Anne Davidson

Using spatial profiling, Nishide et al. (https://doi.org/10.1084/jem.20260506) identified activated neutrophils in kidneys in anti-myeloperoxidase (MPO)–associated vasculitis. They developed one-armed antibodies that block pathogenic anti-MPO autoantibodies and prevent Fc receptor–mediated neutrophil activation, thereby attenuating renal injury in a passive transfer model. This nontoxic precision approach for disease treatment and flare prevention addresses a critical unmet need.

Objectives: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), leading to progressive renal fibrosis and functional decline. Understanding the interplay between immune cells and stromal cells is needed to develop effective therapeutic strategies. Here, we investigated the landscape of macrophage-fibroblast interactions in human LN and validated these findings in mouse models. Methods: We characterized distinct fibroblast subsets and their interactions with renal macrophages using single-cell RNA sequencing (scRNAseq) of 156 human LN biopsies and 30 healthy controls from the AMP-SLE cohort, and spatial transcriptomics of biopsies from 6 LN patients. In vitro co-culture studies using mouse models were performed to further define functional consequences of these interactions. Results: We identified two myofibroblast subsets: a pro-inflammatory subset (Myofib1) enriched in the tubulointerstitium, and a fibrotic/remodeling subset (Myofib2) in glomeruli, both correlating with the histologic chronicity index. Spatial transcriptomics revealed different colocalization patterns, with Myofib1 interacting with activated resident macrophage (RM) subsets and Myofib2 with glomerular infiltrating disease-associated macrophages. In vitro co-culture studies demonstrated that nephritic RMs promote a pro-inflammatory, remodeling fibroblast phenotype that impairs wound healing and drives a Myofib1-like gene program, whereas disease-associated macrophages generated profibrotic fibroblasts with dysregulated reparative capacity. Cell-cell communication analyses identified key ligand-receptor interactions mediating this crosstalk, including Spp1/integrins, Sema4/PlexinB, and NAMPT/INSR. Conclusions: Our data reveal a spatially and functionally heterogeneous landscape of macrophage-fibroblast crosstalk in LN. These findings advance our understanding of renal fibrogenesis in LN, highlighting specific fibro-inflammatory circuits that may represent therapeutic targets to prevent chronic renal damage.

Anti-phospholipid (APL) autoantibodies confer a high risk for adverse pregnancy outcomes, especially in Systemic Lupus Erythematosus (SLE). While human TLR8 (huTLR8) has been implicated in APL antibody-mediated placental injury in vitro , its in vivo role in pregnancy is unexplored. We report a novel mouse model of pregnancy loss in SLE-prone mice expressing huTLR8. Placental analysis revealed early developmental defects starting post-implantation, including a thin junctional zone, impaired vascularization, infarcts, and inflammation. Profound immune dysregulation was evident at E8.5 including increased myeloid cells and CD8 T cells and decreased uterine natural killer (uNK) cells. RNA sequencing revealed downregulated pregnancy-specific glycoproteins, reduced uNK cell-associated genes, and an upregulated myeloid cell signature. Bone marrow chimera studies demonstrated preferential activation of huTLR8-expressing placental Ly6C ⁺ monocytes. Spatial transcriptomics at E9.5 confirmed uNK cell loss, decreased IL15 expression by both stromal and myeloid cells, and discrete inflammatory aggregates in the maternal layers containing myeloid cells and IFNγ-expressing CD8 T cells. We propose that huTLR8, likely through myeloid cell activation and cytolytic T cell recruitment, drives placental injury in the context of SLE and APL autoantibodies. This model provides a valuable platform to dissect early pathogenic events in APL-associated pregnancy loss and identify new therapeutic targets.

Objective: Lupus nephritis (LN) management remains challenging, and novel noninvasive biomarkers are needed. This study quantified serum soluble mediators in the Accelerating Medicines Partnership (AMP) LN cohort to identify biomarkers of histologic features and treatment response. Methods: Patients with systemic lupus erythematosus (SLE) (n = 268) undergoing clinically indicated kidney biopsies (urine protein/creatinine ratio [UPCR] ≥ 0.5) were recruited through the AMP Rheumatoid Arthritis and SLE Network. Serum was collected at biopsy and 3‐, 6‐, and 12‐month postbiopsy, alongside samples from 22 healthy controls. Concentrations of 66 immune mediators were quantified using xMAP multiplex assays, and (TACE) measured by enzyme‐linked immunosorbent assay. Seven mediators with >95% values below detection limits were excluded from analyses. Bootstrapped least absolute shrinkage and selection operator (LASSO) regression identified proliferative LN (class III/IV ± V) predictors from baseline mediators. Associations with 12‐month treatment response (complete/partial vs no response) were tested using three‐month changes in LASSO‐selected mediators and UPCR via logistic regression. Molecular clustering of mediator profiles was performed to identify LN subgroups. Results: Proliferative patients with LN (class [III or IV] ± V; n = 160) displayed a distinct mediator profile compared with nonproliferative LN (class I, II, or V; n = 96). LASSO regression identified 20 mediators predictive of proliferative LN (areas under the curve, 0.82; 95% confidence interval [CI], 0.81–0.91), including elevated syndecan‐1, tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, and vascular cell adhesion molecule 1 (VCAM‐1), as well as decreased CCL3//macrophage inflammatory protein 1α, CD40 ligand, and interleukin‐5 levels. Among proliferative patients with LN, 3‐month reductions in syndecan‐1 and VCAM‐1, mediators associated with intrarenal LN activity and/or chronicity, predicted the 12‐month treatment response. A model incorporated these reductions and a decline in UPCR‐predicted treatment response in proliferative LN (0.90; 95% CI, 0.82–0.98). Molecular clustering revealed four distinct LN subgroups with unique soluble mediator signatures and clinical features not captured by histology alone. Conclusion: Serum soluble mediators, particularly syndecan‐1 and VCAM‐1, reflect LN histologic activity, and early decreases predict treatment response, supporting their potential use as noninvasive longitudinal biomarkers. The substantial heterogeneity within LN highlights the potential for biomarker‐guided reclassification to advance precision medicine approaches.

Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis.

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying noninvasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified 3 immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at 1 year. Patients with enriched circulating granzyme B ⁺ T cells showed more active disease and increased numbers of activated CD8 ⁺ T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to 5 simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful noninvasive metrics to assess immune-mediated disease in LN.

Objective: Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response.Methods: Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria. Of these, 268 were diagnosed with LN. Thirteen autoantibody specificities were measured by bead‐based assays (Bio‐Rad Bioplex 2200) and anti‐C1q by enzyme‐linked immunosorbent assay at the time of biopsy (baseline) and at 3, 6, and 12 months after biopsy. Clinical response was determined at 12 months.Results: Proliferative LN (International Society of Nephrology/Renal Pathology Society class III/IV±V, n = 160) was associated with higher concentrations of anti‐C1q, anti‐chromatin, anti–double‐stranded DNA (dsDNA), and anti–ribosomal P autoantibodies compared to nonproliferative LN (classes I/II/V/VI, n = 108). Anti‐C1q and‐dsDNA were independently associated with proliferative LN. In proliferative LN, higher baseline anti‐C1q levels predicted complete response (area under the curve [AUC] 0.72; P = 0.002) better than baseline proteinuria (AUC 0.59; P = 0.21). Furthermore, all autoantibody levels except for anti‐La/SSB decreased over 12 months in patients with proliferative, but not membranous, LN with a complete response.Conclusion: Baseline levels of anti‐C1q and anti‐dsDNA may serve as noninvasive biomarkers of proliferative LN, and anti‐C1q may predict complete response at the time of kidney biopsy. In addition, tracking autoantibodies over time may provide further insights into treatment response and pathogenic mechanisms in patients with proliferative LN. image

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti–spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell–depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti–spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti–type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2–related deaths suggest that T cell immunity contributes to protection in autoimmune disease.