 24.7 per 100 thousand of the country’s population, lower than in other countries with a predominant Asian population or in comparison with Asian populations. A cohort of patients with SLE was represented by people of the Asian race (83.33%), Kazakhs (76.47%), and young people (33.85±10.58). The analysis revealed a delayed verification of the diagnosis of SLE (on average 4.5 (3; 12) years). Acute variants of the course of the disease with high disease activity according to SLEDAI-2K prevail. Common clinical manifestations of SLE are skin lesions, both acute and chronic (98%), joints (79.4%), damage to the nervous system (49%), hematological (54.9%) and immunological disorders (100%).

Transgenic prolactin−/− mice: effect of trauma-hemorrhage on splenocyte functions

2005 ◽  
Vol 288 (5) ◽  
pp. C1109-C1116 ◽  
Author(s):  
Takeshi Matsutani ◽  
T. S. Anantha Samy ◽  
Loring W. Rue ◽  
Kirby I. Bland ◽  
Irshad H. Chaudry
Keyword(s):  
Transgenic Mice ◽  
Immune Functions ◽  
Wild Type ◽  
Female Mice ◽  
Nb2 Cells ◽  
In The Wild ◽  
Ifn Γ ◽  
Local Release ◽  
Very High

Prolactin (PRL) is involved in the regulation of immune functions under normal and pathological conditions. Trauma-hemorrhage (T-H) produces profound immunosuppression in male mice but not in proestrus female mice. Administration of PRL in males after T-H, however, restores immune functions. In this study, PRL+/+ and transgenic (PRL−/−) male and female mice were used to assess immune suppression after T-H and to determine the reasons for the hormone's beneficial effect. In vitro lymphoproliferation assay with Nb2 cells showed complete absence of PRL in the circulation of the transgenic PRL−/− mice of both sexes, whereas very high levels of the hormone were detected in the wild-type PRL+/+ mice of both sexes. Moreover, T-H resulted in the appearance of significant levels of the hormone in circulation, but only in PRL+/+ mice. Splenocyte proliferation in male PRL−/− mice was significantly lower than in PRL+/+ mice after T-H. Marginal differences between PRL+/+ and PRL−/− mice were observed in the release of IL-2 and IFN-γ by splenocytes, while the release of IL-10 was significantly higher in PRL−/− than in PRL+/+ mice. A significant observation of our study is the release of a ∼25-kDa protein in the concanavalin A-stimulated splenocytes of male PRL+/+ and PRL−/− mice that was active in the in vitro lymphoproliferation assay with Nb2 cells. It is unlikely that this protein is PRL because it is also present in the splenocyte extracts of PRL−/− transgenic mice. Nonetheless, because control of lymphoid cell proliferation is considered one of the characteristics of the immune system, the local release of this protein may be significant in the differences observed in splenocyte cytokine release after T-H in wild-type as well as transgenic mice.

scholarly journals Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus

2020 ◽  
Vol 6 (47) ◽  
pp. eabd1471 ◽  
Author(s):  
Marat Khodoun ◽  
Ameet A. Chimote ◽  
Farhan Z. Ilyas ◽  
Heather J. Duncan ◽  
Halima Moncrieffe ◽  
...  
Keyword(s):  
T Cell ◽  
Lupus Erythematosus ◽  
Healthy Donor ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Organ Damage ◽  
Interferon Γ ◽  
Peripheral Blood Mononuclear ◽  
Voltage Dependent

Lupus nephritis (LN) is an autoimmune disease with substantial morbidity/mortality and limited efficacy of available therapies. Memory T (Tm) lymphocytes infiltrate LN kidneys, contributing to organ damage. Analysis of LN, diabetic nephropathy, and healthy donor kidney biopsies revealed high infiltration of active CD8+ Tm cells expressing high voltage-dependent Kv1.3 potassium channels—key T cell function regulators—in LN. Nanoparticles that selectively down-regulate Kv1.3 in Tm cells (Kv1.3-NPs) reduced CD40L and interferon-γ (IFNγ) in Tm cells from LN patients in vitro. Kv1.3-NPs were tested in humanized LN mice obtained by engrafting peripheral blood mononuclear cells (PBMCs) from LN patients into immune-deficient mice. LN mice exhibited features of the disease: increased IFNγ and CD3+CD8+ T cell renal infiltration, and reduced survival versus healthy donor PBMC engrafted mice. Kv1.3-NP treatment of patient PBMCs before engraftment decreased CD40L/IFNγ and prolonged survival of LN mice. These data show the potential benefits of targeting Kv1.3 in LN.

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