Biology subjects

DeBerg, H. A.

Publications and source records attributed to DeBerg, H. A..

6 recordsLinked to original sources

bioRxiv2026

Homeostatic fibroblast niche collapse in clinically uninvolved skin marks a pre-fibrotic stage of systemic sclerosis

Systemic sclerosis, or scleroderma, is a chronic autoimmune disease characterized by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Heterogeneous clinical presentation and polygenic risk complicate our understanding of disease mechanisms and the path to effective therapy. Single-cell analyses have revealed substantial transcriptional diversity in skin, but disease-associated reprogramming remains poorly defined. To address this, we performed high-resolution spatial transcriptomic profiling of paired clinically uninvolved and clinically affected scleroderma donor skin alongside healthy controls. We identified a continuum of cellular, molecular, and spatial changes to the stroma that were already evident in clinically uninvolved tissue yet still distinct from the broader and more advanced changes in paired fibrotic samples. Uninvolved skin was comparable to healthy tissue by clinical and histopathological assessment, but distinguishable by the numerical reduction, transcriptional reprogramming, and spatial isolation of LGR5+SCARA5+PI16+ progenitor fibroblasts. In parallel, the dermal vascular smooth muscle compartment shifted from a contractile to a synthetic, activated state, suggesting reprogramming that begins before overt fibrosis. Cell neighborhood analysis revealed that progenitor fibroblasts occupy dense stromal niches in healthy skin that collapse in clinically uninvolved tissue, replaced by isolated, disease-associated cellular networks. These data indicate that clinically uninvolved skin occupies an intermediate stage along the pathologic continuum of scleroderma, establishing a framework for strategies to preserve homeostatic fibroblast niches before tissue remodeling and fibrotic commitment.

immunology↗

bioRxiv2026

Type I Interferon-Driven Monocyte Dysregulation and MAS-associated CD8+ T cells During Macrophage Activation Syndrome

Macrophage activation syndrome (MAS) is driven by a hyperinflammatory response characterized by aberrant activation of lymphocytes and phagocytes. While monocytes and macrophages are thought to be important in MAS pathogenesis, their role remains poorly understood. We used bulk and single-cell RNA sequencing (RNA-Seq) on sorted monocytes from children with MAS and healthy controls to identify transcriptional changes during MAS. We defined a MAS signature in classical monocytes that correlated with ferritin and was elevated in monocytes from systemic lupus erythematosus and COVID-19 patients. We also identified a subset of classical monocytes with high levels of interferon-stimulated genes (ISGs) that expanded during MAS. Surprisingly, the transcriptional signature of these cells was driven by type I IFNs, rather than IFN{gamma}. Consistent with this finding, we detected increased levels of circulating IFN{beta} during MAS, suggesting that IFN{beta} plays an unrecognized role in driving MAS monocyte responses. We also identified a MAS-associated CD8+ T cell population with a distinctive transcriptional signature. We used cell-cell communication algorithms to predict increased immunoregulatory interactions between monocytes and T cells during MAS. Together, these results provide new evidence for a role for type I IFN during MAS and identify a unique CD8+ T cell population that may contribute to MAS pathophysiology.

immunology↗

bioRxiv2025

The altered T cell landscape in Systemic Sclerosis patients is characterized by dysfunctional type 1 immunity.

BackgroundT cells in patients with chronic autoimmunity show features of dysfunction and exhaustion. However, the functionally-defined T cell subsets affected by these changes remain poorly characterized. Here, we sought to reveal aberrations in the composition, phenotype and function of canonical T cell subsets in the blood of Systemic Sclerosis (SSc) patients, compared to healthy subjects and Systemic Lupus Erythematosus (SLE) patients. MethodsWe developed a novel multidimensional flow-cytometry panel to simultaneously detect lineage-defining transcription factors, co-inhibitory receptors and other functional markers to characterize T cell subsets without in vitro restimulation. We compared T cell landscapes in SSc and SLE patients, and healthy subjects, using Optimized t-SNE and PhenoGraph algorithms. Cytokine production in patient samples was determined using intracellular cytokine staining. Transcriptomic analysis was performed to assess the role of IFN-{gamma} in fibroblasts. ResultsThe data show altered distribution and aberrant functional states of transcription factor-defined T cell subsets in patients with autoimmunity, with shared and unique features between diseases and their subtypes. Strikingly, SSc and SLE patients showed a severe deficiency in subsets of CD8+ and CD4-CD8- T cells that expressed T-bet, which is critical for IFN-{gamma}-dependent type 1 immunity, and exhibited features of exhaustion. Moreover, TIGIT+Foxp3+ regulatory T cells, known to suppress Th1 responses, were selectively increased in SSc. Functionally, T cells from SSc patients produced less IFN-{gamma}, a cytokine that suppresses pro-fibrotic gene expression in fibroblasts. ConclusionOur study demonstrates that SSc patients have a defective IFN-{gamma}-producing T cell compartment that may lead to reduced anti-fibrotic T cell activity, enabling chronic fibrosis development. FundingNational Institute of Allergy and Infectious Diseases/NIH, National Institute of Arthritis and Musculoskeletal Diseases/NIH, National Heart, Lung and Blood Institute/NIH, National Scleroderma Foundation, National Jewish Health

immunology↗

bioRxiv2024

Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells.

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they alter disease risk via changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. We tested >18,000 autoimmune disease-associated variants for allele-specific expression using massively parallel reporter assays in primary human CD4+ T cells. The 545 expression-modulating variants (emVars) identified greatly enrich for likely causal variants. We provide evidence that many emVars are mediated by common upstream regulatory conduits, and that putative target genes of primary T cell emVars are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and novel target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.

genetics↗

bioRxiv2024

T cells promote distinct transcriptional programs of cutaneous inflammatory disease in human skin structural cells

T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside altered structural cell frequencies and transcriptional states, but to what extent different T cells promote disease-associated changes remains unclear. We show that functionally diverse circulating and skin-resident CD4+CLA+ T cell populations promote distinct transcriptional outcomes in human keratinocytes and fibroblasts associated with inflamed or healthy tissue. We identify Th17 cell-induced genes in keratinocytes that are enriched in psoriasis patient skin and normalized by anti-IL-17 therapy. We also describe a CD103+ skin-resident T cell-induced transcriptional module enriched in healthy controls that is diminished during psoriasis and scleroderma and show that CD103+ T cell frequencies are altered during disease. Interrogating clinical data using immune-dependent transcriptional signatures defines the T cell subsets and genes distinguishing inflamed from healthy skin and allows investigation of heterogeneous patient responses to biologic therapy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=35 SRC="FIGDIR/small/606077v4_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@fb573corg.highwire.dtl.DTLVardef@11c4eb3org.highwire.dtl.DTLVardef@17304cforg.highwire.dtl.DTLVardef@40d6ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells

Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

immunology↗