Tubular expression of Toll-like receptor 9 in lupus and primary membranous nephropathy.

INTRODUCTION: Toll-like- receptors (TLR) control important aspects of innate and adaptive immune responses. Renal cells are among the non-immune cells that express (TLR). Therefore, their activation might be implicated in renal tubulo-interstitial injury. AIM: The study aimed to compare TLR9 expression in patients with primary membranous nephropathy (MN) to patients with lupus membranous nephropathy. METHODS: Kidney sections from 10 Lupus nephritis (LN) patients and ten patients with primary MN were analyzed by immunohistochemistry using anti-human TLR9 antibody. RESULTS: Results showed that TLR9 expression was weak and exclusively tubular in primary MN patients' biopsies. There was a significant difference between LN patients' biopsies and primary MN patients' biopsies. TLR9 expression was more diffused in LN patients' specimen than in those with primary MN. CONCLUSION: This study focuses on molecular level pathogenesis of MN. The data suggest that the receptors TLR9 may play role in tubulointerstitial injury in the pathogenesis of LN but not primary membranous nephropathy.

Anti-DNA antibody-targeted D-peptide nanoparticles ameliorate lupus nephritis in MRL/lpr mice.

Peptide ALW (ALWPPNLHAWVP) targeting anti-dsDNA antibodies has shown promising therapeutic effects in alleviating lupus nephritis, but is potentially limited by poor stability and non-kidney targeting. We recently developed a D-form modified ALW, called D-ALW, which has the capacity to widely inhibit pathogenic polyclonal anti-dsDNA antibody reactions. Further modification of D-ALW using PEG-PLGA nanoparticles to enhance good kidney-targeting ability and extend half-life. Here, we demonstrate that the D-form modified ALW maintains higher binding and inhibition efficiencies and achieves higher stability. Most importantly, D-ALW nanoparticles exhibit excellent kidney-targeting ability and prolong the half-life of the peptides in BALB/c mice. Additionally, compared to D-ALW, D-ALW nanoparticles significantly reduce the glomerular deposition of IgG and C3, improve renal histopathologies, such as glomerular proliferation and inflammatory cells infiltration, and markedly prolong lifespan in MRL/lpr lupus-prone mice. Overall, these results establish that the D-ALW nanoparticles offer synergistic benefits in both safety and efficacy, providing long-term renal preservation and treatment advantages in lupus nephritis.

The ion transporter Na+-K+-ATPase enables pathological B cell survival in the kidney microenvironment of lupus nephritis.

The kidney is a comparatively hostile microenvironment characterized by highsodium concentrations; however, lymphocytes infiltrate and survive therein in autoimmune diseases such as lupus. The effects of sodium-lymphocyte interactions on tissue injury in autoimmune diseases and the mechanisms used by infiltrating lymphocytes to survive the highsodium environment of the kidney are not known. Here, we show that kidney-infiltrating B cells in lupus adapt to elevated sodium concentrations and that expression of sodium potassium adenosine triphosphatase (Na+-K+-ATPase) correlates with the ability of infiltrating cells to survive. Pharmacological inhibition of Na+-K+-ATPase and genetic knockout of Na+-K+-ATPase γ subunit resulted in reduced B cell infiltration into kidneys and amelioration of proteinuria. B cells in human lupus nephritis biopsies also had high expression of Na+-K+-ATPase. Our study reveals that kidney-infiltrating B cells in lupus initiate a tissue adaption program in response to sodium stress and identifies Na+-K+-ATPase as an organ-specific therapeutic target.

Anti-DFS70 Antibodies Are Associated With Proliferative Lupus Nephritis and Renal Pathological Activity.

Objective: The significance of anti-dense fine speckles 70 (DFS70) antibodies in systemic lupus erythematosus (SLE) is still unclear, especially in lupus nephritis (LN) patients. We investigated the prevalence, clinical and pathological relevance of anti-DFS70 antibodies in LN patients. Methods: Anti-DFS70 antibodies were measured using enzyme-linked immunosorbent assays in 377 biopsy-proven LN patients, 268 non-LN SLE patients, 232 chronic kidney disease (CKD) patients, and 78 healthy individuals (HI). Demographic, clinical, and pathological parameters were compared between LN patients with and without anti-DFS70 antibodies. Stepwise multivariable logistic regression was performed to identify covariates associated with anti-DFS70 antibodies. Results: The prevalence of anti-DFS70 antibodies in LN (19.6%) was comparable to non-LN SLE patients (19.8%, P=0.9630), but was significantly higher than CKD patients (13.4%, P=0.0468) and HI (9.0%, P=0.0252). Using multivariable logistic regression analysis, the titer of anti-double-stranded DNA (dsDNA) antibodies (adjusted odds ratio=1.002, 95% confidence interval 1.001-1.003, P=0.004) was associated with positive anti-DFS70 antibodies in LN patients. In addition, anti-DFS70 antibodies were more prevalent in proliferative LN (22.0%, 68/309) compared to membrane LN patients (10.2%, 6/59, P=0.0376). Furthermore, LN patients with positive anti-DFS70 antibodies had significantly higher activity index (AI) compared to patients who were negative (8.0 vs 6.0, P=0.0131). However, the chronicity index was similar between the groups (3.0 vs 3.0, P=0.8412). Conclusion: Anti-DFS70 antibodies were not associated with LN development in SLE patients but were associated with anti-dsDNA antibodies, proliferative LN, and renal AI. This suggests their potential to serve as a non-histological biomarker for LN subclass and activity status.

B Cell-Specific Deletion of CR6-Interacting Factor 1 Drives Lupus-like Autoimmunity by Activation of Interleukin-17, Interleukin-6, and Pathogenic Follicular Helper T Cells in a Mouse Model.

OBJECTIVE: CR6-interacting factor 1 (CRIF1) is a nuclear transcriptional regulator and a mitochondrial inner membrane protein; however, its functions in B lymphocytes have been poorly defined. This study was undertaken to investigate the effects of CRIF1 on B cell metabolic regulation, cell function, and autoimmune diseases. METHODS: Using mice with B cell-specific deletion of CRIF1 (Crif1ΔCD19 mice), we assessed the relevance of CRIF1 function for lupus disease parameters, including anti-double-stranded DNA (anti-dsDNA), cytokines, and kidney pathology. RNA sequencing was performed on B cells from Crif1ΔCD19 mice. The phenotypic and metabolic changes in immune cells were evaluated in Crif1ΔCD19 mice. Roquinsan/+ mice crossed with Crif1ΔCD19 mice were monitored to assess the functionality of CRIF1-deficient B cells in lupus development. RESULTS: Crif1ΔCD19 mice showed an autoimmune lupus-like phenotype, including high levels of autoantibodies to dsDNA and severe lupus nephritis with increased mesangial hypercellularity. While loss of CRIF1 in B cells showed impaired mitochondrial oxidative function, CRIF1-deficient B cells promoted the production of interleukin-17 (IL-17) and IL-6 and was more potent in helping T cells develop into follicular helper T cells. In a mouse model of autoimmune lupus, depletion of CRIF1 in B cells exacerbated lupus severity, and CRIF1 overexpression prevented lupus development in roquinsan/san mice. CONCLUSION: These results demonstrated that CRIF1 negatively correlates with disease severity and that overexpression of CRIF1 ameliorates disease development. Our findings suggest that CRIF1 is essential for preventing lupus development by maintaining B cell self tolerance.

Panax notoginseng saponins reverse P-gp-mediated steroid resistance in lupus: involvement in the suppression of the SIRT1/FoxO1/MDR1 signalling pathway in lymphocytes.

BACKGROUND: P-glycoprotein (P-gp)-mediated steroid resistance (SR) has been suggested to play a significant role in lupus nephritis (LN) treatment failure. Panax notoginseng saponins (PNS), the main effective components of the traditional Chinese medicine notoginseng, exhibited potent reversal capability of P-gp-mediated SR, but its mechanism remains unknown. This study aimed to investigate the effect of PNS on reversing SR in lupus and its underlying mechanism in vivo and in vitro. METHODS: In this study, an SR animal and splenic lymphocyte model were established using low-dose methylprednisolone (MP). Flow cytometry was used to detect the effect of PNS on reversing P-gp-mediated SR and the expression of P-gp in different T-cells phenotypes. Serum levels of ANA and dsDNA in lupus mice were measured by ELISA. Apoptosis was identified by Annexin V-FITC/PI staining. RT-PCR and Western blotting were used to detect the protein and mRNA expression levels of SIRT1, FoxO1, and MDR1 in SR splenic lymphocytes from lupus mice (SLCs/MPs). RESULTS: PNS could reverse the SR in lupus mice. Simultaneously, PNS increased the apoptotic effect of MP on SLCs/MP cells. The increased accumulation of rhodamine-123 (Rh-123) indicated that intracellular steroid accumulation could be increased by the action of PNS. Moreover, PNS decreased the expression of P-gp levels. Further experiments elucidated that the SIRT1/FoxO1/MDR1 signalling pathway existed in SLCs/MP cells, and PNS suppressed its expression level to reverse SR. The expression of P-gp in Th17 from SLCs/MP cells was increased, while PNS could reduce its level in a more obvious trend. CONCLUSION: The present study suggested that PNS reversed P-gp-mediated SR via the SIRT1/FoxO1/MDR1 signalling pathway, which might become a valuable drug for the treatment of SR in lupus. Th17 might be the main effector cell of PNS reversing SR.

Gut dysbiosis is associated with acceleration of lupus nephritis.

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or "leakiness" was also detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.

De novo lupus-like glomerulonephritis after pediatric non-kidney organ transplantation.

BACKGROUND: We propose a novel clinically significant finding, de novo lupus-like glomerulonephritis (DNLLGN), in patients with autoantibodies and kidney abnormalities in pediatric liver transplant (LT) and intestinal inclusive transplants (ITx). METHODS: We describe the clinical, serologic, and histopathologic presentation and kidney outcomes in eight patients from our center found to have DNLLGN on kidney biopsy. RESULTS: Pediatric recipients of non-kidney solid organ transplants developed an unusual de novo immune complex glomerulonephritis with morphologic similarity to lupus nephritis. Six had isolated LT (0.9% of all pediatric LT at our center) and two had ITx (2.1% of all ITx). Five (63%) presented with nephrotic syndrome. Five patients had autoantibodies. Patients underwent kidney biopsy at a mean of 11.5 years in LT and 2.8 years in ITx after the index transplant. Biopsies demonstrated changes similar to focal or diffuse active lupus. Follow-up eGFR at a mean of 6 years after biopsy showed a mean decrease of 30 ml/min/1.73 m2 in all patients (p = 0.11). CONCLUSIONS: DNLLGN has not been previously recognized in this clinical setting, yet 8 kidney biopsies from pediatric recipients of LT and ITx at our center in 25 years demonstrated this finding. DNLLGN appears to be an under-reported phenomenon of clinical significance. A higher resolution version of the Graphical abstract is available as Supplementary information.

P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance.

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a "de novo" variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.

Clinical relevance of glomerular IgM deposition in patients with lupus nephritis.

BACKGROUND: The aim of the study was to investigate the clinical relevance of IgM deposition in patients with lupus nephritis (LN) in a large cohort. RESULTS: 217 patients with renal biopsy-proven active LN were enrolled. The associations between glomerular IgM deposition and clinicopathological parameters were further analyzed. IgM deposition was positively correlated with glomerular C1q and C3 deposition moderately (r = 0.436, P < 0.001; r = 0.408, P < 0.001, respectively), and inversely correlated with plasma levels of C3 and CFH mildly (r = - 0.138, P = 0.043; r = - 0.147, P = 0.037, respectively). By multivariate analysis, we found that glomerular IgM deposition independently contributed to glomerular C3 deposition in patients with LN (OR = 2.002, 95% CI 1.295-3.094, P = 0.002). In addition, we also found that patients with IgM 0-2+ had similar plasma CFH levels, but in patients with IgM3+-4+, plasma CFH levels were significantly lower (300.4 ± 155.8 µg/mL vs. 429.9 ± 187.5 µg/mL, P < 0.001). Furthermore, patients with high density of glomerular IgM and low levels of CFH had heavier proteinuria, higher serum creatinine and lower plasma C3 levels (5.7 ± 3.1 g/d vs. 4.7 ± 3.5 g/d, P = 0.037; 150.1 ± 121.0 µmol/L vs. 105.6 ± 97.1 µmol/L, P = 0.005; 0.3 ± 0.2 µg/L vs. 0.4 ± 0.2 µg/L, P = 0.04, respectively), comparing with those with low density of glomerular IgM and low levels of CFH. CONCLUSIONS: Our results suggested the involvement of glomerular deposited IgM in complement activation and renal injury in LN.

Complement-mediated M2/M1 macrophage polarization may be involved in crescent formation in lupus nephritis.

The function of the complement and macrophage crosstalk during the formation of crescents in lupus nephritis has not yet been reported. This study therefore aimed to explore the association of crescents, complements, and M2 macrophages with clinical features in lupus nephritis. We assessed a Chinese cohort comprising 301 patients with lupus nephritis. Renal biopsy specimens were collected from 64 patients with proliferative lupus nephritis (class III/III + V or IV/IV + V). The renal deposition of cluster of differentiation (CD) 68, inducible nitric oxide synthase, CD163, and C3a receptor (C3aR) was evaluated by immunostaining. The associations among crescents, complements, and M2 macrophages were also analyzed. Next, the underlying mechanism was investigated in vitro using C3a-treated macrophages. We found that M2-phenotype macrophages (CD163+) were the dominant subpopulation in human lupus nephritis. Additionally, a significant association was observed among the CD163+ macrophages, crescents, and complement activation. C3aR co-localized with CD163 and correlated with crescents and could induce polarization of macrophages to an M2 phenotype. Overall, these results suggest that complement-mediated M2/M1 macrophage polarization may contribute to the formation of crescents in lupus nephritis.

Lupus nephritis in children. / Nefropatía lúpica en pacientes pediátricos.

INTRODUCTION: Lupus nephritis is an early manifestation in the development of systemic lupus erythematosus that worsens the morbidity and mortality of these patients. OBJECTIVE: To study the form of presentation in patients with lupus nephritis, the clinical and immunological characteristics, and their relationship with renal histology. PATIENTS AND METHOD: Retrospective study in children under 18 years of age, with lupus nephritis, in follow-up in a third level children's hospital in Madrid, between January 2012 and May 2020. We recorded demographic, clinical, and laboratory data (blood count, renal function, liver function, protein, ionogram, blood glucose, uric acid, lactate dehydrogenase, coagulation, and urine analysis), as well as immunological data (immunoglobulins, antinuclear antibodies, comple ment, and lupus anticoagulant), and histological classification data. Descriptive analysis and analysis of associations between variables was performed, with a significant p < 0.05. RESULTS: 16 patients (11 women) were included, the median age at presentation was 10.6 ± 2.3 years (5.7-15.3). The median time between symptoms onset and renal involvement was 6.3 months ± 10.5 (range 0 - 33.6). Renal involvement was the initial manifestation in 37.5% of patients. 50% had arthralgias or arthritis prior to diagnosis, and 25% had fever and constitutional symptoms (asthenia, anorexia, and/or weight loss). The most frequent form of renal involvement was microhematuria associated with proteinuria in non-nephrotic range. In the renal anatomo-pathological study, according to the ISN/RPS 2003 classification, grades III (46.6%) and IV (33.3%) predominated. CONCLUSIONS: Six patients presented renal involvement at baseline with musculoskeletal involvement being more frequent. Most patients (86.6%) presented advanced lupus nephritis in the histological study at diagnosis. Immunologic in volvement was the only marker that correlated with systemic involvement.

5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development.

Retinoic­acid­receptor­related orphan nuclear hormone receptor gamma t (RORγt), a critical transcriptional factor of Th17 cells, is a potential therapeutic target for Th17-mediated autoimmune diseases. In addition, RORγt is essential for thymocyte survival and lymph node development, and RORγt inhibition or deficiency causes abnormal thymocyte development, thymus lymphoma, and lymph node defect. Recent study demonstrated that specific regulation of Th17 differentiation related to the hinge region of RORγt. In this research, we investigated the effect of RORγt inhibitor, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative (TTP), in the therapy of lupus nephritis and its safety on thymocyte development. We demonstrated that TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in the pristane-induced lupus nephritis mice model. The treatment of TTP in the mice did not interfere with thymocyte development, including total thymocyte number and proportion of CD4+CD8+ double-positive populations in the thymus, and had no substantial effects on the pathogenesis of thymoma. The TTP had a stronger affinity with full-length RORγt protein compared with the truncated RORγt LBD region via surface plasmon resonance, which indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed that the best binding pocket of TTP to RORγt is located in the hinge region of RORγt. In summary, as a RORγt inhibitor, TTP had a potential to develop the clinical medicine for treating Th17-mediated autoimmune diseases with low safety risk for thymocyte development.

Association between tubulointerstitial CD8+T cells and renal prognosis in lupus nephritis.

OBJECTIVE: Inflammatory cell infiltration is a pathological change commonly seen in renal biopsies from patients with lupus nephritis(LN), but its clinicalcorrelationwith clinical parameters and prognosis is unclear. METHODS: Included in this retrospective study were 197 patients with ISN/ RPS Class III-V LN, in whom renal biopsy was performed to analyze the histological pattern. Tubulointerstitial infiltrates were quantitated by standard histochemical staining. Clinical and histologic variables were evaluated using a Cox proportional hazards model. End-stagerenaldisease(ESRD) progression was defined as a two-fold increase in serum creatinine (SCr) after biopsy, GFR decreased over 40%, initiation of dialysis, transplantation, or death. RESULTS: Of the 197 patients, 166 patients (84.3%) had proliferative LN. The number of tubulointerstitial infiltrates was the lowest in LN patients with ISN/RPS class V, and the number of CD68+ macrophages was the highest in all ISN/RPS classes of LN. In addition, the number of CD8+T cell infiltrates was positively correlated the SLEDAI sore, SCr level, proteinuria, the ratio of glomerulosclerosis and the degree of tubulointerstitial inflammation, interstitial fibrosis and tubular atrophy, activity and chronicity indices, and negatively correlated with C3 level at presentation. Multivariate survival analysis showed that tubulointerstitial CD8 + T cells > 130/mm2 was associated with ESRD progression (HR 1.007; 95% CI 1.003 to 1.011; p < 0.001). CONCLUSION: Tubulointerstitial CD8+T cells correlate with clinicohistologic impairment in LN. Tubulointerstitial CD8+T cells > 130/mm2 is independently associated with an unfavorable long-term kidney outcome.

Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis.

Exostosin 1 and exostosin 2 (EXT1/EXT2) on glomerular basement membrane (GBM) were recently reported as novel putative antigens in secondary membranous nephropathy with autoimmune disease. However, the clinical significance of glomerular EXT1/EXT2 remains elusive in patients with lupus nephritis (LN). The immunofluorescence staining pattern of glomerular EXT1/EXT2 is also undetermined in membranous LN (MLN) or proliferative LN (PLN). We cross-sectionally analyzed patients with MLN (pure class V, n = 11) and PLN (class III, IV, and mixed class III/IV + V, n = 22) who underwent renal biopsies between 2010 and 2020 at Showa University Hospital. Glomerular EXT1/EXT2 expressions were evaluated by immunofluorescence. T-helper (Th) cell-related serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The positivity for both EXT1/EXT2 was higher in patients with MLN than PLN (90.9% vs 63.6%, P = 0.212). MLN showed global and bright granular EXT1/EXT2 expressions along GBM, while PLN showed segmental and moderate expressions on GBM. Additionally, glomerular EXT1/EXT2 positivity was not associated with the degree of proteinuria or renal function in MLN and PLN patients, but the levels of serum anti-dsDNA antibody and circulating immune complexes were lower in patients with EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Moreover, serum complement levels and IL-4/IFN-γ ratios were elevated in EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Collectively, immunofluorescence staining for glomerular EXT1/EXT2 had characteristic patterns between MLN and PLN. Glomerular EXT1/EXT2 expressions tended to be high in Th2-dominant MLN patients without severe hypocomplementemia and elevated autoantibodies. Thus, EXT1/EXT2 might be involved in the unique developmental mechanism of MLN.

Use of rituximab in paediatric nephrology.

Rituximab is a chimeric monoclonal antibody capable of depleting B cell populations by targeting the CD20 antigen expressed on the cell surface. Its use in oncology, initially in B cell lymphoma and post-transplant lymphoproliferative disorders, predates its current utility in various fields of medicine wherein it has become one of the safest and most effective antibody-based therapies. It was subsequently found to be effective for rheumatological conditions such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. Over the past decade, rituximab has generated a lot of interest in nephrology and has become an emerging or accepted therapy for multiple renal conditions, including systemic lupus erythematosus, lupus nephritis, vasculitis, nephrotic syndrome and in different scenarios before and after kidney transplantation. This review outlines its current use in paediatric nephrology practice, focusing on the knowledge required for general paediatricians who may be caring for children prescribed this medication and reviewing them on a shared care basis.

TACI haploinsufficiency protects against BAFF-driven humoral autoimmunity in mice.

Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.

Role of clinicopathological features for the early prediction of prognosis in lupus nephritis.

Ambiguities remain regarding the role of clinicopathological characteristics in the early prediction of the prognosis of lupus nephritis (LN). Systemic lupus erythematosus (SLE) patients who completed routine follow-up were identified and retrospectively reviewed for eligible cases. Poor prognosis was defined as all-cause mortality or a persistent decrease of eGFR greater than half the baseline level or progression to end-stage renal disease (ESRD). An optimal Cox regression model was constructed for the early prediction of a poor prognosis for LN. Among the 2163 SLE patients, 376 eligible LN cases were enrolled in the study, with a median follow-up time of 55 [27.0, 87.0] months. The male-to-female ratio was 1:7.2, and 37 patients (9.8%) progressed to the composite endpoint. The ISN/RPS class was significantly associated with proteinuria levels (P-value < 0.001), and class IV/IV + V patients, but not class V patients, had the most severe proteinuria. Our optimal multivariate Cox regression model indicated that sex, ISN/RPS class, tubular atrophy/interstitial fibrosis, serum albumin, tertiles of proteinuria, and their interaction were independently associated with a poor prognosis. ROC analysis and external validation demonstrated that our model was efficient and robust for distinguishing LN patients with a poor prognosis. Our study constructed a robust and early predictive model for convenience in clinical practice to identify poor prognosis in LN patients. We found a significant interaction effect between proteinuria and serum albumin for the prediction of poor prognosis. LN patients with low-level proteinuria and hypoalbuminemia exhibit an increased hazard of progression to poor outcomes.

Association of antiphospholipid antibodies with clinical activity and renal pathological activity in patients with lupus nephritis.

OBJECTIVES: This study aimed to investigate the association of antiphospholipid antibodies (aPL) with clinical activity and renal pathological activity in patients with lupus nephritis (LN). METHODS: Levels of anticardiolipin () antibodies, anti-ß2-glycoprotein I (anti-ß2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained during the same period before renal biopsy. RESULTS: A total of 83 patients with LN were included in this study, 40 patients (48.2%) in the s positive group and 43 patients in the aPL negative group. LN patients with positive aPL had significantly higher SLEDAI (p = 0.012), more hematuria (p = 0.043), lower serum C3 (p = 0.003) and C4 (p = 0.014), and a higher pathological activity index (p = 0.012), more micro-thrombosis (p = 0.046) and more C3 deposits (p = 0.038) in the glomerulus than patients with negative aPL The level of IgG- was significantly correlated with SLEDAI and serum level of C3 (r = 0.44, p < 0.001; r = -0.39, p = 0.003, respectively). The level of IgM- was significantly correlated with SLEDAI, and serum levels of C3 and C4 (r = 0.27, p = 0.014; r = -0.22, p = 0.041; r = -0.23, p = 0.035, respectively). CONCLUSIONS: Our work suggests that aPL, especially, are correlated with both clinical activity and renal pathological activity in patients with LN.

Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice.

Systemic lupus erythematosus is characterized by high levels of IgG class autoantibodies that contribute to the pathophysiology of the disease. The formation of these autoantibodies occurs in the germinal centers, where there is cooperation between follicular T helper cells (TFH) and autoreactive B cells. Prolactin has been reported to exacerbate the clinical manifestations of lupus by increasing autoantibody concentrations. The objective of this study was to characterize the participation of prolactin in the differentiation and activation of TFH cells, by performing in vivo and in vitro tests with lupus-prone mice, using flow cytometry and real-time PCR. We found that TFH cells express the long isoform of the prolactin receptor and promoted STAT3 phosphorylation. Receptor expression was higher in MRL/lpr mice and correlative with the manifestations of the disease. Although prolactin does not intervene in the differentiation of TFH cells, it does favor their activation by increasing the percentage of TFH OX40+ and TFH IL21+ cells, as well as leading to high serum concentrations of IL21. These results support a mechanism in which prolactin participates in the emergence of lupus by inducing overactive TFH cells and perhaps promoting dysfunctional germinal centers.