Clinical features and prognosis of ANCA-associated vasculitis patients who were double-seropositive for myeloperoxidase-ANCA and proteinase 3-ANCA.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with dual positivity for proteinase 3-ANCA (PR3-ANCA) and myeloperoxidase-ANCA (MPO-ANCA) are uncommon. We aimed to investigate these idiopathic double-positive AAV patients' clinical features, histological characteristics, and prognosis. We reviewed all the electronic medical records of patients diagnosed with AAV to obtain clinical data and renal histological information from January 2010 to December 2020 in a large center in China. Patients were assigned to the MPO-AAV group or PR3-AAV group or idiopathic double-positive AAV group by ANCA specificity. We explored features of idiopathic double-positive AAV. Of the 340 patients who fulfilled the study inclusion criteria, 159 (46.76%) were female, with a mean age of 58.41 years at the time of AAV diagnosis. Similar to MPO-AAV, idiopathic double-positive AAV patients were older and had more severe anemia, lower Birmingham Vasculitis Activity Score (BVAS) and C-reactive protein (CRP) levels, less ear, nose, and throat (ENT) involvement, higher initial serum creatinine and a lower estimated glomerular filtration rate (eGFR) when compared with PR3-AAV (P < 0.05). The proportion of normal glomeruli of idiopathic double-positive AAV was the lowest among the three groups (P < 0.05). The idiopathic double-positive AAV patients had the worst remission rate (58.8%) among the three groups (P < 0.05). The relapse rate of double-positive AAV (40.0%) was comparable with PR3-AAV (44.8%) (P > 0.05). Although there was a trend toward a higher relapse rate of idiopathic double-positive AAV (40.0%) compared with MPO-AAV (23.5%), this did not reach statistical significance (P > 0.05). The proportion of patients who progressed to ESRD was 47.1% and 44.4% in the idiopathic double-positive AAV group and MPO-AAV group respectively, without statistical significance. Long-term patient survival also varied among the three groups (P < 0.05). Idiopathic double-positive AAV is a rare clinical entity with hybrid features of MPO-AAV and PR3-AAV. MPO-AAV is the "dominant" phenotype in idiopathic double-positive AAV.

The Influence of Cross-Reactive T Cells in COVID-19.

Memory T cells form from the adaptive immune response to historic infections or vaccinations. Some memory T cells have the potential to recognise unrelated pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and generate cross-reactive immune responses. Notably, such T cell cross-reactivity has been observed between SARS-CoV-2 and other human coronaviruses. T cell cross-reactivity has also been observed between SARS-CoV-2 variants from unrelated microbes and unrelated vaccinations against influenza A, tuberculosis and measles, mumps and rubella. Extensive research and debate is underway to understand the mechanism and role of T cell cross-reactivity and how it relates to Coronavirus disease 2019 (COVID-19) outcomes. Here, we review the evidence for the ability of pre-existing memory T cells to cross-react with SARS-CoV-2. We discuss the latest findings on the impact of T cell cross-reactivity and the extent to which it can cross-protect from COVID-19.

Smith-specific regulatory T cells halt the progression of lupus nephritis.

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Single-cell transcriptomics uncover hub genes and cell-cell crosstalk in patients with hypertensive nephropathy.

Hypertensive nephropathy (HTN) is one of the leading causes of end-stage renal disease, yet the molecular mechanisms are still unknown. To explore novel mechanisms and gene targets for HTN, the gene expression profiles of renal biopsy samples obtained from 2 healthy living donor controls and 5 HTN patients were determined by single-cell RNA sequencing. Key hub genes expression were validated by the Nephroseq v5 platform. The HTN endothelium upregulated cellular adhesion genes (ICAM2 and CEACAM1), inflammatory genes (ETS2 and IFI6) and apoptosis related genes (CNN3). Proximal tubules in HTN highly expressed hub genes including BBOX1, TPM1, TMSB10, SDC4, and NUP58, which might be potential novel targets for proximal tubular injury. The upregulated genes in tubules of HTN were mainly participating in inflammatory signatures including IFN-γ signature, NF-κB signaling, IL-12 signaling and Wnt signaling pathway. Receptor-ligand interaction analysis indicated potential cell-cell crosstalk between endothelial cells or mesangial cells with other renal resident cells in HTN. Together, our data identify a distinct cell-specific gene expression profile, pathogenic inflammatory signaling and potential cell-cell communications between endothelial cells or mesangial cells with other renal resident cells in HTN. These findings may provide a promising novel landscape for mechanisms and treatment of human HTN.

Development of a radiomics nomogram to predict the treatment resistance of Chinese MPO-AAV patients with lung involvement: a two-center study.

Background: Previous studies from our group and other investigators have shown that lung involvement is one of the independent predictors for treatment resistance in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). However, it is unclear which image features of lung involvement can predict the therapeutic response in MPO-AAV patients, which is vital in decision-making for these patients. Our aim was to develop and validate a radiomics nomogram to predict treatment resistance of Chinese MPO-AAV patients based on low-dose multiple slices computed tomography (MSCT) of the involved lung with cohorts from two centers. Methods: A total of 151 MPO-AAV patients with lung involvement (MPO-AAV-LI) from two centers were enrolled. Two different models (Model 1: radiomics signature; Model 2: radiomics nomogram) were built based on the clinical and MSCT data to predict the treatment resistance of MPO-AAV with lung involvement in training and test cohorts. The performance of the models was assessed using the area under the curve (AUC). The better model was further validated. A nomogram was constructed and evaluated by DCA and calibration curves, which further tested in all enrolled data and compared with the other model. Results: Model 2 had a higher predicting ability than Model 1 both in training (AUC: 0.948 vs. 0.824; p = 0.039) and test cohorts (AUC: 0.913 vs. 0.898; p = 0.043). As a better model, Model 2 obtained an excellent predictive performance (AUC: 0.929; 95% CI: 0.827-1.000) in the validation cohort. The DCA curve demonstrated that Model 2 was clinically feasible. The calibration curves of Model 2 closely aligned with the true treatment resistance rate in the training (p = 0.28) and test sets (p = 0.70). In addition, the predictive performance of Model 2 (AUC: 0.929; 95% CI: 0.875-0.964) was superior to Model 1 (AUC: 0.862; 95% CI: 0.796-0.913) and serum creatinine (AUC: 0.867; 95% CI: 0.802-0.917) in all patients (all p< 0.05). Conclusion: The radiomics nomogram (Model 2) is a useful, non-invasive tool for predicting the treatment resistance of MPO-AAV patients with lung involvement, which might aid in individualizing treatment decisions.

Coexistence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and IgA nephropathy.

Co-occurrence of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and IgA nephropathy (IgAN) is extremely uncommon. To date, only a few case reports have described such patients. Here, we describe the clinical presentation, pathologic features, treatment response, and outcome data of five patients with the rare form of co-existing AAV and IgAN and compared the characteristics of these patients to AAV patients with pauci-immune glomerulonephritis (n = 10) and IgAN patients (n = 10) that were selected as controls by stratified random sampling. In addition, we summarize all the previously reported cases of AAV and IgAN. In total, including the current study, 16 AAV/IgAN overlap cases were reported. Our five patients with the coexistence of AAV and IgAN were younger than the ten AAV patients with pauci-immune glomerulonephritis (22.6 ± 8.2 years versus 48.9 ± 15.7 years, respectively, P = 0.004). Histologically, they had a significantly lower percentage of glomeruli with fibrous crescents compared with AAV patients (0.0% versus 4.0%, P = 0.038). Compared with ten IgAN patients, our five AAV/IgAN patients had higher levels of ESR (P = 0.032) and CRP (P = 0.031). After accepting treatment with a combination of steroid and immunosuppressants, all patients showed a positive response to therapy, except for one patient in our cohort and another previously reported patient. We described the clinical presentation, pathologic features, treatment response, and outcome data of five patients with overlapping AAV and IgAN. They had mild glomerular pathological lesions and a positive response to aggressive immunosuppressive therapy. They were quite similar to pauci-immune AAV patients in clinical features, except for younger age. They had a lower percentage of glomeruli with fibrous crescents compared with AAV patients. In contrast to IgAN patients, they had higher levels of ESR and CRP. The mechanism of the coexistence of IgAN and AAV needs further study.

The effect of discontinuation of maintenance therapy in Chinese patients with MPO-ANCA associated vasculitis who were in long-term stable remission.

There is a consensus that maintenance therapy should be used to prevent relapse of myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV), but there is a debate about the optimal duration of maintenance therapy. Therefore, the purpose of this study was to determine whether discontinuation of maintenance therapy in MPO-AAV patients who were in long-term stable remission affects relapse, renal survival and patient survival. Seventy-nine patients with MPO-AAV diagnosed at Xiangya hospital from June 2010 to June 2019 who were in stable remission for at least 18 months following maintenance therapy were included. Patient records were retrospectively reviewed, and based on whether patients discontinued maintenance therapy 18 months after commencing maintenance therapy, patients were assigned into either the withdrawal group (n = 26) or maintenance group (n = 53). The endpoint was the percentage of relapse, relapse-free survival, renal survival and patient survival during follow-up. Ten relapses (38.5%) occurred in the withdrawal group (n = 26) and 8 relapses (15.1%) occurred in the maintenance group (n = 53) (p = 0.020). Compared to the withdrawal group, the maintenance group had similar relapse-free survival (log-rank test p = 0.099). But maintenance group had a better renal survival (p = 0.035), with no difference in patient survival or adverse events. This study suggests that discontinuing maintenance therapy at 18 months following induction of sustained remission leads to a significant increase in the percentage of relapse, and decreases renal survival in patients with MPO-AAV, but does not decrease relapse-free survival or patient survival.

Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients.

Background: Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs. Methods: 109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs. Results: In our study, we found that patients in the DPPs group were older than the other two groups (p = 0.007, MPO-AAV vs. DPPs; p < 0.001, DPPs vs. anti-GBM). The DPPs group had a higher value of serum creatinine (p = 0.041) and lower estimated glomerular filtration rate (eGFR) (p = 0.032) compared with MPO-AAV patients. On the contrary, the DPPs group had a lower serum creatinine (p = 0.003) compared with patients with anti-GBM group. The proportion of patients with cardiac system involvement in the DPPs group was higher than anti-GBM patients (p = 0.014). Cellular crescents could be generally observed in renal biopsy of DPPs and patients with anti-GBM glomerulonephritis. In addition, Bowman's capsule rupture was more common in DPPs than MPO-AAV patients (p = 0.001). MPO-AAV had a better renal and overall survival outcome than DPPs (p < 0.001). There was no significant difference of renal and overall survival outcome between DPPs and patients with anti-GBM disease. The incidence of ESRD in DPPs was negatively associated with lymphocyte count (HR 0.153, 95% CI 0.027 to 0.872, p = 0.034) and eGFR (HR 0.847, 95% CI 0.726 to 0.989, p = 0.036). Elevated serum creatinine was confirmed as a risk factor of both renal (HR 1.003, 95% CI 1.000 to 1.005, p = 0.019) and patient survival in DPPs (HR1.461, 95% CI 1.050 to 2.033, p = 0.024). Conclusion: In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.

Intrarenal Single-Cell Sequencing of Hepatitis B Virus Associated Membranous Nephropathy.

To date, the pathogenesis of hepatitis B virus (HBV)-associated membranous nephropathy (MN) remains elusive. This study aimed to decipher the etiopathogenesis of HBV-associated MN by performing single-cell RNA sequencing (scRNA-seq) of kidney biopsy specimens from a patient with HBV-associated MN and two healthy individuals. We generated 4,114 intrarenal single-cell transcriptomes from the HBV-associated MN patient by scRNA-seq. Compared to healthy individuals, podocytes in the HBV-associated MN patient showed an increased expression of extracellular matrix formation-related genes, including HSPA5, CTGF, and EDIL3. Kidney endothelial cells (ECs) in the HBV-associated MN were enriched in inflammatory pathways, including NF-kappa B signaling, IL-17 signaling, TNF signaling and NOD-like receptor signaling. Gene ontology (GO) functional enrichment analysis and Gene Set Variation Analysis (GSVA) further revealed that differentially expressed genes (DEGs) of ECs from the HBV-associated MN patients were enriched in apoptotic signaling pathway, response to cytokine and leukocyte cell-cell adhesion. The up-regulated DEGs in glomerular ECs of HBV-associated MN patients were involved in biological processes such as viral gene expression, and protein targeting to endoplasmic reticulum. We further verified that the overexpressed genes in ECs from HBV-associated MN were mainly enriched in regulation of protein targeting to endoplasmic reticulum, exocytosis, viral gene expression, IL-6 and IL-1 secretion when compared with anti-phospholipase A2 receptor (PLA2R)-positive idiopathic membranous nephropathy (IMN). The receptor-ligand crosstalk analysis revealed potential interactions between endothelial cells and other cells in HBV-associated-MN. These results offer new insight into the pathogenesis of HBV-associated MN and may identify new therapeutic targets for HBV-associated MN.

High levels of platelet-to-lymphocyte ratio may predict reduced risk of end stage of renal disease in Chinese patients with MPO-ANCA associated vasculitis. / 血小板/淋巴细胞比率比值升高可能预示中国MPO-ANCAç›¸å ³æ€§è¡€ç®¡ç‚Žæ‚£è€ è¿›å±•è‡³ç»ˆæœ«æœŸè‚¾ç— çš„é£Žé™©è¾ƒä½Ž.

OBJECTIVES: Platelet-to-lymphocyte ratio (PLR) has recently been investigated as a new inflammatory marker in many inflammatory diseases, including systemic lupus erythematosus and immunoglobulin A vasculitis. However, there were very few reports regarding the clinical role of PLR in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. This study was thus undertaken to investigate the relationship between inflammatory response and disease activity in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis. Furthermore, we evaluated whether PLR predicts the progression of end stage of renal disease (ESRD) and all-cause mortality. METHODS: The clinical, laboratory and pathological data, and the outcomes of MPO-ANCA associated vasculitis patients were collected. The Spearman correlation coefficient was computed to examine the association between 2 continuous variables. Cox regression analysis was used to estimate the association between PLR and ESRD or all-cause mortality. RESULTS: A total of 190 consecutive patients with MPO-ANCA associated vasculitis were included in this study. Baseline PLR was positively correlated with CRP (r=0.333, P<0.001) and ESR (r=0.218, P=0.003). PLR had no obvious correlation with Birmingham Vasculitis Activity Score (BVAS). Patients having PLR≥330 exhibited better cumulative renal survival rates than those having PLR<330 (P=0.017). However, there was no significant difference in the cumulative patient survival rates between patients with PLR≥330 and those with PLR<330 at diagnosis (P>0.05). In multivariate analysis, PLR is associated with the decreased risk of ESRD (P=0.038, HR=0.518, 95% CI 0.278 to 0.963). We did not find an association between PLR with all-cause mortality using multivariate analysis (HR=1.081, 95% CI 0.591 to 1.976, P=0.801). CONCLUSIONS: PLR is positively correlated with CRP and ESR. Furthermore, PLR may independently predict the risk of ESRD.

Heterologous Immunity Between SARS-CoV-2 and Pathogenic Bacteria.

Heterologous immunity, when the memory T cell response elicited by one pathogen recognizes another pathogen, has been offered as a contributing factor for the high variability in coronavirus disease 2019 (COVID-19) severity outcomes. Here we demonstrate that sensitization with bacterial peptides can induce heterologous immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) derived peptides and that vaccination with the SARS-CoV-2 spike protein can induce heterologous immunity to bacterial peptides. Using in silico prediction methods, we identified 6 bacterial peptides with sequence homology to either the spike protein or non-structural protein 3 (NSP3) of SARS-CoV-2. Notwithstanding the effects of bystander activation, in vitro co-cultures showed that all individuals tested (n=18) developed heterologous immunity to SARS-CoV-2 peptides when sensitized with the identified bacterial peptides. T cell recall responses measured included cytokine production (IFN-γ, TNF, IL-2), activation (CD69) and proliferation (CellTrace). As an extension of the principle of heterologous immunity between bacterial pathogens and COVID-19, we tracked donor responses before and after SARS-CoV-2 vaccination and measured the cross-reactive T cell responses to bacterial peptides with similar sequence homology to the spike protein. We found that SARS-CoV-2 vaccination could induce heterologous immunity to bacterial peptides. These findings provide a mechanism for heterologous T cell immunity between common bacterial pathogens and SARS-CoV-2, which may explain the high variance in COVID-19 outcomes from asymptomatic to severe. We also demonstrate proof-of-concept that SARS-CoV-2 vaccination can induce heterologous immunity to pathogenic bacteria derived peptides.

Clinical features and outcomes of anti-neutrophil cytoplasmic autoantibody-associated vasculitis in Chinese childhood-onset patients.

Data on anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are limited in children. This study is to determine the clinical features and outcomes of childhood-onset AAV. A retrospective study was performed on patients who were diagnosed with AAV before 18 years old in Xiangya Hospital. Their medical records were analyzed by retrospective review. Sixteen patients were diagnosed with AAV before 18 years old in the past 9 years, with an average age of 13.3 ± 3.3 years and 13 of them were female. There were 15 patients with microscopic polyangiitis (MPA) and 1 with Wegener's granulomatosis. The interval between onset of disease and diagnosis of AAV was 2 (1.5-3) months. Most patients (15/16, 93.8%) had multi-organ involvement, and all patients had renal involvement with 7 (43.8%) patients requiring dialysis at presentation. Eleven patients underwent a renal biopsy, of which mixed class and sclerotic class were the most two common histological types. All patients received immunosuppressive therapy for induction therapy including intravenous administrations of methylprednisolone (MP) pulse therapy for 8 patients. 8 patients (50%) achieved remission after induction therapy. After a median follow-up of 46.3 ± 36.1 months, nine (56.3%) patients progressed to end-stage renal disease (ESRD) and 5 (31.3%) patients died. Childhood-onset AAV showed similar clinical and pathological features compared to those of adults, except that it usually occurs in girls. The most commonly involved organ was the kidney, and it had a high risk of progression to ESRD. Early diagnosis and initiation of appropriate immunomodulatory therapy would be important to improve outcomes.

BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity.

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.

Single-Cell Profiling Reveals Transcriptional Signatures and Cell-Cell Crosstalk in Anti-PLA2R Positive Idiopathic Membranous Nephropathy Patients.

Idiopathic membranous nephropathy (IMN) is an organ-specific autoimmune disease of the kidney glomerulus. It may gradually progress to end-stage renal disease (ESRD) characterized by increased proteinuria, which leads to serious consequences. Although substantial advances have been made in the understanding of the molecular bases of IMN in the last 10 years, certain questions remain largely unanswered. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from 6 patients with anti-PLA2R positive IMN and 2 healthy control subjects using single-cell RNA sequencing. We then identified distinct cell clusters through unsupervised clustering analysis of kidney specimens. Identification of the differentially expressed genes (DEGs) and enrichment analysis as well as the interaction between cells were also performed. Based on transcriptional expression patterns, we identified all previously described cell types in the kidney. The DEGs in most kidney parenchymal cells were primarily enriched in genes involved in the regulation of inflammation and immune response including IL-17 signaling, TNF signaling, NOD-like receptor signaling, and MAPK signaling. Moreover, cell-cell crosstalk highlighted the extensive communication of mesangial cells, which infers great importance in IMN. IMN with massive proteinuria displayed elevated expression of genes participating in inflammatory signaling pathways that may be involved in the pathogenesis of the progression of IMN. Overall, we applied single-cell RNA sequencing to IMN to uncover intercellular interactions, elucidate key pathways underlying the pathogenesis, and identify novel therapeutic targets of anti-PLA2R positive IMN.

A Partial Picture of the Single-Cell Transcriptomics of Human IgA Nephropathy.

The molecular mechanisms underlying renal damage of IgA nephropathy (IgAN) remain incompletely defined. Here, single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from IgAN and control subjects to define the transcriptomic landscape at single-cell resolution. We presented a comprehensive scRNA-seq analysis of human renal biopsies from IgAN. We showed for the first time that IgAN mesangial cells displayed increased expression of several novel genes including MALAT1, GADD45B, SOX4, and EDIL3, which were related to cell proliferation and matrix accumulation. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. Furthermore, we compared the results of 4 IgAN patients with the published scRNA-Seq data of healthy kidney tissues of three human donors in order to further validate the findings in our study. The results also verified that the overexpressed genes in tubule cells from IgAN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. The receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. IgAN patients with overt proteinuria displayed elevated genes participating in several signaling pathways compared with microproteinuria group. It needs to be mentioned that based on number of mesangial cells and other kidney cells analyzed in this study, the results of our study are preliminary and needs to be confirmed on larger number of cells from larger number of patients and controls in future studies. Therefore, these results offer new insight into pathogenesis and identify new therapeutic targets for IgAN.

Patient Survival Between Hemodialysis and Peritoneal Dialysis Among End-Stage Renal Disease Patients Secondary to Myeloperoxidase-ANCA-Associated Vasculitis.

BACKGROUND: A significant proportion of anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis eventually progresses to end-stage renal disease (ESRD) thus requiring long-term dialysis. There is no consensus about which dialysis modality is more recommended for those patients with associated vasculitis (AAV-ESRD). The primary objective of this study was to compare patient survival in patients with AAV-ESRD treated with hemodialysis (HD) or peritoneal dialysis (PD). METHODS: This double-center retrospective cohort study included dialysis-dependent patients who were treated with HD or PD. Clinical data were collected under standard format. The Birmingham vasculitis activity score (BVAS) was used to evaluate disease activity at diagnosis and organ damage was assessed using the vasculitis damage index (VDI) at dialysis initiation. RESULTS: In total, 85 patients were included: 64 with hemodialysis and 21 with peritoneal dialysis. The patients with AAV-PD were much younger than the AAV-HD patients (48 vs. 62, P < 0.01) and more were female (76.2 vs. 51.6%, P = 0.05). The laboratory data were almost similar. The comorbidities, VDI score, and immuno-suppressive therapy at dialysis initiation were almost no statistical difference. Patient survival rates between HD and PD at 1 year were 65.3 vs. 90% (P = 0.062), 3 year were 59.6 vs. 90% (P < 0.001), and 5 years were 59.6 vs. 67.5% (P = 0.569). The overall survival was no significant difference between the two groups (P = 0.086) and the dialysis modality (HD or PD) was not shown to be an independent predictor for all-cause death (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.31-1.7; P = 0.473). Cardio-cerebrovascular events were the main cause of death among AAV-HD patients while infection in patients with AAV-PD. CONCLUSION: These results provide real-world data that the use of either hemodialysis or peritoneal dialysis modality does not affect patient survival for patients with AAV-ESRD who need long-term dialysis.

Antigen-driven CD4+ T-cell anergy: a pathway to peripheral T regulatory cells.

In their recent publication, Kuczma and colleagues have provided evidence that advances the relationship between naive T cells, T cell anergy and T regulatory cells. Their findings strengthen the understanding of how these T cell subsets function in relation to self and microbiota-derived epitopes to promote and maintain peripheral tolerance to self and mucosal antigens.

Treg Enhancing Therapies to Treat Autoimmune Diseases.

Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity.

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO409-428), can induce anti-MPO autoimmunity. The peptide (6PGD391-410) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD391-410, or with S. aureus containing a plasmid expressing 6PGD391-410, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD391-410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD391-410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.

HLA-DR15-specific inhibition attenuates autoreactivity to the Goodpasture antigen.

Goodpasture's disease manifests as rapidly progressive glomerulonephritis. Current immunosuppressive treatments do not specifically target the pathological immune response and have significant side effects. Like most autoimmune diseases, the strongest genetic association is with the HLA alleles. Inheritance of HLA-DR15 confers susceptibility, and structure-function studies have shown that HLA-DR15 plays a causative role in activating autoreactive pro-inflammatory T cells. Thus, specific inhibition of HLA-DR15 would provide a targeted therapeutic approach. We hypothesised that PV-267, an HLA-DR15-specific inhibitor, would effectively block HLA-DR15 presentation of the dominant epitope, attenuate the activation of autoreactive T cells, and limit disease. Using humanised HLA-DR15 transgenic mice, α3135-145-specific, pro-inflammatory T cell recall responses were measured using IFN-γ and IL-17A ELISPOTs and by proliferation assay. To determine if PV-267 could limit disease, experimental autoimmune anti-GBM glomerulonephritis was induced in HLA-DR15 transgenic mice (on an Fcgr2b-/- background), and functional and histological disease endpoints were measured. PV-267 effectively inhibited α3135-145-specific immune responses and disease development. Mice treated prior to immunization with α3135-145 had reduced α3135-145-specific recall responses, and limited disease by albuminuria, histological glomerular injury, IgG deposition, and inflammatory cell infiltrates. PV-267 treatment commencing after the onset of active anti-α3(IV)NC1 autoimmunity attenuated functional and histological renal injury. When treatment was administered after disease was established, PV-267 limited the severity of histological injury. In conclusion, HLA-DR15 inhibition attenuates α3(IV)NC1-specific pro-inflammatory responses and could be used as an adjunct therapy for anti-GBM disease.