Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.08.27.745373

Antibody-dependent priming of spontaneous germinal centers by autoreactive B cells

Kim, D.·Chiang, K.·Largent, A. D.·Pitner, R. A.·Ponnan, S. M.·McKinney, B. J.·James, R. G.·Rawlings, D. J.·Jackson, S. W.
View original source ↗Export metadata ↓

Abstract

Autoreactive germinal centers (GCs) are central to autoimmune pathogenesis, yet the mechanisms by which single autoreactive B cell clones prime systemic autoimmunity remain unclear. Using the 564Igi mixed chimera model, we demonstrate that autoreactive 564Igi B cells break tolerance in wild-type B cells through an unexpected mechanism independent of cognate T cell interactions. While B cell-intrinsic TLR7 signaling was essential for spontaneous GC formation, deletion of MHC class II, CD40, or CD80/86 on GC-priming 564Igi B cells failed to prevent GCs. Instead, CRISPR-mediated deletion of Prdm1 (encoding BLIMP-1) in 564Igi B cells ablated spontaneous GCs, implicating autoantibody production as the primary driver. These findings reveal that autoantibodies can initiate feed-forward mechanisms that propagate systemic autoimmunity, independent of B cell-intrinsic antigen presentation.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kim, D., Chiang, K., Largent, A. D., Pitner, R. A., Ponnan, S. M., McKinney, B. J., James, R. G., Rawlings, D. J., Jackson, S. W.. 2026-09-01. Antibody-dependent priming of spontaneous germinal centers by autoreactive B cells. https://doi.org/10.64898/2026.08.27.745373

Cite the original work for its findings. Save a collection to share your selection of sources.

Discover connections

CRISPR methodPreprint resourcePreprint subjectimmunology subject

Connections use source metadata and explicit phrase matches, not verified experimental comparisons.

KEEP EXPLORING

Related preprints

bioRxiv2026

Dengue Virus Serotype 2 Infection Transcriptionally Reprograms Host Neutrophils to Establish an Immunosuppressive Microenvironment in Mice

Dengue virus (DV) infection triggers profound alterations in host immune responses, yet the transcriptomic reprogramming of innate immune cells during disease progression remains incompletely understood. Here, we demonstrated that Dengue virus serotype 2 (DV-2) infection transcriptionally reprograms host neutrophils, establishing an immunosuppressive microenvironment that facilitates pathogenesis. Through scRNA transcriptomic profiling of bone marrow and spleen cells from the DV-2-infected AG129 mouse model, we delineated a distinct neutrophil signature that shows dynamic shifts in immature and activated populations over the course of dengue infection. We also characterized a specific Ly6Glow subpopulation, notably Fibrinogen-like protein 2 (FGL2)-expressing subsets, that appeared with disease progression. Serum FGL2 levels were significantly elevated in both DV-2-infected mice and human dengue-positive patients. Furthermore, treatment of splenocytes with FGL2 or FGL2-enriched neutrophil secretomes suppressed T cell functional activity and promoted an immunosuppressive phenotype. Together, these findings reveal how DV-2-driven neutrophil reprogramming shapes an immunosuppressive network, highlighting the importance of studying FGL2-expressing neutrophil subsets to understand dengue immunopathogenesis.

immunology↗
bioRxiv2026

Structures of MyD88 and its oncogenic mutant reveal DNA binding with implications for cytosolic DNA sensing

MyD88 is a universal adaptor that connects to Toll-like receptors and interleukin-1 receptors through its Toll/IL-1R homology (TIR) domain and activates inflammatory signaling via its death domain (DD). However, how MyD88TIR serves as the platform for these functions and if it has additional functions remain unclear. Here, we report cryogenic electron microscopy (cryo-EM) structures of MyD88TIR and its cancer-specific mutant L252P (previously L265P) mainly in ring and spiral forms, respectively. Both assemblies are formed by antiparallel double-filaments, using canonical TIR interfaces within each strand but unique surfaces between the strands, and position MyD88DD at the same sides of the assemblies for self-oligomerization and pathway activation. Surprisingly, these WT or L252P filaments are bound to dsDNA using the concave sides of the rings and the spirals. In vitro assays and cellular studies establish that MyD88 directly binds dsDNA and promotes inflammatory cytokine expression, particularly pro-IL-1{beta}, following dsDNA transfection or viral infection. Notably, these responses are unaffected by deficiency of UNC93B1, the essential chaperone required for trafficking endosomal nucleic acid-sensing TLRs. Structure-guide MyD88 mutant that disrupts dsDNA binding specifically compromises dsDNA-induced transcriptional program while maintaining TLR signaling. RNA-seq further reveals that MyD88 plays a crucial role in inducing gene expression upon dsDNA sensing and that about half of cGAS-dependent genes are also MyD88-dependent. Together, our structural, biochemical and genetic data support the findings that MyD88 directly engages with cytosolic dsDNA and cooperates with cGAS to promote the full innate immune transcriptional response.

immunology↗
bioRxiv2026

A Synthetic Consensus Chiroptera IFN-β Induces IFN-I Signaling Across Diverse Bat Taxa

Bat-associated viruses consistently spill over from bats into humans and other animals. Many bat-associated viruses, including Marburg virus and Nipah virus, cause severe disease in humans but their presentation is subclinical in bats. Advancements in tools and resources to study bat innate antiviral immune responses, including the type I IFN (IFN-I) pathway, are needed to evaluate the mechanisms that underlie differential infection outcomes between reservoir bats and spillover hosts. Commercially available IFN-Is are not bat-specific, and conspecific IFN-Is are impractical to produce for the over 1,500 described bat species. Here, we design and validate a bat order-level consensus IFN (Chiroptera IFN-{beta}) that is functional in bat cells from six diverse bat families, including representatives from both suborders. Using Jamaican fruit bat cells, we demonstrate that Chiroptera IFN-{beta} induces an IFN-stimulated gene repertoire comparable to conspecific IFN-{beta}. This valuable resource can accelerate the capacity of the field to study bat innate antiviral responses and illuminate differences between bats and humans.

immunology↗