Biology subjects

Billi, A. C.

Publications and source records attributed to Billi, A. C..

6 recordsLinked to original sources

bioRxiv2025

TWEAK Signaling Drives the Transition from Psoriasis to Atopic Dermatitis-like Inflammation in Paradoxical Skin Reactions

Targeted biologics have significantly advanced the treatment of inflammatory skin diseases such as psoriasis; however, some patients paradoxically develop eczematous skin reactions during or after anti-TNF, IL-17, or IL-23 therapy. Although these paradoxical reactions resemble atopic dermatitis clinically and histologically, the molecular mechanisms that drive their development are not fully understood. Here, we generated high-resolution cellular and spatial maps of healthy skin, psoriasis, atopic dermatitis, and paradoxical reactions using single-cell RNA sequencing, spatial transcriptomics, immunohistochemistry, and in vitro assays. In paradoxical reactions, we identified a distinct transcriptional landscape characterized by myeloid and T-cell expansion and an altered keratinocyte phenotype shaped by TWEAK signaling. Mechanistically, we showed that TWEAK synergizes with IL-13 to drive the Th2/type I interferon-polarized epithelial program. Notably, anti-TNF therapy induced TWEAK gene expression in myeloid cells, suggesting a compensatory inflammatory circuit. Together, these findings identify the TWEAK-IL-13 axis as a central driver of paradoxical skin reactions and provide a mechanistic framework for how cytokine blockade may rewire cutaneous immune responses. One Sentence Summary The TWEAK-IL-13 signaling axis is a key driver of immune reprogramming underlying paradoxical skin reactions.

immunology↗

bioRxiv2025

VGLL3-centered network connects placental, vascular, and immune defects in preeclampsia

Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche. Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription co-regulator in the Hippo pathway, is upregulated in preeclamptic placentas. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction, all of which contribute to pregnancy-related hypertension, fetal growth restriction, and offspring mortality. Our data reveal that VGLL3 acts upstream of preeclampsia-associated processes, including the production of sFLT1, a key biomarker of the disease. Notably, targeting VGLL3--either by genetic deletion in mouse placentas or through therapeutic inhibition in human placentas--protects against preeclampsia and alleviates disease pathology. These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.

immunology↗

bioRxiv2025

A Transcriptomic Atlas of Healthy Human Skin Links Regional Identity to Inflammatory Disease.

Human skin is not a uniform organ but a mosaic of anatomically distinct niches, with each site finely tuned to unique environmental demands and immune pressures. Yet, the molecular determinants that define these regional identities and their relationship to site-specific vulnerability to inflammatory disease remain poorly understood. Here, we generate a high-resolution single-cell atlas of human skin, profiling 274,834 cells from 96 healthy samples across 7 anatomically distinct sites (acral, arm, axilla, back, face, leg and scalp). Our analysis reveals striking region-specific transcriptional and cellular networks, uncovering how local immune-stromal crosstalk governs tissue homeostasis and underpins anatomical susceptibility to distinct inflammatory diseases such as such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis. These findings illuminate the tissue-intrinsic foundations of regional immune identity and provide a blueprint/resource for the development of precision therapies tailored to the distinct immunological microenvironments of specific anatomical skin sites.

systems biology↗

bioRxiv2024

Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet's syndrome

Sweets syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweets syndrome revealed a prominent interferon signature in Sweets syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweets syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweets syndrome through recognition of type I interferons.

immunology↗

bioRxiv2021

Single cell transcriptomics reveals distinct effector profiles of infiltrating T cells in lupus skin and kidney

Cutaneous lupus is commonly present in patients with systemic lupus erythematosus (SLE) but can also exist as an isolated manifestation without further systemic involvement. T cells have been strongly suspected to contribute to the pathology of cutaneous lupus, yet our understanding of the T cell phenotypes and functions in the skin in lupus remains incomplete, and the extent to which lupus T cell infiltrates in skin resemble those in other tissue beds is unknown. Here, we present a detailed single-cell RNA sequencing profile of T and NK cell populations present within lesional and non-lesional skin biopsies of patients with cutaneous lupus. We identified multiple lymphocyte clusters, including both CD4 and CD8 T cells, NK cells, regulatory T cells, and a population of strongly interferon-responding cells that was present in patients with cutaneous lupus but absent in healthy donors. T cells across clusters from both lesional and non-lesional skin biopsies expressed elevated levels of interferon simulated genes (ISGs); however, compared to T cells from control skin, T cells from cutaneous lupus lesions did not show elevated expression profiles of activation, cytotoxicity, or exhaustion. Integrated analyses comparing skin T/NK cells to lupus nephritis kidney T/NK cells indicated that skin lymphocytes appeared less activated and lacked the expanded cytotoxic populations prominent in lupus nephritis. An integrated comparison of skin T cells from lupus and systemic sclerosis revealed similar activation profiles but an elevated ISG signature specific to cells from lupus skin biopsies. Overall, these data represent the first detailed transcriptomic analysis of the of T and NK cells in cutaneous lupus at the single cell level and have enabled a cross-tissue comparison that highlighted the stark differences in composition and activation of T/NK cells in distinct tissues in lupus.

immunology↗

bioRxiv2021

Non-lesional and Lesional Lupus Skin Share Inflammatory Phenotypes that Drive Activation of CD16+ Dendritic Cells

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Studies to date suggest that non-lesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA-sequencing and spatial-seq. We demonstrate that normal-appearing skin of lupus patients represents a type I interferon-rich, prelesional environment that skews gene transcription in all major skin cell types and dramatically distorts cell-cell communication. Further, we show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining pro-inflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and non-lesional skin in lupus and identify a role for skin education of CD16+ dendritic cells in CLE pathogenesis.

immunology↗