Biology subjects

Lanz, T. V.

Publications and source records attributed to Lanz, T. V..

5 recordsLinked to original sources

bioRxiv2026

EBV reprograms autoreactive B cells as antigen presenting cells in multiple sclerosis

Summary paragraphMultiple sclerosis (MS) is a chronic autoimmune disease targeting the central nervous system (CNS). MS develops almost exclusively in individuals previously infected with Epstein-Barr virus (EBV)1, yet the mechanisms linking EBV infection to MS pathogenesis remain incompletely defined. Here we characterized EBV-infected B cells in MS and demonstrated that EBV directly infects autoreactive anti-CNS antigen B cells and reprograms them into pro-inflammatory antigen-presenting cells (APCs). EBV B cells in MS were enriched within the CD27CD21low memory B-cell subset and exhibited upregulated B cell activation and APC transcriptional programs. Recombinant antibodies derived from MS blood and cerebrospinal fluid (CSF) EBV B cells bound brain tissue, and several cross-bound both MS-associated autoantigens and Epstein-Barr virus nuclear antigen-1 (EBNA1). In vitro, EBV B cells functioned as APCs that stimulated T peripheral helper cells, with associated activation of EBV- anti-CNS antigen B cells. Collectively, these findings support a mechanistic framework in which EBV infects and transcriptionally reprograms autoreactive anti-CNS antigen B cells into APCs that drive pathogenic anti-CNS antigen T cell and EBV- B cell responses in MS.

immunology↗

bioRxiv2026

Selective Immune Silencing by Targeted TGF-β Agonists

Depletion of pathogenic T and B cells is a pillar of therapies for autoimmune, inflammatory, and transplantation-related immunological diseases. However, adverse events, safety concerns in immunocompromised patients, and disease relapse limit clinical utility. Here, we exploit the immunosuppressive properties of a transforming growth factor beta (TGF-{beta}) mimic repurposed from helminths for cell type-specific therapeutic silencing, as a new approach to complement existing therapies. Mouse CD4 and CD8 T cell-targeted TGF-{beta} agonists selectively and potently silence antigen-specific T cell responses in OVA-immunized mice by suppressing pro-inflammatory effector, cytotoxic, and T follicular helper programs, while skewing cells toward a quiescent state biased toward regulatory and type 17 T cell phenotypes. Similarly, human CD4 and CD8 T cell-targeted TGF-{beta} agonists precisely and effectively suppress live-attenuated influenza vaccine (LAIV)-induced T cell activation and expansion in human spleen organoids. Correspondingly, CD4 T cell-targeted TGF-{beta} agonist effectively ameliorated disease activity and promoted disease remission in CD4 T cell-driven models of autoimmune neuroinflammation and allergic airway inflammation, demonstrating efficacy in both prophylactic and established inflammatory settings. Moreover, both CD4 and CD8 T cell-targeted TGF-{beta} agonists ameliorated disease activity in graft-versus-host disease. Additionally, a human CD19 B cell-targeted TGF-{beta} agonist robustly inhibits germinal center B cell-to-plasmablast maturation and antibody responses in LAIV-stimulated human spleen organoids. These early-stage results suggest that cell-selective TGF-{beta} agonism merits further investigation as a versatile therapeutic approach for the precise silencing of pathogenic adaptive immune responses.

immunology↗

bioRxiv2025

Senescent Activated Naive B Cells Promote Anti-Citrullinated Antigen T Cell Responses and the Transition to Clinical Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by joint and systemic inflammation. Anti-citrullinated protein antibodies (ACPAs) define an at-risk stage that precedes clinically apparent inflammatory arthritis (clinical RA) onset, yet the molecular mechanisms driving progression remain poorly understood. Here, we applied single-cell multi-omics to profile B cells longitudinally collected from ACPA individuals who either convert to clinical RA (Converters) or do not (Nonconverters). We identified a striking expansion of CXCR5CD69 activated naive B cells (aNAVs) uniquely in Converters prior to clinical RA. These aNAVs exhibited a pro-inflammatory, senescent transcriptional program and persist through to clinical RA. In Converters, aNAVs expressed polyreactive, autoreactive IgM with distinctive V-J gene rearrangements that dominate the BCR repertoire. Furthermore, in Converters most IgM aNAVs were developmentally arrested in the peripheral blood, while a subset undergoes class switching and follows divergent somatic hypermutation trajectories. Mechanistically, aNAVs infiltrated RA synovium and served as potent antigen presenting cells to activate both anti-citrullinated antigen CD4 and CD8 T cells in an HLA-dependent manner. Chronic exposure to citrullinated antigens and CpG synergistically drove aNAV activation and senescence. These findings establish a mechanistic link between naive B cell senescence and clinical RA development in ACPA+ individuals, providing a rationale for therapeutically targeting aNAV B cells for the prevention of RA. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/682430v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@153b185org.highwire.dtl.DTLVardef@1aba6eeorg.highwire.dtl.DTLVardef@5c886eorg.highwire.dtl.DTLVardef@10109a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Sequence-Independent RNA Sensing in Living Mammalian Cells

Recently, several groups described sensors in living cells that take advantage of adenosine deaminases acting on RNA (ADARs) to link the presence of an RNA (a "target transcript") to the translation of a payload from a second, exogenously introduced mRNA. These sensors share the key mechanism of editing a stop codon opposite a specific sequence motif in the target transcript, where this motif requirement is dictated by ADARs strong sequence preference. This constrains sensor design and precludes the sensing of short sequences that lack such motifs, often essential for key applications such as sensing viral RNAs and differentiating splice isoforms. Here we address this limitation with modular RNA sensors using adenosine deaminases acting on RNA ("modulADAR"). ModulADAR features two key elements that mirror the modularity of ADARs: regions that hybridize with the target transcript to recruit ADARs dsRNA-binding domains, and a stem-loop for stop-codon editing by ADARs catalytic domain. We optimize modulADAR and apply it to detect short subsequences that cannot be sensed by prior-generation sensors. We anticipate that modulADAR will empower broader basic science and therapeutic applications, especially those that will uniquely benefit from programmable RNA detection in living cells.

synthetic biology↗

bioRxiv2023

Anti-citrullinated protein antibodies with diverse specificities ameliorate collagen antibody-induced arthritis in a time-dependent manner

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and have long been considered to contribute to pathogenesis. In this study, we sequenced the plasmablast antibody repertoires of RA patients and functionally characterized their encoded ACPAs. Recombinantly expressed monoclonal ACPAs bound citrullinated autoantigens, as well as autocitrullinated peptidylarginine deiminase 4 (PAD4). Using the collagen antibody induced arthritis (CAIA) mouse model, we demonstrated that the recombinant ACPAs significantly reduced paw thickness and arthritis severity as compared to isotype-matched control antibodies. Treatment with recombinant ACPAs also significantly reduced bone erosions, synovitis, and cartilage damage in histologic analysis of paws. This amelioration was observed for all the ACPAs tested and was independent of citrullinated antigen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model, implying that ACPAs anti-inflammatory effects were more preventative than therapeutic. This study highlights a potential protective role for ACPAs in RA.

immunology↗