Fecal microbiota changes in NZB/W F1 mice after induction of lupus disease

The association between the gut microbiota and the development of lupus is unclear. We investigated alterations in the gut microbiota after induction of lupus in a murine model using viral peptide of human cytomegalovirus (HCMV). Three treatment arms for the animals were prepared: intraperitoneal injection of HCMVpp65 peptide, adjuvant alone, and PBS injection. Feces were collected before and after lupus induction biweekly for 16S rRNA sequencing. HCMVpp65 peptide immunization induced lupus-like effects, with higher levels of anti-dsDNA antibodies, creatinine, proteinuria, and glomerular damage, compared with mice treated with nothing or adjuvant only. The Simpson diversity value was higher in mice injected with HCMVpp65 peptide, but there was no difference in ACE or Chao1 among the three groups. Statistical analysis of metagenomic profiles showed a higher abundance of various families (Saccharimonadaceae, Marinifiaceae, and Desulfovibrionaceae) and genera (Candidatus Saccharimonas, Roseburia, Odoribacter, and Desulfovibrio) in HCMVpp65 peptide-treated mice. Significant correlations between increased abundances of related genera (Candidatus Saccharimonas, Roseburia, Odoribacter, and Desulfovibrio) and HCMVpp65 peptide immunization-induced lupus-like effects were observed. This study provides insight into the changes in the gut microbiota after lupus onset in a murine model.

Prevalence of Anti-Nuclear Antibodies and Anti-Phospholipid Antibodies in an Egyptian Cohort with Schizophrenia: A Case-Control Study

Background: Psychiatric disorders, including schizophrenia could herald other manifestation(s) of systemic lupus erythematosus (SLE) potentially hindering timely and optimal management. Moreover, schizophrenia is among the described ‘extra-criteria’ manifestations of anti-phospholipid syndrome (APS). Hence, screening schizophrenia patients for SLE and APS may pose diagnostic and therapeutic implications. Objectives: Examine schizophrenia patients with no overt connective tissue disease(s) manifestation(s) for clinical and/or serologic evidence of SLE and/or APS. Methods: The study included 92 schizophrenia patients [61 (66.3%) males] and 100 age- and gender-matched healthy controls. Both groups were tested for anti-nuclear antibodies (ANAs), anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies, complement 3 (C3) and C4, and criteria anti-phospholipid antibodies (aPL) [anticardiolipin Immunoglobulin (Ig) G and IgM, anti-beta-2-glycoprotein I IgG and IgM, and lupus anticoagulant (LAC)]. Results: The patients’ mean age and disease duration were 28.8 ± 8.1 and 5.7 ± 2.2 years, respectively. The prevalence of ANA positivity, height of titre, and pattern was comparable between patients and controls (p = 0.9, p = 0.8 and p = 0.1, respectively). Anti-dsDNA antibodies and hypocomplementemia were absent in both groups. A significantly higher frequency of positive LAC was observed among patients compared with controls (7.6 % vs. 1 %, p = 0.02), whereas other aPL were comparable between both groups. None of the patients or controls demonstrated clinically meaningful (medium or high) aPL titres. Conclusion: In our study, schizophrenia was solely associated with LAC. Thus, in the absence of findings suggestive of SLE or APS, routine screening for both diseases is questionable.

Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus

ABSTRACTObjectivesTo evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE).MethodsSIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020.ResultsSLE was confirmed in 76 of 232 patients (32.8%) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared to patients without SLE (p<0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were > 99.9 % and 0.1 %, respectively. Using ROC analysis and Delong testing, the area under the curve (AUC) for SIGLEC1 (AUC=0.95) was significantly higher than for ANA (AUC=0.88, p=0.031), C3 (AUC=0.83, p=0.001) and C4 (AUC=0.83, p=0.002) but not for anti-dsDNA antibodies (AUC=0.90, p=0.163).ConclusionIFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.

Transplantation of mesenchymal stem cells ameliorates systemic lupus erythematosus and upregulates B10 cells through TGF-β1

Background Considerable experimental and clinical evidences have proved that human umbilical cord mesenchymal stem cells (UC-MSCs) transplantation was powerful in systemic lupus erythematosus (SLE) treatment. MSCs could upregulate regulatory B cells (Bregs) in the mice model of the other immune disease. However, the regulation of MSCs on Bregs in SLE environment remains unclear. Methods To assess the abilities of UC-MSCs to treat SLE, MSCs were transferred intravenously to 17- to 18-week-old MRL/lpr mice. Four weeks later, mice were sacrificed. Survival rates, anti-dsDNA antibodies and renal histology were evaluated. CD4+ T helper (Th) cell subgroups and interleukin (IL)-10+ Bregs (B10) in the spleen were quantitated by flow cytometry. The changes of transforming growth factor (TGF)-β1, IL-6 and indoleamine 2,3-dioxyenase (IDO) mRNAs expressed by MSCs after co-cultured with B cells were detected using real-time polymerase chain reaction (RT-PCR). MSCs were infected by lentivirus carrying TGF-β1 shRNAs, then MSCs with low expression of TGF-β1 were conducted for co-culture in vitro and transplantation experiments in vivo. Results UC-MSCs transplantation could efficiently downregulate 24 h proteinuria and anti-dsDNA antibodies, correct Treg/Th17/Th1 imbalances and increase the frequency of B10 cells. The expression of TGF-β1 in MSCs was significantly increased after co-culture with B cells. Downregulation of TGF-β1 in MSCs could significantly attenuate the upregulation of B10 by MSCs in vitro and in vivo. Downregulation of TGF-β1 also compromised the immunomodulation effects of MSCs on Th17 and Treg cells and the therapeutic effects of MSC transplantation. Conclusions UC-MSCs could protect against SLE in mice and upregulate IL-10+ Bregs via TGF-β1.

The Therapeutic Strategies for SLE by Targeting Anti-dsDNA Antibodies

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by diverse serological autoantibodies. Anti-dsDNA antibodies are involved in multiple organ damage, especially the kidney, skin, and central nervous system. Anti-dsDNA antibodies play a pivotal role in SLE, and researchers have developed therapeutic strategies targeting these antibodies. Approaches to reduce anti-dsDNA antibodies via B cell targeted biologics against B cell surface antigens, B cell survival factors, or Bruton’s tyrosine kinase have effectively eliminated B cells. However, their non-specific depletion hampers normal immune system functioning and limits the therapeutic benefits. Thus, scientists have attempted anti-dsDNA antibodies or lupus-specific strategies, such as the immature dendritic cell vaccine and immunoadsorption. Recently, synthetic mimic peptides (hCDR1, pCONs, DWEYS, FISLE-412, and ALW) that directly block anti-dsDNA autoantibodies have attracted attention, which could ameliorate lupus, decrease the serological autoantibody titer, reduce the deposition of renal autoantibodies, and improve pathological performance. These potent small peptide molecules are well tolerated, non-toxic, and non-immunogenic, which have demonstrated a benign safety profile and are expected to be hopeful candidates for SLE management. In this review, we clarify the role of anti-dsDNA antibodies in SLE, mainly focus on the current strategies targeting anti-dsDNA antibodies, and discuss their potential clinical value.

Anti-dsDNA Antibodies Increase the Cardiovascular Risk in Systemic Lupus Erythematosus Promoting a Distinctive Immune and Vascular Activation

Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk. Approach and Results: Eighty SLE patients were included. Extensive clinical/analytical evaluation was performed, including cardiovascular disease parameters (endothelial function, proatherogenic dyslipidemia, and carotid intima-media thickness). Gene and protein expression profiles were evaluated in monocytes from patients diagnosed positive or negative for anti-dsDNA antibodies by using NanoString and cytokine arrays, respectively. NETosis and circulating inflammatory profile was assessed in both neutrophils and plasma. Positivity and persistence of anti-dsDNA antibodies in SLE patients were associated to endothelial dysfunction, proatherogenic dyslipidemia, and accelerated atherosclerosis. In parallel, anti-dsDNA antibodies were linked to the aberrant activation of innate immune cells, so that anti-dsDNA(+) SLE monocytes showed distinctive gene and protein expression/activity profiles, and neutrophils were more prone to suffer NETosis in comparison with anti-dsDNA(−) patients. Anti-dsDNA(+) patients further displayed altered levels of numerous circulating mediators related to inflammation, NETosis, and cardiovascular risk. In vitro, Ig-dsDNA promoted NETosis on neutrophils, apoptosis on monocytes, modulated the expression of inflammation and thrombosis-related molecules, and induced endothelial activation, at least partially, by FcR (Fc receptor)-binding mechanisms. Conclusions: Anti-dsDNA antibodies increase the cardiovascular risk of SLE patients by altering key molecular processes that drive a distinctive and coordinated immune and vascular activation, representing a potential tool in the management of this comorbidity.