Maria Rosaria Vitale

All Publications

• Zanubrutinib monotherapy for IgG4-related head and neck disease. Annals of the rheumatic diseases Baker, M. C., Gawde, S., Horomanski, A., Fairchild, R. M., Liu, Y., Mikelov, A., Sun, Y., Vitale, M. R., Maestri, E., Held, F., Deluna, M., Park, W. G., Siddiqi, H., Taylor, L., Bopardikar, S., Khalighi, M., Franc, B. L., Penta, M., Boyd, S. D., Khatri, P., Zhu, H., Pham, N., Guja, K. E., Lanz, T. V. 2026

  Abstract

  Immunoglobulin (Ig) G4-related disease (IgG4-RD) is commonly treated with glucocorticoids and B-cell depletion, but cumulative toxicity and relapse underscore the need for alternative approaches. We evaluated the efficacy, safety, and immunological effects of Bruton's tyrosine kinase (BTK) inhibition with zanubrutinib in active IgG4-RD.In this phase 2, open-label, proof-of-concept trial, 10 participants with lacrimal and submandibular gland IgG4-RD received zanubrutinib 80 mg twice daily for up to 24 weeks without glucocorticoid induction or background immunosuppression. The primary endpoint was change in lacrimal and submandibular gland volume at week 24 by blinded fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (evaluable n = 8). Secondary endpoints included metabolic imaging parameters, clinical disease activity, serologic biomarkers, and safety. Single-cell RNA sequencing with immune repertoire profiling was performed to define cellular mechanisms.At week 24, mean gland volume decreased by 46.7% (lacrimal) and 29.9% (submandibular) (both P = .008), with concordant reductions in total lesion glycolysis (-91.6 g; P = .05) and total metabolic lesion volume (-20.7 cm³; P = .05). Clinical disease activity improved (IgG4-RD Responder Index -6.0 points; P = .01), alongside reductions in serum IgG4 (-417 mg/dL; P = .008) and circulating plasmablasts. Imaging and serologic changes were strongly correlated. Single-cell analyses demonstrated treatment-associated modulation of B-cell transcriptional programmes, reductions in IgG4-skewed plasmablasts, and attenuation of cytotoxic CD4⁺ T cells. Adverse events were predominantly mild; 1 serious event (COVID-19) occurred off treatment.Zanubrutinib monotherapy produced substantial imaging-defined and clinical improvements in active glandular IgG4-RD without glucocorticoid induction. BTK inhibition was associated with modulation of B-cell differentiation states and downstream immune programmes, supporting its development as a steroid-sparing, non-B-cell-depleting therapeutic strategy.

  View details for DOI 10.1016/j.ard.2026.06.020

  View details for PubMedID 42448495

• Generation of three induced pluripotent stem cell lines from an immune checkpoint inhibitor-induced myocarditis patient and controls. Stem cell research Sun, Y., Vitale, M. R., Hnatiuk, A. P., Wagner, N. S., Sun, S., Yang, X., Liu, L., Khatua, S., Sundar, H. A., Chou, H., Huang, Y. V., Waliany, S., Zhuge, Y., Witteles, R., Mercola, M., Wu, J. C., Zhu, H. 2026; 95: 104057

  Abstract

  Immune checkpoint inhibitor-associated myocarditis (ICIM) is an uncommon but potentially fatal inflammatory heart disease triggered by cancer immunotherapy, with up to 40% mortality. The underlying mechanisms are still elusive, partly due to the lack of appropriate human disease models. Here, we report the generation of three induced pluripotent stem cell (iPSC) lines derived from an ICIM patient, an ICI-treated patient without myocarditis, and a healthy donor. These lines exhibit typical pluripotent stem cell morphology, express pluripotency markers, maintain normal karyotypes, and differentiate into derivatives of the three germ layers, providing a valuable platform for mechanistic studies and therapeutic discovery.

  View details for DOI 10.1016/j.scr.2026.104057

  View details for PubMedID 42418861

• <ol><li> <underline>Uncovering the Role of T-Cell and Fibroblast Crosstalk in Immunotherapy-Induced Myocarditis</underline></li></ol> Wagner, N., Vitale, M., Sun, Y., Zambrano, M., Bayer, A., Alcaide, P., Moslehi, J., Zhu, H. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1161/circ.152.suppl_3.4369397

  View details for Web of Science ID 001613863200044

• Novel Therapeutic Approach Targeting CXCR3 to Treat Immunotherapy Myocarditis. Circulation research Huang, Y. V., Sun, Y., Chou, H., Wagner, N., Vitale, M. R., Bayer, A. L., Xu, B., Lee, D., Lin, Z., Branche, C., Waliany, S., Neal, J. W., Wakelee, H. A., Witteles, R. M., Nguyen, P. K., Graves, E. E., Berry, G. J., Alcaide, P., Wu, S. M., Zhu, H. 2025

  Abstract

  Immune checkpoint inhibitors (ICIs) are successful in treating many cancers but may cause immune-related adverse events. ICI-mediated myocarditis has a high fatality rate with severe cardiovascular consequences. Targeted therapies for ICI myocarditis are currently limited.We used a genetic mouse model of PD1 deletion (MRL/Pdcd1-/-) along with a novel drug-treated ICI myocarditis mouse model to recapitulate the disease phenotype. We performed single-cell RNA-sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes on immune cells isolated from MRL and MRL/Pdcd1-/- mice at serial time points. We assessed the impact of macrophage deletion in MRL/Pdcd1-/- mice, then inhibited CXCR3 (C-X-C motif chemokine receptor 3) in ICI-treated mice to assess the therapeutic effect on myocarditis phenotype. Furthermore, we delineated the functional and mechanistic effects of CXCR3 blockade on T-cell and macrophage interactions. We then correlated the results in human single-cell multiomics data from blood and heart biopsy data from patients with ICI myocarditis.Single-cell multiomics demonstrated expansion of CXCL (C-X-C motif chemokine ligand) 9/10+CCR2+ macrophages and CXCR3hi (C-X-C motif chemokine receptor 3 high-expressing) CD8+ (cluster of differentiation) effector T lymphocytes in the hearts of MRL/Pdcd1-/- mice correlating with onset of myocarditis development. Both depletion of CXCL9/10+CCR2+ (C-C motif chemokine receptor) macrophages and CXCR3 blockade, respectively, led to decreased CXCR3hi CD8+ T-cell infiltration into the heart and significantly improved survival. Transwell migration assays demonstrated that the selective blockade of CXCR3 and its ligand, CXCL10, reduced CXCR3+CD8+ T-cell migration toward macrophages, implicating this interaction in T-cell cardiotropism toward cardiac macrophages. Furthermore, cardiomyocyte apoptosis was induced by CXCR3hi CD8+ T cells. Cardiac biopsies from patients with confirmed ICI myocarditis demonstrated infiltrating CXCR3+ T cells and CXCL9+/CXCL10+ macrophages. Both mouse cardiac immune cells and patient peripheral blood immune cells revealed expanded TCR s (T-cell receptors) correlating with CXCR3hi CD8+ T cells in ICI myocarditis samples.These findings bring forth the CXCR3-CXCL9/10 axis as an attractive therapeutic target for ICI myocarditis treatment, and more broadly as a druggable pathway in cardiac inflammation.

  View details for DOI 10.1161/CIRCRESAHA.124.325652

  View details for PubMedID 39931812

• Generation of a ST3GAL3 null mutant induced pluripotent stem cell (iPSC) line (UKWMPi002-A-3) by CRISPR/Cas9 genome editing. Stem cell research Diouf, D., Vitale, M. R., Zöller, J. E., Pineau, A. M., Klopocki, E., Hamann, C., Ziegler, G. C., Vanmierlo, T., Van den Hove, D., Lesch, K. P. 2023; 67: 103038

  Abstract

  Fibroblasts isolated from a skin biopsy of a healthy individual were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate an isogenic cell line carrying an inactivation of ST3GAL3, a risk gene associated with neurodevelopmental and psychiatric disorders. This ST3GAL3 null mutant (ST3GAL3-/-) iPSC line, which displays the expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal karyotype, is a powerful tool to investigate the impact of deficient sialylation of glycoproteins in neural development and plasticity.

  View details for DOI 10.1016/j.scr.2023.103038

  View details for PubMedID 36746102

• Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers. Stem cell research Ziegler, G. C., Radtke, F., Vitale, M. R., Preuße, A., Klopocki, E., Herms, S., Lesch, K. P. 2021; 56: 102526

  Abstract

  Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries.

  View details for DOI 10.1016/j.scr.2021.102526

  View details for PubMedID 34492570

• A Common CDH13 Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD. Genes Ziegler, G. C., Ehlis, A. C., Weber, H., Vitale, M. R., Zöller, J. E., Ku, H. P., Schiele, M. A., Kürbitz, L. I., Romanos, M., Pauli, P., Kalisch, R., Zwanzger, P., Domschke, K., Fallgatter, A. J., Reif, A., Lesch, K. P. 2021; 12 (9)

  Abstract

  The cell-cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.

  View details for DOI 10.3390/genes12091356

  View details for PubMedID 34573337

  View details for PubMedCentralID PMC8471784

• Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks MOLECULAR PSYCHIATRY Mossink, B., Van Rhijn, J., Wang, S., Linda, K., Vitale, M. R., Zoller, J. E. M., van Hugte, E. J. H., Bak, J., Verboven, A. H. A., Selten, M., Negwer, M., Latour, B. L., van der Werf, I., Keller, J. M., Gunnewiek, T., Schoenmaker, C., Oudakker, A., Anania, A., Jansen, S., Lesch, K., Frega, M., van Bokhoven, H., Schubert, D., Kasri, N. 2022; 27 (1): 1-18

  Abstract

  Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

  View details for DOI 10.1038/s41380-021-01117-x

  View details for Web of Science ID 000648813500001

  View details for PubMedID 33972691

  View details for PubMedCentralID PMC8960401

• Generation of induced pluripotent stem cell (iPSC) lines carrying a heterozygous (UKWMPi002-A-1) and null mutant knockout (UKWMPi002-A-2) of Cadherin 13 associated with neurodevelopmental disorders using CRISPR/Cas9. Stem cell research Vitale, M. R., Zöller, J. E., Jansch, C., Janz, A., Edenhofer, F., Klopocki, E., van den Hove, D., Vanmierlo, T., Rivero, O., Nadif Kasri, N., Ziegler, G. C., Lesch, K. P. 2021; 51: 102169

  Abstract

  Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13+/-) and a CDH13 null mutant (CDH13-/-) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype.

  View details for DOI 10.1016/j.scr.2021.102169

  View details for PubMedID 33486346

• Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly. Journal of neural transmission (Vienna, Austria : 1996) Jansch, C., Ziegler, G. C., Forero, A., Gredy, S., Wäldchen, S., Vitale, M. R., Svirin, E., Zöller, J. E., Waider, J., Günther, K., Edenhofer, F., Sauer, M., Wischmeyer, E., Lesch, K. P. 2021; 128 (2): 225-241

  Abstract

  Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.

  View details for DOI 10.1007/s00702-021-02303-5

  View details for PubMedID 33560471

  View details for PubMedCentralID PMC7914246