Biology subjects

Belmont, H. M.

Publications and source records attributed to Belmont, H. M..

6 recordsLinked to original sources

bioRxiv2026

Rethinking the Benign Nature of Class II Lupus Nephritis

Introduction: Class II lupus nephritis (LN) is considered clinically benign, yet up to 50% of patients progress to more severe disease and no molecular characterization exists. We aimed to define the single-cell landscape of Class II LN and identify cellular and transcriptional features associated with kidney outcome. Methods: We performed single-cell RNA sequencing on kidney biopsies from fifteen Class II LN patients (eight de novo, seven regressed from prior proliferative or membranous disease) and six healthy controls, integrated with 155 LN and 30 healthy-control samples from the Accelerating Medicines Partnership in SLE spanning proliferative, membranous, and mixed LN. Findings were correlated with 52-week renal response and supported by urinary proteomics. Results: Despite histologically minimal changes, Class II LN exhibited marked immune cell expansion comparable to proliferative and membranous LN, including CCL3+ CCL4+ intermediate monocytes producing TNF, FOLR2+ SIGLEC1+ macrophages producing TGF{beta} and PDGF, and CD69+ CD8+ effector memory T cells producing IFN{gamma}. Fibroblasts and myofibroblasts were significantly expanded and displayed divergent transcriptional programs: pro-fibrotic and inflammatory myofibroblast modules were associated with worse 52-week outcomes, while interferon-responsive and matrix-remodeling fibroblast programs were associated with improvement. Pathogenic and protective fibroblast populations received overlapping immune-derived signals, suggesting that fibroblast transcriptional state, rather than the identity of incoming signals, shapes the stromal response. Baseline chronicity index captured this stromal heterogeneity and was the clinical parameter most associated with outcome. Urinary proteomics aligned Class II with proliferative rather than membranous disease. Conclusions: Class II LN harbors substantial molecular activity not captured by routine histology. Fibroblast transcriptional programs and baseline chronicity index are candidate correlates of kidney outcome that warrant validation in larger, prospectively followed cohorts.

genomics↗

bioRxiv2026

Serum proteomic atlas reveals distinct molecular signatures of lupus nephritis activity, chronicity, and treatment response

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), features heterogeneous renal pathology and reliance on invasive biopsies for diagnosis, prognosis, and treatment selection. Current peripheral clinical markers inadequately capture disease activity and progression. Here, we performed comprehensive serum proteomic profiling of over 5,000 proteins in the large, longitudinal Accelerating Medicines Partnership Rheumatoid Arthritis/SLE cohort of 270 LN patients and 63 healthy controls. Machine learning identified distinct molecular signatures that classified LN versus controls, differentiated histological classes, and delineated activity- and chronicity-associated pathways, including inflammatory cytokine, PI3K/AKT, TGFb, and complement/coagulation pathways. An increase in VSIG4, CD27, HAVCR1, and LAIR1 consistently emerged as top biomarkers across multiple clinical contexts, and early decreases in these markers at 3 months were associated with complete treatment response at 1 year. By resolving coordinated serum protein modules linked to key inflammatory, PI3K/AKT, TGFb, and complement pathways, these signatures mechanistically connect circulating proteomic perturbations to intrarenal immune activation, tissue injury, and repair in LN. These findings demonstrate that serum proteomics reflect complex intrarenal immunopathology and offer a promising noninvasive "liquid biopsy" approach to refine LN classification and guide personalized management, potentially reducing the need for repeated invasive biopsies and improving therapeutic decision-making.

immunology↗

bioRxiv2025

Deep profiling of lupus nephritis kidneys reveals dynamic changes in myeloid cells associated with disease progression

ObjectivesLupus nephritis (LN) is a common, potentially fatal manifestation of systemic lupus erythematosus. We aim to gain new insights into the immune responses underlying LN and their relation to the histologic heterogeneity observed in this disease, focusing on myeloid cells. MethodsSingle-cell RNA-sequencing (scRNA-seq) was used to profile dissociated kidney samples from 156 LN patients and 30 healthy individuals. Spatial transcriptomics (ST), utilizing a gene panel designed to capture all myeloid subsets identified in the scRNA-seq data, was applied to kidney samples acquired from 6 LN patients and 2 healthy controls. ResultsWe generated a full catalog of the myeloid subsets found in LN kidneys. Our analyses indicated that an increase in irreversible tissue damage, as measured by the NIH chronicity index (CI), is associated with a gradual switch of the local immune response from one dominated by monocytes and macrophages to one featuring expanded CD4+ T, GZMK+CD8+ T, B and dendritic cells, with a parallel decrease in the interferon response. In proliferative/mixed LN only, the degree of active inflammation correlates with expansion of disease-specific macrophage (DMac) subsets, which later contract as the CI increases. Trajectory analysis of the scRNA-seq data suggested that DMacs arise from both infiltrating monocytes and tissue-resident macrophages; this was supported by the ST data, as well as cell cultures. DMacs are indicated to interact with parietal epithelial cells, promoting the development of glomerulosclerosis. ConclusionsWe suggest a detailed picture of the changes in the kidney immune mechanisms in LN as this disease progresses.

immunology↗

bioRxiv2025

A population-scale atlas of blood and tissue in lupus nephritis

One Sentence SummaryA single-cell atlas of paired blood and tissue samples from Lupus Nephritis patients and healthy controls identified stromal and immune populations within renal tissue, including the scar-associated macrophage populations, which correlate with and may drive renal disease activity. Lupus nephritis (LN), a severe manifestation of Systemic Lupus Erythematosus (SLE), is a heterogeneous disease driven by diverse immune and tissue cell types. We obtained 538K single-cell and 140K single-nuclear profiles from kidney biopsies of 155 LN patients and 30 pre-implantation transplant biopsy controls, along with 325K single-cell blood profiles overlapping many of these patients. We identified key tissue cell types and cell states, and immune cell states; we were able to determine cell states that were tissue specific, and those that were present in the blood. We observed that LN pathological features are significantly associated with cell states using differential gene expression and Covarying Neighborhood Analysis (CNA). These analyses revealed broad changes in cell states associated with irreversible chronic tissue damage. After controlling for the effects of ongoing tissue damage, we observed that expansion of key glomerular and Scar Associated Macrophages (SAMs) populations tracked with increasing inflammatory disease activity. SAMs appear to drive LN fibrosis and, in active disease, infiltrate the glomeruli more than other myeloid cells. These observations strongly support that therapeutic targeting of myeloid populations may offer an as-of-yet unproven strategy to prevent renal inflammation and ongoing kidney damage in LN.

molecular biology↗

bioRxiv2023

Intrarenal myeloid subsets associated with kidney injury are comparable in mice and patients with lupus nephritis

Resident macrophages and infiltrating monocytes in kidneys of patients with lupus nephritis are altered both in frequency and function relative to their counterparts in healthy kidneys. The extent to which mouse models might be useful in developing approaches to target these cells for treating lupus nephritis is poorly understood. Here, we studied four common lupus mouse models that share clinical, serologic, and histopathologic kidney changes with humans. Using single-cell profiling and multiplex spatial imaging to analyze the intrarenal myeloid compartment with the onset of clinical disease in these models, we identified monocyte and macrophage subsets that expand or contract in kidneys with clinical nephritis. A unique subset of classical monocytes expanded with the onset of disease and expressed genes such as CD9, Spp1, Ctsd, Cd63, Apoe, and Trem2 that were previously shown to be induced by tissue injury and play a role in inflammation, lipid metabolism and tissue repair in other organs. Resident macrophages transitioned from a pro-inflammatory to a similar injury-associated state with onset of disease. To test whether these findings in mouse models were also observed in humans, we re-analyzed monocytes and macrophages in a single-cell RNAseq dataset of kidney biopsies from 155 patients with lupus nephritis and 30 healthy donors, collected by the NIH AMP RA/SLE consortium. Human monocytes and macrophages showed conserved changes in gene expression programs associated with lupus nephritis disease indices, and localized to similar kidney microenvironments as in mice. By identifying myeloid subsets and disease-associated alterations in biological processes that are conserved across species, we provide a strong rationale for functional studies of these cells and pathways in mice to uncover mechanisms and find targets relevant to human lupus nephritis. One sentence summaryThis study characterizes intrarenal myeloid cells from four lupus mouse models and 155 patients with lupus nephritis using single-cell RNA-seq and imaging, and identifies novel infiltrating and resident myeloid subsets that are conserved between mouse and human lupus nephritis, thus providing a map and strong rationale for functional studies in mice with relevance to human disease.

immunology↗

bioRxiv2018

Insights from Comparison of the Renal and Skin Single Cell Transcriptomes in Lupus Nephritis

Lupus nephritis (LN) occurs in up to 50% of patients with systemic lupus erythematosus (SLE), and is a major contributor to mortality and morbidity. LN presents as a highly heterogeneous disease both in histopathology and response to therapy. The molecular and cellular processes leading to renal damage and to the heterogeneity of the disease are not well understood. To elucidate the processes underpinning the heterogeneity of LN, we applied singlecell RNA-sequencing (scRNA-seq) to renal biopsies from LN patients. Skin biopsies were evaluated as a source of biomarkers for monitoring kidney disease. Type-I interferon (IFN) response signatures were identified in tubular cells and keratinocytes, differentiating LN patients from healthy controls. Non-responders associated with higher IFN signatures in both tissue compartments. Moreover, non-response was also associated with a fibrotic signature in the tubular cells. Receptor-ligand interaction analysis indicated that the fibrotic process is likely mediated by FGF receptors with the initiating signal originating from infiltrating leukocytes. Differential expression analysis of tubular cells between proliferative and membranous LN pointed to several fibrosis-relevant pathways, which may offer insight into their histological differences. In summary, scRNA-seq was applied to LN to deconstruct its heterogeneity and provide novel targets for personalized approaches to therapy.

immunology↗