Biology subjects

Ring, A. M.

Publications and source records attributed to Ring, A. M..

5 recordsLinked to original sources

bioRxiv2026

High prevalence of CNS-directed autoantibodies in patients with schizophrenia

Schizophrenia is a severe neuropsychiatric disorder whose etiology and biological heterogeneity remain poorly understood. Immune dysregulation has long been implicated, but the breadth and clinical significance of autoantibody responses remain unclear beyond rare individual examples. Here we use Rapid Extracellular Antigen Profiling-a proteome-scale assay for autoantibodies against extracellular and secreted proteins-to profile 352 individuals with schizophrenia and 971 community controls. We find that schizophrenia is marked by a striking elevation in extracellular autoantibody burden, present near disease onset, and approaching nearly twice control levels in the most severely ill patients. This burden increases with age in a pattern that diverges from controls and targets central nervous system antigens, including neuroactive receptors, neuronal ion channels, proteins involved in synaptic function, and blood-brain barrier integrity. Autoantibodies against blood-brain barrier antigens impair barrier function ex vivo and are associated with broader central nervous system autoreactivity, supporting a model in which barrier disruption promotes loss of tolerance to brain antigens. At the clinical level, higher baseline autoantibody burden predicts reduced responsiveness to the antipsychotic risperidone, suggesting that autoantibodies contribute to treatment resistance. Together, these findings identify humoral autoimmunity as a pervasive component of schizophrenia and imply that therapies that reset humoral immunity or reduce autoantibody burden may benefit patients beyond those with currently recognized antibody-mediated syndromes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/722731v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@e51fb5org.highwire.dtl.DTLVardef@84c86forg.highwire.dtl.DTLVardef@1832712org.highwire.dtl.DTLVardef@17a0f84_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Helicobacter pylori allelic variation in cell surface genes influences human exoproteome binding and stomach tissue adherence

Helicobacter pylori, the primary etiological agent of gastric cancer, requires chronic infection to promote severe disease. Throughout colonization, the bacteria accumulate genetic variation, which can reshape the interaction between host and pathogen. In this study, we probed adherence as one important characteristic of this relationship. We leveraged a panel of H. pylori strains, representing both inter- and intra-host diversity, and BASEHIT, a comprehensive barcoded yeast display library of the human exoproteome, to evaluate the human exoprotein binding characteristics of H. pylori. We identified a set of lineage-correlated binding phenotypes and a set of polymorphic cell surface-associated loci that we predict to govern heterogeneous binding. We also identified a general increase in gastric tissue adherence during mouse passage and structural modifications in the O-antigen component lipopolysaccharide. Subsequent sequence analyses identified C-terminal repeat length reduction in either futB or glycosyltransferase family 25 galactose transferases as sufficient to alter lipopolysaccharide. Shorter repeat variants were favored during both acute and chronic colonization and conferred a colonization advantage in coinfection. Our data indicate that shorter enzymes, and the resulting shorter O-antigen repeats, are favored during infection. We hypothesize that repeat length polymorphisms modulate enzyme efficiency and disrupt the balance of competing reactions required for O-antigen synthesis. ImportanceIn this study, we used a high throughput assay to evaluate the adherence of genetically diverse Helicobacter pylori isolates to human proteins they may encounter in the stomach. We showed that more closely related H. pylori strains bind human proteins similarly. We linked changes in bacterial binding to genetic differences affecting cell surface components. In particular, H. pylori strains passaged through mice exhibited increased adherence to stomach tissue, which we associated with structural variation in the enzymes responsible for synthesizing the O-antigen portion of lipopolysaccharide. We also showed that shorter enzyme variants produce distinct O-antigen structures that enhance colonization of the mouse stomach.

microbiology↗

bioRxiv2021

REAP: A platform to identify autoantibodies that target the human exoproteome

Autoantibodies that recognize extracellular proteins (the "exoproteome") exert potent biological effects but have proven challenging to detect with existing screening technologies. Here, we developed Rapid Extracellular Antigen Profiling (REAP) as a technique for comprehensive, high-throughput discovery of exoproteome-targeting autoantibodies. With REAP, patient samples are applied to a genetically-barcoded library containing 2,688 human extracellular proteins displayed on the surface of yeast. Antibody-coated cells are isolated by magnetic selection and deep sequencing of their barcodes is used to identify the displayed antigens. To benchmark the performance of REAP, we screened 77 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). REAP sensitively and specifically detected known autoantibody reactivities in APECED in addition to numerous previously unidentified reactivities. We further screened 106 patients with systemic lupus erythematosus (SLE) and identified novel autoantibody reactivities against a diverse set of antigens including growth factors, extracellular matrix components, cytokines, and immunomodulatory proteins. Several of these responses were associated with disease severity and specific clinical manifestations of SLE and exerted potent functional effects on cell signaling ex vivo. These findings demonstrate the utility of REAP to atlas the expansive landscape of exoproteome-targeting autoantibodies and their impacts on patient health outcomes.

immunology↗

bioRxiv2020

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.

immunology↗

bioRxiv2017

Platform for rapid nanobody discovery in vitro

Camelid single-domain antibody fragments (\"nanobodies\") provide the remarkable specificity of antibodies within a single immunoglobulin VHH domain. This unique feature enables applications ranging from their use as biochemical tools to therapeutic agents. Virtually all nanobodies reported to date have been obtained by animal immunization, a bottleneck restricting many applications of this technology. To solve this problem, we developed a fully in vitro platform for nanobody discovery based on yeast surface display of a synthetic nanobody scaffold. This platform provides a facile and cost-effective method for rapidly isolating nanobodies targeting a diverse range of antigens. We provide a blueprint for identifying nanobodies starting from both purified and non-purified antigens, and in addition, we demonstrate application of the platform to discover rare conformationally-selective nanobodies to a lipid flippase and a G protein-coupled receptor. To facilitate broad deployment of this platform, we have made the library and all associated protocols publicly available.

biochemistry↗