Lennard Ostendorf

Proliferative lupus nephritis (LN) is triggered by deposition of autoantibodies in glomeruli and paralleled by a T cell–rich kidney infiltrate. Although these T cells have been attributed to the propagation of tissue injury, it is unclear how they are activated and whether T cell autoreactivity drives local inflammation. Kidney-infiltrating T cells are also observed in urine, where they have high resemblance to interstitial T cells. Therefore, urinary T cells are a proxy for investigating tissue pathogenesis. Here, we analyzed urinary T cells to elucidate whether a kidney-specific T cell autoimmune reaction contributes to tubulointerstitial inflammation in LN. Using single-cell RNA sequencing, we compared transcriptomes and clonotypes of T cells from the blood and urine of patients with active LN and showed that urinary T cells were mostly activated CD8 effector memory cells recruited from a circulating CX3CR1 ⁺ subset. Several urinary CD8 T cell clones were expanded. However, upon in vitro testing of their T cell receptors, we did not observe autoreactivity against autologous tubular epithelial cells. Instead, ~20% of expanded clonotypes were Epstein-Barr virus–specific or cytomegalovirus-specific, but respective viral antigens were undetectable in kidney biopsies or urine. Conversely, kidney-infiltrating T cells had access to interleukin-15 and interferon-β (IFN-β), and stimulation with these cytokines was sufficient to trigger degranulation and production of tumor necrosis factor, IFN-γ, and granzyme K. Together, these results show that CD8 ⁺ CX3CR1 ⁺ T cells are recruited into the kidney in LN, where they are activated by cytokines, enabling them to contribute to local inflammation.

Antibody-secreting cells (ASCs) play a central role in the pathophysiology of systemic lupus erythematosus (SLE). This single-arm, open-label, phase 2 clinical trial aims to evaluate the safety and efficacy of the ASC-depleting anti-CD38 monoclonal antibody daratumumab in patients with SLE (NCT04810754). The primary endpoint is the reduction in serum anti-double-stranded DNA (anti-dsDNA) antibody levels at week 12. Key secondary end points include safety, clinical efficacy, and immunologic changes. Ten female patients with active disease and inadequate responses to at least two immunosuppressive drugs have received eight subcutaneous injections of 1800 mg daratumumab weekly, with dexamethasone as premedication (20 mg for first two injections, then 10 mg). By week 12, anti-dsDNA antibody levels have been reduced by a median of 109.6 IU/ml (95% CI 38.1 – 274.5). The treatment resulted in rapid and sustained clinical improvements across all patients and organ domains, reflected by a 100% SRI-4 (Systemic Lupus Erythematosus Responder Index-4) response rate at week 12. Hypogammaglobulinemia occurred in 5/10 patients, requiring immunoglobulin substitution. Daratumumab treatment has depleted circulating ASCs, reduced type I interferon activity, and profoundly modulated the T-cell responses. These findings highlight the pivotal role of ASCs in SLE pathogenesis and support daratumumab as therapeutic option for SLE.

Introduction: Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common finding on histopathology among patients with ICI-associated acute kidney injury (ICI-AKI). Patients with ICI-AIN often have T cell-dominant infiltration of the kidney and high tissue levels of CXCR3 ligands like CXCL9, 10, and 11; however, the mechanisms of inflammation in ICI-AIN are not well-understood. Methods: We applied a sub-cellular spatial transcriptomics platform (Xenium Prime 5K) to compare the cellular composition of kidney biopsy tissue from patients with ICI-AIN with ICI-treated patients with acute tubular necrosis (ICI-ATN). Results: Across 8 kidney biopsy specimens (4 with ICI-AIN, 4 with ICI-ATN), we analyzed 332,000 cells, comprising kidney parenchymal cells and infiltrating immune cells. Using a spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to unique fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-γ)/STAT1 signaling as strongly increased in ICI-AIN compared to ICI-ATN. While all inflammatory niches were overrepresented in ICI-AIN, CD8 ⁺ T cell infiltration and proinflammatory myeloid cells were the dominant immune niches. Spatial niche crosstalk analysis revealed that CD8 ⁺ T cell-derived IFN-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. Conclusions: Spatial transcriptomics reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN. IFN-γ-producing CD8 ⁺ T cells are likely key drivers of ICI-AIN and should be investigated as future therapeutic targets. Translational Statement: Spatial transcriptomics may provide insight into differences in the cellular and spatial composition of immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) and ICI-associated acute tubular necrosis (ICI-ATN). Using the novel Xenium 5K platform, we demonstrate that IFN-γ-producing CD8 ⁺ T cells are central to the pathogenesis of ICI-AIN, and that CD8 ⁺ T cell-derived IFN-γ likely induces a proinflammatory state in myeloid cells, with increased tissue production of CXCL9, 10, and 11. We then show that a reduction in oxidative phosphorylation and an IFN-γ-driven influx of proinflammatory myeloid cells may further drive kidney damage in ICI-AIN. Many of these pathways represent potential druggable targets, and our findings may therefore inform future therapeutic approaches for ICI-AIN.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) with limited biomarkers for early detection. While neutrophils contribute to SLE pathogenesis, their phenotypic heterogeneity in disease remains poorly characterized. Here, we used mass cytometry to profile blood neutrophils from patients with biopsy‐confirmed proliferative LN and healthy controls. We identified a distinct population of activated neutrophils, marked by surface expression of lysosomal‐associated membrane protein 1 (LAMP1/CD107a), that was virtually absent in healthy individuals. We demonstrate that LAMP1 resides intracellularly in resting neutrophils and translocates to the cell surface upon activation. Transcriptomic analysis revealed no difference in LAMP1 mRNA expression between patients with SLE and controls, confirming that surface LAMP1 reflects neutrophil activation rather than increased transcription. Soluble LAMP1 was significantly elevated in serum from patients with SLE compared with controls, with the highest levels in proliferative LN. In a large cohort of 225 patients with LN, urinary LAMP1 correlated with glomerular filtration rate, proteinuria, and histological activity indices. Together, our findings reveal LAMP1 as a marker of neutrophil activation in SLE and identify serum and urinary LAMP1 as potential noninvasive biomarkers for proliferative LN.

Myasthenia gravis (MG) is an autoimmune disease most frequently caused by autoantibodies (auto-Abs) against the acetylcholine receptor (AChR) located at the neuromuscular junction. Thymic follicular hyperplasia is present in most of the patients with early-onset AChR-Ab⁺ MG (EOMG), but its cellular and molecular drivers and development remain poorly understood. We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG. Multiplex histology and ELISA were used to determine migration inhibitory factor (MIF) levels. Within EOMG thymi, we consistently observed 6 distinct clusters of B-cell populations maturing toward germinal center (GC)–associated and Ab-secreting cells, featuring prominent GC activity, as indicated by substantial clonal expansions and cycling B-cell subsets. Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis. Multiplex histology confirmed abundant expression of CD74 in MG thymic B cells. Circulating MIF levels in EOMG correlated with higher disease severity as assessed by Myasthenia Gravis Foundation of America status. Our data not only illustrate and define hyperplastic thymic niches in MG as favorable environments for pathogenic B-cell proliferation, maturation, and persistence but also suggest that the MIF-CD74 axis should be investigated for potential novel therapeutic targeting in EOMG.

Objective Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases. Methods A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome. Results 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%). Conclusion Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.