Journal: The Journal of Clinical Investigation

Abbreviation

J Clin Invest

Publisher

American Society for Clinical Investigation

Journal Volumes

ISSN

1558-8238
0021-9738

Description

Filters

Reset filters

Search Results

Publications1 - 10 of 37
  • Aggressive B cell lymphomas retain ATR-dependent determinants of T cell exclusion from the germinal center dark zone
    Item type: Journal Article
    Cancila, Valeria; Bertolazzi, Giorgio; Chan, Allison S.Y.; et al. (2025)
    The Journal of Clinical Investigation
    The germinal center (GC) dark zone (DZ) and light zone represent distinct anatomical regions in lymphoid tissue where B cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse large B cell lymphomas (DLBCLs) with DZ-like gene expression profiles exhibit poor outcomes, though the reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T cells, prompting exploration of whether T cell paucity contributes to DZ-like DLBCL. We used spatial transcriptomic approaches to achieve higher resolution of T cell spatial heterogeneity in the GC and to derive potential pathways that underlie T cell exclusion. We showed that T cell exclusion from the DZ was linked to DNA damage response (DDR) and chromatin compaction molecular features characterizing the spatial DZ signature, and that these programs were independent of activation-induced cytidine deaminase (AID) activity. As ATR is a key regulator of DDR, we tested its role in the T cell inhibitory DZ transcriptional imprint. ATR inhibition reversed not only the DZ transcriptional signature, but also DZ T cell exclusion in DZ-like DLBCL in vitro microfluidic models and in in vivo samples of murine lymphoid tissue. These findings highlight that ATR activity underpins a physiological scenario of immune silencing. ATR inhibition may reverse the immune-silent state and enhance T cell–based immunotherapy in aggressive lymphomas with GC DZ–like characteristics.
  • Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner
    Item type: Journal Article
    Spalinger, Marianne R.; Schmidt, Thomas S.B.; Schwarzfischer, Marlene; et al. (2019)
    The Journal of Clinical Investigation
    The gut microbiota is crucial for our health, and well-balanced interactions between the host’s immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host’s response to the intestinal microbiota.
  • Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling
    Item type: Journal Article
    Lang, Karl S.; Georgiev, Panco; Recher, Mike; et al. (2006)
    The Journal of Clinical Investigation
  • Loss of the Fanconi anemia-associated protein NIPA causes bone marrow failure
    Item type: Journal Article
    Kreutmair, Stefanie; Erlacher, Miriam; Andrieux, Geoffroy; et al. (2020)
    The Journal of Clinical Investigation
    Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function, and cancer susceptibility. Diagnosis of IBMFS presents a major challenge due to the large variety of associated phenotypes, and novel, clinically relevant biomarkers are urgently needed. Our study identified nuclear interaction partner of ALK (NIPA) as an IBMFS gene, as it is significantly downregulated in a distinct subset of myelodysplastic syndrome–type (MDS-type) refractory cytopenia in children. Mechanistically, we showed that NIPA is major player in the Fanconi anemia (FA) pathway, which binds FANCD2 and regulates its nuclear abundance, making it essential for a functional DNA repair/FA/BRCA pathway. In a knockout mouse model, Nipa deficiency led to major cell-intrinsic defects, including a premature aging phenotype, with accumulation of DNA damage in hematopoietic stem cells (HSCs). Induction of replication stress triggered a reduction in and functional decline of murine HSCs, resulting in complete bone marrow failure and death of the knockout mice with 100% penetrance. Taken together, the results of our study add NIPA to the short list of FA-associated proteins, thereby highlighting its potential as a diagnostic marker and/or possible target in diseases characterized by hematopoietic failure.
  • Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface
    Item type: Journal Article
    Di Zenzo, Giovanni; Di Lullo, G.; Corti, Davide; et al. (2012)
    The Journal of Clinical Investigation
  • VSIG4, a B7 family-related protein, is a negative regulator of T cell activation
    Item type: Journal Article
    Vogt, Lorenz; Schmitz, Nicole; Kurrer, Michael O.; et al. (2006)
    The Journal of Clinical Investigation
  • Exceptionally potent human monoclonal antibodies are effective for prophylaxis and treatment of tetanus in mice
    Item type: Journal Article
    Pirazzini, Marco; Grinzato, Alessandro; Corti, Davide; et al. (2021)
    The Journal of Clinical Investigation
    We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin–specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.
  • Role of Foxa-2 in adipocyte metabolism and differentiation
    Item type: Journal Article
    Wolfrum, Christian; Shih, David Q.; Kuwajima, Satoru; et al. (2003)
    The Journal of Clinical Investigation
  • Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
    Item type: Journal Article
    Ahmed, Kashan; LaPierre, Mary P.; Gasser, Emanuel; et al. (2017)
    The Journal of Clinical Investigation
    MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood. Genetic deletion of mir-7a2 causes infertility, with low levels of gonadotropic and sex steroid hormones, small testes or ovaries, impaired spermatogenesis, and lack of ovulation in male and female mice, respectively. We found that miR-7a2 is highly expressed in the pituitary, where it suppresses golgi glycoprotein 1 (GLG1) expression and downstream bone morphogenetic protein 4 (BMP4) signaling and also reduces expression of the prostaglandin F2a receptor negative regulator (PTGFRN), an inhibitor of prostaglandin signaling and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Our results reveal that miR-7a2 critically regulates sexual maturation and reproductive function by interconnecting miR-7 genomic circuits that regulate FSH and LH synthesis and secretion through their effects on pituitary prostaglandin and BMP4 signaling.
  • HIV-1–specific CD4+ T lymphocyte turnover and activation increase upon viral rebound
    Item type: Journal Article
    Scriba, Thomas J.; Zhang, Hua-Tang; Brown, Helen L.; et al. (2005)
    The Journal of Clinical Investigation
    HIV-specific CD4+ T helper lymphocytes are preferred targets for infection. Although complete interruption of combination antiretroviral therapy (ART) can form part of therapeutic manipulations, there is grave concern that the resumption of viral replication might destroy, perhaps irreversibly, these T helper populations. High viremia blocks the proliferation capacity of HIV-specific helper cells. However, cytokine production assays imply that some antigen-specific effector function is retained. Despite this careful work, it remains unclear whether the return of HIV-1 replication physically destroys HIV-1–specific T helper cells in the peripheral blood. Difficulties in producing stable peptide-MHC class II complexes and the very low frequencies of antigen-specific CD4+ T cells have delayed the application of this powerful technique. Here we employ HLA class II tetramers and validate a sensitive, quantitative cell-enrichment technique to detect HIV-1 T helper cells. We studied patients with early-stage HIV infection who were given a short, fixed course of ART as part of a clinical study. We did not find significant deletion of these cells from the peripheral circulation when ART was stopped and unfettered HIV replication returned. The turnover of these virus-specific cells increased and they adopted an effector phenotype when viremia returned.
Publications1 - 10 of 37