Biology subjects

Fein, M. R.

Publications and source records attributed to Fein, M. R..

4 recordsLinked to original sources

bioRxiv2026

SPP1hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium

In chronic inflammatory diseases, maladaptive tissue remodelling is driven by a complex interplay of resident cells, immune filtrates and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes assive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this ggressive growth are incompletely defined. Using spatial transcriptomics profiling of patient tissue, we detected an bundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to SPP1hi macrophages. Notably, ese synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. While the SPP1hi acrophages phenotypically resemble pro-fibrotic macrophages that drive lung and liver fibrosis, these niches were devoid f the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1hi macrophages degrade and hagocytose fibrin matrices and promote fibroblast proliferation. As fibrin provides transient matrices for de novo tissue eneration in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1hi acrophages, fibroblasts and fibrin matrices adhered to the exterior synovial tissue surface. While current RA therapies rimarily aim to dampen pro-inflammatory responses, our findings provide rationale for targeting pro-generative pathways nd SPP1hi macrophages. Once Sentence SummarySPP1hi macrophages in RA synovial fibrin deposits promote tissue hyperplasia.

immunology↗

bioRxiv2026

Diverse high-fat diets drive multi-omic reprogramming that persists after dietary reversal

Dietary fat composition modulates host physiology and the gut microbiome, but the long-term effects of specific fat sources and the extent to which these changes resolve after dietary reversal remain incompletely defined. Here, we present a longitudinal multi-omic resource of mice maintained for one year on a purified control diet, seven high-fat diets differing in predominant fat source, or reversal regimens in which animals were switched from high-fat to control diet after 4 or 9 months. We further incorporated two cohorts with distinct pre-existing microbiome configurations to determine how baseline community structure shapes diet-induced remodeling of the gut microbiome ecosystem. By integrating longitudinal phenotyping, fecal metagenomics, fecal metabolomics, plasma metabolomics and lipidomics, and intestinal single-cell RNA sequencing, we defined the shared and dietary fat-specific responses across host and microbiome compartments. Baseline microbiome composition strongly influenced microbial responses to diet, indicating that pre-existing community structure is a major determinant of dietary ecosystem remodeling. Although many altered features shifted toward baseline after dietary reversal, only approximately half of diet-associated microbial changes recovered within the study window. A subset of taxa exhibited persistent alterations, including sustained depletion of Lactobacillus johnsonii and Bifidobacterium pseudolongum and sustained enrichment of Alistipes finegoldii, consistent with a "microbiome memory" of prior high-fat diet exposure. This memory effect is mirrored in the host, by sustained suppression of major histocompatibility complex class II (MHC-II) gene expression in intestinal epithelial cells after dietary reversal. These findings indicate that dietary fats leave a lasting imprint on the host-microbiome interactome that survives dietary intervention. Together, these data establish a resource for defining how dietary fat source, baseline microbiome composition, and dietary history shape host-microbiome states. The entire resource is available online as an RShiny app.

systems biology↗

bioRxiv2021

Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis

Immune checkpoint inhibitor (ICI) therapies that promote T cell activation have improved outcomes for advanced malignancies yet also elicit harmful autoimmune reactions. The T cell mechanisms mediating these iatrogenic autoimmune events remain unclear. Here we assayed T cells from joints of patients affected by ICI-induced inflammatory arthritis (ICI-arthritis), which can present clinically indistinguishable from rheumatoid arthritis (RA). Compared to the autoimmune arthritides RA and psoriatic arthritis (PsA), ICI-arthritis joints contained an expanded CD38hi CD127- CD8+ T cell subset that displays cytotoxic, effector, and interferon (IFN) response signatures. The abundance of CD38hi CD8 T cells in ICI-arthritis resulted from a limited number of clones that could be found proliferating in the joint. Exposure of synovial T cells to Type I IFN, more so than IFN-{gamma}, induces the CD38hi cytotoxic phenotype. Relative to other CD8+ T cell subsets in the joints, the CD38hi population is distinct from a dysfunctional population and clonally most related to TCF7+ memory populations. Examination of synovial tissue from bilateral knee arthroplasty demonstrated considerable sharing of TCR clonotypes in the CD38hi CD8 T cell fraction from both knees. These results define a distinct CD8 T cell subset that may be directly activated by ICI therapy and mediate a tissue-specific autoimmune cellular reaction in patient joints.

immunology↗

bioRxiv2018

Cancer cell CCR2 orchestrates suppression of the adaptive immune response

C-C chemokine receptor type 2 (CCR2) is expressed on monocytes and facilitates their recruitment to tumors. Though breast cancer cells also express CCR2, its functions in these cells are unclear. We found that Ccr2 deletion in cancer cells led to reduced tumor growth and [~]2-fold longer survival in an orthotopic, isograft breast cancer mouse model. Deletion of Ccr2 in cancer cells resulted in multiple alterations associated with better immune control: increased infiltration and activation of cytotoxic T lymphocytes (CTLs) and CD103+ cross-presenting dendritic cells (DCs), as well as upregulation of MHC class I and downregulation of checkpoint regulator PD-L1 on the cancer cells. Pharmacological or genetic targeting of CCR2 increased cancer cell sensitivity to CTLs and enabled the cancer cells to induce DC maturation toward the CD103+ subtype. Consistently, Ccr2-/- cancer cells did not induce immune suppression in Batf3-/- mice lacking CD103+ DCs. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response. SummaryC-C chemokine receptor type 2 (CCR2) expressed on monocytes facilitates their recruitment to tumors. Here, CCR2 signaling in cancer cells is shown to suppress immune control of tumors, in part by reducing CD103+ dendritic cell recruitment.

cancer biology↗