High Systemic Type I Interferon Activity is Associated with Active Class III/IV Lupus Nephritis

2021 ◽  
pp. jrheum.210391
Author(s):  
Taro Iwamoto ◽  
Jessica M. Dorschner ◽  
Shanmugapriya Selvaraj ◽  
Valeria Mezzano ◽  
Mark A. Jensen ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Type I Interferon ◽  
Renal Tissue ◽  
High Serum ◽  
Complement C3 ◽  
Type I ◽  
Class Iii ◽  
Dsdna Antibody ◽  
The Impact ◽  
Active Class

Objective Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the impact of IFN in LN. Methods 221 systemic lupus erythematosus (SLE) patients were studied. Serum IFN activity was measured by WISH bioassay. mRNA in-situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, interferon-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C or BDCA2). Podocyte cell line gene expression was measured by real-time PCR. Results Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (OR=5.48, p=4.0x10-7). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely co-localized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. Conclusion Systemic high IFN is involved in the pathogenesis of severe LN. We do not find co-localization of pDCs with IFN signature in renal tissue, and instead observe the greatest intensity of IFN signature in glomerular areas, which could suggest a blood source of IFN.

Early-stage predictors for treatment responses in patients with active lupus nephritis

Lupus ◽  
2019 ◽  
Vol 28 (3) ◽  
pp. 283-289 ◽  
Author(s):  
G Liu ◽  
H Wang ◽  
J Le ◽  
L Lan ◽  
Y Xu ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Serum Albumin ◽  
Immunosuppressive Therapy ◽  
Early Stage ◽  
Complement C3 ◽  
Class Iii ◽  
Class V ◽  
Predictive Values ◽  
Cutoff Value ◽  
Active Lupus Nephritis

Objective We analyzed data of lupus nephritis (LN) patients to find parameters that can predict remission. Methods Sixty-four LN patients who were diagnosed with class III, IV, V or V + III/IV by renal biopsy and were followed up for more than six months in our center were enrolled retrospectively. Receiver operating characteristic curves were used to test the predictive values of urinary protein-to-creatinine ratio (UPCR), serum albumin and complement C3 at the first, second and third months as predictors for remission at the sixth month. Results The patients' renal pathologies were class III (five cases), class IV (33 cases), class V (nine cases) and class V + III/IV (17 cases). All patients received standard immunosuppressive therapy. Forty-six (71.9%) patients (grouped as the remission group) achieved remission at the end of the sixth month, including 23 complete remissions and 23 partial remissions. The other 18 patients were grouped as the no-remission group. There were no significant differences in clinical data, proportion of immunosuppressive therapy or renal pathological characteristics between the remission group and no-remission group at baseline, except the serum urea nitrogen of the remission group was lower than in the no-remission group. The UPCR were significantly lower in the remission group than in the no-remission group at months 1, 2, 3 and 6, respectively, while the serum albumin was significantly higher in the remission group than in the no-remission group at months 3 and 6, respectively. There were no significant differences in serum creatinine between the remission group and no-remission group, except at month 1. The C3 levels were higher in the remission group than in the no-remission group at months 1, 2 and 3, respectively. The areas under the curve (AUC) of the change percentage of UPCR at month 3 and the serum albumin at month 3 were the most significant (AUC 0.778, p = 0.002; AUC 0.773, p = 0.001, respectively). The cutoff value of the change percentage of UPCR at month 3 was 59%. The cutoff value of serum albumin at month 3 was 32.9g/l. Conclusion The change percentage of UPCR ≥59% and the serum albumin ≥32.9 g/l at the third month were valuable for predicting remission at the sixth month in LN. Because of the small-size and retrospective nature, this study needs to be validated.

scholarly journals Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

2021 ◽  
Author(s):  
Mengmeng Jin ◽  
Ranji Xu ◽  
Mahabub Maraj Alam ◽  
Ziyuan Ma ◽  
Sining Zhu ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Type I Interferon ◽  
Chromosome 21 ◽  
Type I ◽  
Chimeric Mouse ◽  
Interferon Signaling ◽  
Alzheimers Disease ◽  
Human Microglia ◽  
The Impact

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic neurotransmission, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA-sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide first in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau by exhibiting accelerated senescence and dystrophic phenotypes. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

scholarly journals MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells

2016 ◽  
Vol 68 (9) ◽  
pp. 2232-2243 ◽  
Author(s):  
Xiao Han ◽  
Yan Wang ◽  
Xiaoyan Zhang ◽  
Yuting Qin ◽  
Bo Qu ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Mesangial Cells ◽  
Type I Interferon ◽  
Type I ◽  
Murine Lupus ◽  
Interferon Pathway
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