Browsing by Author "Jia, Wei"

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    Alphavirus Replicon Particle Vaccine Breaks B Cell Tolerance and Rapidly Induces IgG to Murine Hematolymphoid Tumor Associated Antigens.
    (Frontiers in immunology, 2022-01) Su, Hsuan; Imai, Kazuhiro; Jia, Wei; Li, Zhiguo; DiCioccio, Rachel A; Serody, Jonathan S; Poe, Jonathan C; Chen, Benny J; Doan, Phuong L; Sarantopoulos, Stefanie
    De novo immune responses to myeloid and other blood-borne tumors are notably limited and ineffective, making our ability to promote immune responses with vaccines a major challenge. While focus has been largely on cytotoxic cell-mediated tumor eradication, B-cells and the antibodies they produce also have roles in anti-tumor responses. Indeed, therapeutic antibody-mediated tumor cell killing is routinely employed in patients with hematolymphoid cancers, but whether endogenous antibody responses can be incited to blood-born tumors remains poorly studied. A major limitation of immunoglobulin therapies is that cell surface expression of tumor-associated antigen (TAA) targets is dynamic and varied, making promotion of polyclonal, endogenous B cell responses appealing. Since many TAAs are self-antigens, developing tumor vaccines that enable production of antibodies to non-polymorphic antigen targets remains a challenge. As B cell responses to RNA vaccines are known to occur, we employed the Viral Replicon Particles (VRP) which was constructed to encode mouse FLT3. The VRP-FLT3 vaccine provoked a rapid IgG B-cell response to this self-antigen in leukemia and lymphoma mouse models. In addition, IgGs to other TAAs were also produced. Our data suggest that vaccination with RNA viral particle vectors incites a loss of B-cell tolerance that enables production of anti-tumor antibodies. This proof of principle work provides impetus to employ such strategies that lead to a break in B-cell tolerance and enable production of broadly reactive anti-TAA antibodies as potential future therapeutic agents for patients with hematolymphoid cancers.
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    Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.
    (Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018-10-08) MahmoudianDehkordi, Siamak; Arnold, Matthias; Nho, Kwangsik; Ahmad, Shahzad; Jia, Wei; Xie, Guoxiang; Louie, Gregory; Kueider-Paisley, Alexandra; Moseley, M Arthur; Thompson, J Will; St John Williams, Lisa; Tenenbaum, Jessica D; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Bhattacharyya, Sudeepa; Toledo, Jon B; Schafferer, Simon; Klein, Sebastian; Koal, Therese; Risacher, Shannon L; Kling, Mitchel Allan; Motsinger-Reif, Alison; Rotroff, Daniel M; Jack, John; Hankemeier, Thomas; Bennett, David A; De Jager, Philip L; Trojanowski, John Q; Shaw, Leslie M; Weiner, Michael W; Doraiswamy, P Murali; van Duijn, Cornelia M; Saykin, Andrew J; Kastenmüller, Gabi; Kaddurah-Daouk, Rima; Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
    INTRODUCTION:Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS:Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS:In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION:We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
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    Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.
    (Blood advances, 2024-02) Bracken, Sonali J; Suthers, Amy N; DiCioccio, Rachel A; Su, Hsuan; Anand, Sarah; Poe, Jonathan C; Jia, Wei; Visentin, Jonathan; Basher, Fahmin; Jordan, Collin Z; McManigle, William C; Li, Zhiguo; Hakim, Frances T; Pavletic, Steven Z; Bhuiya, Nazmim S; Ho, Vincent T; Horwitz, Mitchell E; Chao, Nelson J; Sarantopoulos, Stefanie

    Abstract

    Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.
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    Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.
    (JCI insight, 2023-06) Poe, Jonathan C; Fang, Jiyuan; Zhang, Dadong; Lee, Marissa R; DiCioccio, Rachel A; Su, Hsuan; Qin, Xiaodi; Zhang, Jennifer Y; Visentin, Jonathan; Bracken, Sonali J; Ho, Vincent T; Wang, Kathy S; Rose, Jeremy J; Pavletic, Steven Z; Hakim, Frances T; Jia, Wei; Suthers, Amy N; Curry-Chisolm, Itaevia M; Horwitz, Mitchell E; Rizzieri, David A; McManigle, William C; Chao, Nelson J; Cardones, Adela R; Xie, Jichun; Owzar, Kouros; Sarantopoulos, Stefanie
    Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.