Tobias Lanz

All Publications

• Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM. Nature Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J. S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G. S., Bartley, C. M., Schubert, R. D., Hawes, I. A., Vazquez, S. E., Iyer, M., Zuchero, J. B., Teegen, B., Dunn, J. E., Lock, C. B., Kipp, L. B., Cotham, V. C., Ueberheide, B. M., Aftab, B. T., Anderson, M. S., DeRisi, J. L., Wilson, M. R., Bashford-Rogers, R. J., Platten, M., Garcia, K. C., Steinman, L., Robinson, W. H. 2022

  Abstract

  Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.

  View details for DOI 10.1038/s41586-022-04432-7

  View details for PubMedID 35073561

• BNT162b2 vaccine induces divergent B cell responses to SARS-CoV-2 S1 and S2 NATURE IMMUNOLOGY Brewer, R., Ramadoss, N. S., Lahey, L. J., Jahanbani, S., Robinson, W. H., Lanz, T. 2021

  Abstract

  The first ever US Food and Drug Administration-approved messenger RNA vaccines are highly protective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-3. However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating B cell repertoire analysis with single-cell transcriptomics pre- and post-vaccination. The first vaccine dose elicits a recall response of IgA+ plasmablasts targeting the S subunit S2. Three weeks after the first dose, we observed an influx of minimally mutated IgG+ memory B cells that targeted the receptor binding domain on the S subunit S1 and likely developed from the naive B cell pool. This response was strongly boosted by the second dose and delivers potently neutralizing antibodies against SARS-CoV-2 and several of its variants.

  View details for DOI 10.1038/s41590-021-01088-9

  View details for Web of Science ID 000723985200001

  View details for PubMedID 34848871

• Autoantibodies against central nervous system antigens in a subset of B cell-dominant multiple sclerosis patients. Proceedings of the National Academy of Sciences of the United States of America Kuerten, S. n., Lanz, T. V., Lingampalli, N. n., Lahey, L. J., Kleinschnitz, C. n., Mäurer, M. n., Schroeter, M. n., Braune, S. n., Ziemssen, T. n., Ho, P. P., Robinson, W. H., Steinman, L. n. 2020

  Abstract

  Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), with characteristic inflammatory lesions and demyelination. The clinical benefit of cell-depleting therapies targeting CD20 has emphasized the role of B cells and autoantibodies in MS pathogenesis. We previously introduced an enzyme-linked immunospot spot (ELISpot)-based assay to measure CNS antigen-specific B cells in the blood of MS patients and demonstrated its usefulness as a predictive biomarker for disease activity in measuring the successful outcome of disease-modifying therapies (DMTs). Here we used a planar protein array to investigate CNS-reactive antibodies in the serum of MS patients as well as in B cell culture supernatants after polyclonal stimulation. Anti-CNS antibody reactivity was evident in the sera of the MS cohort, and the antibodies bound a heterogeneous set of molecules, including myelin, axonal cytoskeleton, and ion channel antigens, in individual patients. Immunoglobulin reactivity in supernatants of stimulated B cells was directed against a broad range of CNS antigens. A group of MS patients with a highly active B cell component was identified by the ELISpot assay. Those antibody reactivities remained stable over time. These assays with protein arrays identify MS patients with a highly active B cell population with antibodies directed against a swathe of CNS proteins.

  View details for DOI 10.1073/pnas.2011249117

  View details for PubMedID 32817492

• Single-Cell High-Throughput Technologies in Cerebrospinal Fluid Research and Diagnostics. Frontiers in immunology Lanz, T. V., Pröbstel, A. K., Mildenberger, I., Platten, M., Schirmer, L. 2019; 10: 1302

  Abstract

  High-throughput single-cell technologies have recently emerged as essential tools in biomedical research with great potential for clinical pathology when studying liquid and solid biopsies. We provide an update on current single-cell methods in cerebrospinal fluid research and diagnostics, focusing on high-throughput cell-type specific proteomic and genomic technologies. Proteomic methods comprising flow cytometry and mass cytometry as well as genomic approaches including immune cell repertoire and single-cell transcriptomic studies are critically reviewed and future directions discussed.

  View details for DOI 10.3389/fimmu.2019.01302

  View details for PubMedID 31244848

  View details for PubMedCentralID PMC6579921

• Immunomodulatory receptors are differentially expressed in B and T cell subsets relevant to autoimmune disease. Clinical immunology (Orlando, Fla.) Murphy, K. A., Bhamidiphati, K. n., Rubin, S. J., Kipp, L. n., Robinson, W. H., Lanz, T. V. 2019: 108276

  Abstract

  Inhibitory cell-surface receptors on lymphocytes, often called immune checkpoints, are powerful targets for cancer therapy. Despite their direct involvement in autoimmune pathology, they are currently not exploited therapeutically for autoimmune diseases. Understanding the receptors' expression patterns in health and disease is essential for targeted drug design. Here, we designed three 23-colour flow cytometry panels for peripheral-blood T cells, including 15 lineage-defining markers and 21 immunomodulatory cell-surface receptors, and a 22-marker panel for B cells. Blood samples from healthy individuals, multiple sclerosis (MS), and lupus (SLE) patients were included in the study. Several receptors show differential expression on regulatory T cells (Treg) compared to T helper (Th) 1 and Th17 cells, and functional relevance of this difference could be shown for BTLA and CD5. Unbiased multiparametric analysis revealed a subset of activated CD8+ T cells and a subset of unswitched memory B cells that are diminished in MS and SLE, respectively.

  View details for DOI 10.1016/j.clim.2019.108276

  View details for PubMedID 31669582

• Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis. Scientific reports Lanz, T. V., Williams, S. K., Stojic, A., Iwantscheff, S., Sonner, J. K., Grabitz, C., Becker, S., Böhler, L. I., Mohapatra, S. R., Sahm, F., Küblbeck, G., Nakamura, T., Funakoshi, H., Opitz, C. A., Wick, W., Diem, R., Platten, M. 2017; 7: 41271

  Abstract

  The catabolism of tryptophan to immunosuppressive and neuroactive kynurenines is a key metabolic pathway regulating immune responses and neurotoxicity. The rate-limiting step is controlled by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO). IDO is expressed in antigen presenting cells during immune reactions, hepatic TDO regulates blood homeostasis of tryptophan and neuronal TDO influences neurogenesis. While the role of IDO has been described in multiple immunological settings, little is known about TDO's effects on the immune system. TDO-deficiency is neuroprotective in C. elegans and Drosophila by increasing tryptophan and specific kynurenines. Here we have determined the role of TDO in autoimmunity and neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We created reporter-TDO mice for in vivo imaging to show that hepatic but not CNS TDO expression is activated during EAE. TDO deficiency did not influence myelin-specific T cells, leukocyte infiltration into the CNS, demyelination and disease activity. TDO-deficiency protected from neuronal loss in the spinal cord but not in the optic nerves. While this protection did not translate to an improved overt clinical outcome, our data suggest that spatially distinct neuroprotection is conserved in mammals and support TDO as a potential target for treatment of diseases associated with neurodegeneration.

  View details for DOI 10.1038/srep41271

  View details for PubMedID 28117398

• Protein kinase C beta as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lanz, T. V., Becker, S., Osswald, M., Bittner, S., Schuhmann, M. K., Opitz, C. A., Gaikwad, S., Wiestler, B., Litzenburger, U. M., Sahm, F., Ott, M., Iwantscheff, S., Grabitz, C., Mittelbronn, M., von Deimling, A., Winkler, F., Meuth, S. G., Wick, W., Platten, M. 2013; 110 (36): 14735-14740

  Abstract

  Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.

  View details for DOI 10.1073/pnas.1302569110

  View details for Web of Science ID 000323886200057

  View details for PubMedID 23959874

  View details for PubMedCentralID PMC3767524

• Angiotensin II sustains brain inflammation in mice via TGF-beta JOURNAL OF CLINICAL INVESTIGATION Lanz, T. V., Ding, Z., Ho, P. P., Luo, J., Agrawal, A. N., Srinagesh, H., Axtell, R., Zhang, H., Platten, M., Wyss-Coray, T., Steinman, L. 2010; 120 (8): 2782-2794

  Abstract

  The renin-angiotensin-aldosterone system (RAAS) is a key hormonal system regulating blood pressure. However, expression of RAAS components has recently been detected in immune cells, and the RAAS has been implicated in several mouse models of autoimmune disease. Here, we have identified Ang II as a paracrine mediator, sustaining inflammation in the CNS in the EAE mouse model of MS via TGF-beta. Ang II type 1 receptors (AT1Rs) were found to be primarily expressed in CNS-resident cells during EAE. In vitro, astrocytes and microglia responded to Ang II treatment by inducing TGF-beta expression via a pathway involving the TGF-beta-activating protease thrombospondin-1 (TSP-1). TGF-beta upregulation in astrocytes and microglia during EAE was blocked with candesartan (CA), an inhibitor of AT1R. Treatment of EAE with CA ameliorated paralysis and blunted lymphocyte infiltration into the CNS, outcomes that were also seen with genetic ablation of AT1Ra and treatment with an inhibitor of TSP-1. These data suggest that AT1R antagonists, frequently prescribed as antihypertensives, may be useful to interrupt this proinflammatory, CNS-specific pathway in individuals with MS.

  View details for DOI 10.1172/JCI41709

  View details for Web of Science ID 000280492100015

  View details for PubMedID 20628203

  View details for PubMedCentralID PMC2912186

• Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Science translational medicine Brewer, R. C., Lanz, T. V., Hale, C. R., Sepich-Poore, G. D., Martino, C., Swafford, A. D., Carroll, T. S., Kongpachith, S., Blum, L. K., Elliott, S. E., Blachere, N. E., Parveen, S., Fak, J., Yao, V., Troyanskaya, O., Frank, M. O., Bloom, M. S., Jahanbani, S., Gomez, A. M., Iyer, R., Ramadoss, N. S., Sharpe, O., Chandrasekaran, S., Kelmenson, L. B., Wang, Q., Wong, H., Torres, H. L., Wiesen, M., Graves, D. T., Deane, K. D., Holers, V. M., Knight, R., Darnell, R. B., Robinson, W. H., Orange, D. E. 2023; 15 (684): eabq8476

  Abstract

  Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15+HLADRhi and CD48highS100A2pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.

  View details for DOI 10.1126/scitranslmed.abq8476

  View details for PubMedID 36812347

• Roadmap for understanding mechanisms on how Epstein-Barr virus triggers multiple sclerosis and for translating these discoveries in clinical trials. Clinical & translational immunology Lanz, T. V., Robinson, W. H., Ho, P. P., Steinman, L. 2023; 12 (2): e1438

  Abstract

  Here, we offer a roadmap for what might be studied next in understanding how EBV triggers MS. We focus on two areas: The first area concerns the molecular mechanisms underlying how clonal antibody in the CSF emanates in widespread molecular mimicry to key antigens in the nervous system including GlialCAM, a protein associated with chloride channels. A second and equally high priority in the roadmap concerns various therapeutic approaches that are related to blocking the mechanisms whereby EBV triggers MS. Therapies deserving of attention include clinical trials with antivirals and the development of 'inverse' vaccines based on nucleic acid technologies to control or to eradicate the consequences of EBV infection. High enthusiasm is given to continuation of ongoing clinical trials of cellular adoptive therapy to attack EBV-infected cells. Clinical trials of vaccines to EBV are another area deserving attention. These suggested topics involving research on mechanism, and the design, implementation and performance of well-designed trials are not intended to be an exhaustive list. We have splendid tools available to our community of medical scientists to tackle how EBV triggers MS and then to perhaps change the world with new therapies to potentially eradicate MS, as we have done with nearly complete success for poliomyelitis.

  View details for DOI 10.1002/cti2.1438

  View details for PubMedID 36815946

• RNA-seq characterization of histamine-releasing mast cells as potential therapeutic target of osteoarthritis. Clinical immunology (Orlando, Fla.) Zhao, X., Younis, S., Shi, H., Hu, S., Zia, A., Wong, H. H., Elliott, E. E., Chang, T., Bloom, M. S., Zhang, W., Liu, X., Lanz, T. V., Sharpe, O., Love, Z. Z., Wang, Q., Robinson, W. H. 2022: 109117

  Abstract

  OBJECTIVE: Mast cells in the osteoarthritis (OA) synovium correlate with disease severity. This study aimed to further elucidate the role of mast cells in OA by RNA-Seq analysis and pharmacological blockade of the activity of histamine, a key mast cell mediator, in murine OA.METHODS: We examined OA synovial tissues and fluids by flow cytometry, immunostaining, single-cell and bulk RNA-Seq, qPCR, and ELISA. Cetirizine, a histamine H1 receptor (H1R) antagonist, was used to treat the destabilization of the medial meniscus (DMM) mouse model of OA.RESULTS: Flow cytometry and immunohistology analysis of OA synovial cells revealed KIT+ FcepsilonRI+ and TPSAB1+ mast cells. Single-cell RNA-Seq of OA synovial cells identified the expression of prototypical mast cell markers KIT, TPSAB1, CPA3 and HDC, as well as distinctive markers HPGD, CAVIN2, IL1RL1, PRG2, and CKLF, confirmed by bulk RNA-Seq and qPCR. A mast cell prototypical marker expression score classified 40 OA patients into three synovial pathotypes: mast cell-high, -medium, and -low. Additionally, we detected mast cell mediators including histamine, tryptase AB1, CPA3, PRG2, CAVIN2, and CKLF in OA synovial fluids. Elevated H1R expression was detected in human OA synovium, and treatment of mice with the H1 receptor antagonist cetirizine reduced the severity and OA-related mediators in DMM.CONCLUSION: Based on differential expression of prototypical and distinct mast cell markers, human OA joints can be stratified into mast cell-high, -medium, and -low synovial tissue pathotypes. Pharmacologic blockade of histamine activity holds the potential to improve OA disease outcome.

  View details for DOI 10.1016/j.clim.2022.109117

  View details for PubMedID 36109004

• Rheumatoid Arthritis Patient-derived Anti-citrullinated Protein Antibodies (ACPAs) Ameliorate Joint Inflammation in Early Collagen-antibody Induced Arthritis (CAIA) Gomez, A., Brewer, C., Moon, J., Acharya, S., Lanz, T. V., Wang, Q., Min-Oo, G., Niedziela-Majka, A., Robinson, W. WILEY. 2022: 69-70

  View details for Web of Science ID 000877386500045

• SARS-CoV-2 infection of monocytes: balancing acts of antibodies and inflammasomes. Signal transduction and targeted therapy Brewer, R. C., Robinson, W. H., Lanz, T. V. 2022; 7 (1): 250

  View details for DOI 10.1038/s41392-022-01112-w

  View details for PubMedID 35871170

• Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination. Proceedings of the National Academy of Sciences of the United States of America Chunder, R., Weier, A., Maurer, H., Luber, N., Enders, M., Luber, G., Heider, T., Spitzer, A., Tacke, S., Becker-Gotot, J., Kurts, C., Iyer, R., Ho, P. P., Robinson, W. H., Lanz, T. V., Kuerten, S. 2022; 119 (10): e2117034119

  Abstract

  Significance Multiple sclerosis (MS) is the most prevalent autoimmune disease of the central nervous system (CNS), leading to irreversible deficits in young adults. Its pathophysiology is believed to be influenced by environmental determinants. As far back as the 1990s, it had been suggested that there is a correlation between the consumption of cow's milk and the prevalence of MS. Here, we not only demonstrate that a high percentage of MS patients harbor antibodies to bovine casein but also that antibody cross-reactivity between cow's milk and CNS antigens can exacerbate demyelination. Our data broaden the current understanding of how diet influences the etiology of MS and set the stage for combining personalized diet plans with disease-modifying treatment strategies.

  View details for DOI 10.1073/pnas.2117034119

  View details for PubMedID 35235454

• Neutralizing Anti-Interleukin-1 Receptor-Antagonist Autoantibodies Induce Inflammatory and Fibrotic Mediators in IgG4-Related Disease. The Journal of allergy and clinical immunology Jarrell, J. A., Baker, M. C., Perugino, C. A., Liu, H., Bloom, M. S., Maehara, T., Wong, H. H., Lanz, T., Adamska, J. Z., Kongpachith, S., Sokolove, J., Stone, J. H., Pillai, S. S., Robinson, W. H. 2021

  Abstract

  BACKGROUND: IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition involving loss of B cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined.OBJECTIVE: To identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD.METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative monoclonal antibodies (mAb) were expressed and their specificities characterized using cytokine microarrays. The role of anti-interleukin-1 receptor-antagonist (IL-1RA) autoantibodies was investigated using in vitro assays.RESULTS: We identified strong reactivity against human IL-1RA using a clonally-expanded plasmablast-derived mAb from a patient with IgG4-RD. IgG4-RD patient plasma exhibited elevated levels of reactivity against IL-1RA compared to controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from IgG4-RD patients. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared to controls.CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote pro-inflammatory and pro-fibrotic meditator production via IL-1RA neutralization. These findings support a novel immunological mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

  View details for DOI 10.1016/j.jaci.2021.05.002

  View details for PubMedID 33974929

• Hypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Production. Frontiers in immunology Mohapatra, S. R., Sadik, A. n., Sharma, S. n., Poschet, G. n., Gegner, H. M., Lanz, T. V., Lucarelli, P. n., Klingmüller, U. n., Platten, M. n., Heiland, I. n., Opitz, C. A. 2021; 12: 590532

  Abstract

  The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

  View details for DOI 10.3389/fimmu.2021.590532

  View details for PubMedID 33679737

  View details for PubMedCentralID PMC7933006

• CD52 Is Elevated on B cells of SLE Patients and Regulates B Cell Function. Frontiers in immunology Bhamidipati, K. n., Silberstein, J. L., Chaichian, Y. n., Baker, M. C., Lanz, T. V., Zia, A. n., Rasheed, Y. S., Cochran, J. R., Robinson, W. H. 2020; 11: 626820

  Abstract

  Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgMlo anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.

  View details for DOI 10.3389/fimmu.2020.626820

  View details for PubMedID 33658999

  View details for PubMedCentralID PMC7917337

• Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis. PLoS pathogens Lercher, A. n., Popa, A. M., Viczenczova, C. n., Kosack, L. n., Klavins, K. n., Agerer, B. n., Opitz, C. A., Lanz, T. V., Platten, M. n., Bergthaler, A. n. 2020; 16 (10): e1008973

  Abstract

  The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis.

  View details for DOI 10.1371/journal.ppat.1008973

  View details for PubMedID 33045014

• Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology. Nature communications Sonner, J. K., Keil, M., Falk-Paulsen, M., Mishra, N., Rehman, A., Kramer, M., Deumelandt, K., Rowe, J., Sanghvi, K., Wolf, L., von Landenberg, A., Wolff, H., Bharti, R., Oezen, I., Lanz, T. V., Wanke, F., Tang, Y., Brandao, I., Mohapatra, S. R., Epping, L., Grill, A., Roth, R., Niesler, B., Meuth, S. G., Opitz, C. A., Okun, J. G., Reinhardt, C., Kurschus, F. C., Wick, W., Bode, H. B., Rosenstiel, P., Platten, M. 2019; 10 (1): 4877

  Abstract

  The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan - from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.

  View details for DOI 10.1038/s41467-019-12776-4

  View details for PubMedID 31653831

• Suppression of Th1 differentiation by tryptophan supplementation in vivo. Amino acids Lanz, T. V., Becker, S., Mohapatra, S. R., Opitz, C. A., Wick, W., Platten, M. 2017

  Abstract

  Metabolism of the essential amino acid tryptophan (trp) is a key endogenous immunosuppressive pathway restricting inflammatory responses. Tryptophan metabolites promote regulatory T cell (Treg) differentiation and suppress proinflammatory T helper cell (Th)1 and Th17 phenotypes. It has been shown that treatment with natural and synthetic tryptophan metabolites can suppress autoimmune neuroinflammation in preclinical animal models. Here, we tested if oral intake of tryptophan would increase immunosuppressive tryptophan metabolites and ameliorate autoimmune neuroinflammation as a safe approach to treat autoimmune disorders like multiple sclerosis (MS). Without oral supplementation, systemic kynurenine levels decrease during the initiation phase of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, indicating systemic activation of tryptophan metabolism. Daily oral gavage of up to 10 mg/mouse/day was safe and increased serum kynurenine levels by more than 20-fold for more than 3 h after the gavage. While this treatment resulted in suppression of myelin-specific Th1 responses, there was no relevant impact on clinical disease activity. These data show that oral trp supplementation at subtoxic concentrations suppresses antigen-specific Th1 responses, but suggest that the increase in trp metabolites is not sustained enough to impact neuroinflammation.

  View details for DOI 10.1007/s00726-017-2415-4

  View details for PubMedID 28421297

• General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation. Journal of neuroimmunology Keil, M., Sonner, J. K., Lanz, T. V., Oezen, I., Bunse, T., Bittner, S., Meyer, H. V., Meuth, S. G., Wick, W., Platten, M. 2016; 297: 117-26

  Abstract

  Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood. In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation. Failure to recover from acute inflammation was associated with reduced frequencies of CNS-infiltrating Tregs. GCN2 deficient Tregs displayed impaired migration to a CCL2 gradient. These data suggest an important contribution of the T cell stress response to the resolution of autoimmune neuroinflammation.

  View details for DOI 10.1016/j.jneuroim.2016.05.014

  View details for PubMedID 27397084

• Normal mast cell numbers in the tissues of AhR-deficient mice EXPERIMENTAL DERMATOLOGY Pilz, C., Feyerabend, T., Sonner, J., Redaelli, C., Peter, K., Kunze, A., Haas, K., Esser, C., Schaekel, K., Wick, W., Rodewald, H., Lanz, T. V., Platten, M. 2016; 25 (1): 62-63

  Abstract

  The transcription factor aryl hydrocarbon receptor (AhR) acts as an immunomodulatory molecule in several immune cell lineages. Recently, it has been implicated in development and maintenance of immune cells in barrier tissues such as skin and mucosa. To investigate its role on mast cell development and maintenance in skin, peritoneal exudate cells (PECs) and lymph nodes, we studied in depth their phenotype in AhR-deficient mice. Our findings do not provide any evidence for a suspected role of the AhR in mast cell homeostasis.

  View details for DOI 10.1111/exd.12864

  View details for Web of Science ID 000367837500013

  View details for PubMedID 26443189

• Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice. Biochemical pharmacology Redaelli, C., Gaffarogullari, E. C., Brune, M., Pilz, C., Becker, S., Sonner, J., Jäschke, A., Gröne, H., Wick, W., Platten, M., Lanz, T. V. 2015; 98 (3): 484-492

  Abstract

  The intracellular transcription factor aryl hydrocarbon receptor (AHR) is bound and activated by xenobiotics, thereby promoting their catabolism by inducing expression of cytochrome P450 oxidase (CYP) genes through binding xenobiotic response elements (XRE) in their promoter region. In addition, it is involved in several cellular pathways like cell proliferation, differentiation, regeneration, tumor invasiveness and immune responses. Several pharmaceutical compounds like benzimidazoles activate the AHR and induce their own metabolic degradation. Using newly generated XRE-reporter mice, which allow in vivo bioluminescence imaging of AHR activation, we show here that the AHR is activated in vivo by teriflunomide (TER), which has recently been approved for the treatment of multiple sclerosis. While we did not find any evidence that the AHR mediates the immunomodulatory effects of TER, AHR activation led to metabolism and detoxification of teriflunomide, most likely via CYP. Mice deficient for the AHR show higher blood levels of teriflunomide, suffer from enhanced thrombo- and leukopenia and elevated liver enzymes as well as from severe gastrointestinal ulcers and bleeding which are lethal after 8-11 days of treatment. Leukopenia, acute liver damage and diarrhea have also been described as common side effects in human trials with TER. These data suggest that the AHR is relevant for detoxification not only of environmental toxins but also of drugs in clinical use, with potential implications for the application of AHR-modifying therapies in conjunction to TER in humans. The XRE-reporter mouse is a useful novel tool for monitoring AHR activation using in vivo imaging.

  View details for DOI 10.1016/j.bcp.2015.08.111

  View details for PubMedID 26341389

• Aryl hydrocarbon receptor control of a disease tolerance defence pathway NATURE Bessede, A., Gargaro, M., Pallotta, M. T., Matino, D., Servillo, G., Brunacci, C., Bicciato, S., Mazza, E. M., Macchiarulo, A., Vacca, C., Iannitti, R., Tissi, L., Volpi, C., Belladonna, M. L., Orabona, C., Bianchi, R., Lanz, T. V., Platten, M., Della Fazia, M. A., Piobbico, D., Zelante, T., Funakoshi, H., Nakamura, T., Gilot, D., Denison, M. S., Guillemin, G. J., Duhadaway, J. B., Prendergast, G. C., Metz, R., Geffard, M., Boon, L., Pirro, M., Iorio, A., Veyret, B., Romani, L., Grohmann, U., Fallarino, F., Puccetti, P. 2014; 511 (7508): 184-?

  Abstract

  Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.

  View details for DOI 10.1038/nature13323

  View details for Web of Science ID 000338649800036

  View details for PubMedID 24930766

• Immature mesenchymal stem cell-like pericytes as mediators of immunosuppression in human malignant glioma JOURNAL OF NEUROIMMUNOLOGY Ochs, K., Sahm, F., Opitz, C. A., Lanz, T. V., Oezen, I., Couraud, P., von Deimling, A., Wick, W., Platten, M. 2013; 265 (1-2): 106-116

  Abstract

  Malignant gliomas are primary brain tumors characterized by profound local immunosuppression. While the remarkable plasticity of perivascular cells - resembling mesenchymal stem cells (MSC) - in malignant gliomas and their contribution to angiogenesis is increasingly recognized, their role as potential mediators of immunosuppression is unknown. Here we demonstrate that FACS-sorted malignant glioma-derived pericytes (HMGP) were characterized by the expression of CD90, CD248, and platelet-derived growth factor receptor-β (PDGFR-β). HMGP shared this expression profile with human brain vascular pericytes (HBVP) and human MSC (HMSC) but not human cerebral microvascular endothelial cells (HCMEC). CD90+PDGFR-β+perivascular cells distinct from CD31+ endothelial cells accumulated in human gliomas with increasing degree of malignancy and negatively correlated with the presence of blood vessel-associated leukocytes and CD8+ T cells. Cultured CD90+PDGFR-β+HBVP were equally capable of suppressing allogeneic or mitogen-activated T cell responses as human MSC. HMGP, HBVP and HMSC expressed prostaglandin E synthase (PGES), inducible nitric oxide synthase (iNOS), human leukocyte antigen-G (HLA-G), hepatocyte growth factor (HGF) and transforming growth factor-β (TGF-β). These factors but not indoleamine 2,3-dioxygenase-mediated conversion of tryptophan to kynurenine functionally contributed to immunosuppression of immature pericytes. Our data provide evidence that human cerebral CD90+ perivascular cells possess T cell inhibitory capability comparable to human MSC and suggest that these cells, besides their critical role in tumor vascularization, also promote local immunosuppression in malignant gliomas and possibly other brain diseases.

  View details for DOI 10.1016/j.jneuroim.2013.09.011

  View details for Web of Science ID 000329005100013

  View details for PubMedID 24090655

• Clinically isolated syndrome NERVENARZT Platten, M., Lanz, T., Bendszus, M., Diem, R. 2013; 84 (10): 1247-1257

  Abstract

  A clinically isolated syndrome (CIS) is a term which describes the first clinical onset of a potential multiple sclerosis (MS). It ought to be defined as an MS stage rather than a separate disease entity; however, with respect to the diagnostic work-up, differential diagnoses to be considered, prognostic factors for the development of a clinically confirmed MS and initiation of an immunomodulatory therapy, there are some important considerations supported by recent studies. These considerations as well as the current guidelines are critically discussed in this review article. Additionally, recommendations are given regarding the management of radiologically isolated syndrome (RIS) an imaging-based diagnosis of a potential preclinical stage of MS.

  View details for DOI 10.1007/s00115-013-3845-1

  View details for Web of Science ID 000325127500015

  View details for PubMedID 24081277

• Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1) STEM CELLS AND DEVELOPMENT Lanz, T. V., Opitz, C. A., Ho, P. P., Agrawal, A., Lutz, C., Weller, M., Mellor, A. L., Steinman, L., Wick, W., Platten, M. 2010; 19 (5): 657-668

  Abstract

  Due to their immunosuppressive properties, human mesenchymal stem cells (hMSC) represent a promising tool for cell-based therapies of autoimmune diseases such as multiple sclerosis (MS). Mouse MSC (mMSC) have been used extensively to characterize and optimize route of administration, motility, cellular targets, and immunosuppressive mechanisms in mouse models of autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Tryptophan (trp) catabolism by indolamine-2,3-dioxygenase 1 (IDO1) is a chief endogenous metabolic pathway that tightly regulates unwanted immune responses through depletion of trp and generation of immunosuppressive kynurenines (kyn). IDO1 activity contributes to the immunosuppressive phenotype of hMSC. Here, we demonstrate that although IDO1 is inducible in bone marrow-derived mMSC by proinflammatory stimuli such as interferon-g (IFN-g) and ligands of toll-like receptors (TLR), it does not lead to catabolism of trp in vitro. This failure to catabolize trp is not due to defective TLR signaling as demonstrated by induction of interleukin 6 (IL-6) by TLR activation. While mMSC suppressed the activation of antigen-specific myelin oligodendrocyte glycoprotein (MOG)-reactive T-cell receptor (TCR) transgenic T-helper (TH) cells in co-culture, neither pharmacologic inhibition nor genetic ablation of IDO1 reversed this suppressive effect. Finally, systemic administration of both, IDO1-proficient and phenotypically identical IDO1-deficient mMSC, equally resulted in amelioration of EAE. mMSC, unlike hMSC, do not display IDO1-mediated suppression of antigen-specific T-cell responses.

  View details for DOI 10.1089/scd.2009.0385

  View details for Web of Science ID 000277972300009

  View details for PubMedID 19886804

  View details for PubMedCentralID PMC3377946

• Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1-and TH17-mediated autoimmunity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Platten, M., Youssef, S., Hur, E. M., Ho, P. P., Han, M. H., Lanz, T. V., Phillips, L. K., Goldstein, M. J., Bhat, R., Raine, C. S., Sobel, R. A., Steinman, L. 2009; 106 (35): 14948-14953

  Abstract

  The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.

  View details for DOI 10.1073/pnas.0903958106

  View details for Web of Science ID 000269481000040

  View details for PubMedID 19706421

  View details for PubMedCentralID PMC2736463

• Toll-Like Receptor Engagement Enhances the Immunosuppressive Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells by Inducing Indoleamine-2,3-dioxygenase-1 via Interferon-beta and Protein Kinase R STEM CELLS Opitz, C. A., Litzenburger, U. M., Lutz, C., Lanz, T. V., Tritschler, I., Koeppel, A., Tolosa, E., Hoberg, M., Anderl, J., Aicher, W. K., Weller, M., Wick, W., Platten, M. 2009; 27 (4): 909-919

  Abstract

  Mesenchymal stem cells (MSC) display unique suppressive properties on T-cell immunity, thus representing an attractive vehicle for the treatment of conditions associated with harmful T-cell responses such as organ-specific autoimmunity and graft-versus-host disease. Toll-like receptors (TLR) are primarily expressed on antigen-presenting cells and recognize conserved pathogen-derived components. Ligation of TLR activates multiple innate and adaptive immune response pathways to eliminate and protect against invading pathogens. In this work, we show that TLR expressed on human bone marrow-derived MSC enhanced the immunosuppressive phenotype of MSC. Immunosuppression mediated by TLR was dependent on the production of immunosuppressive kynurenines by the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase-1 (IDO1). Induction of IDO1 by TLR involved an autocrine interferon (IFN)-beta signaling loop, which was dependent on protein kinase R (PKR), but independent of IFN-gamma. These data define a new role for TLR in MSC immunobiology, which is to augment the immunosuppressive properties of MSC in the absence of IFN-gamma rather than inducing proinflammatory immune response pathways. PKR and IFN-beta play a central, previously unidentified role in orchestrating the production of immunosuppressive kynurenines by MSC.

  View details for DOI 10.1002/stem.7

  View details for Web of Science ID 000265529400019

  View details for PubMedID 19353519