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4 results on '"Kortbawi H"'

1. Molecular mimicry in multisystem inflammatory syndrome in children.

Author

Bodansky A, Mettelman RC, Sabatino JJ Jr, Vazquez SE, Chou J, Novak T, Moffitt KL, Miller HS, Kung AF, Rackaityte E, Zamecnik CR, Rajan JV, Kortbawi H, Mandel-Brehm C, Mitchell A, Wang CY, Saxena A, Zorn K, Yu DJL, Pogorelyy MV, Awad W, Kirk AM, Asaki J, Pluvinage JV, Wilson MR, Zambrano LD, Campbell AP, Thomas PG, Randolph AG, Anderson MS, and DeRisi JL

Subjects
Child, Humans, Coronavirus Nucleocapsid Proteins chemistry, Coronavirus Nucleocapsid Proteins immunology, Phosphoproteins chemistry, Phosphoproteins immunology, Sorting Nexins chemistry, Sorting Nexins immunology, T-Lymphocytes immunology, Antibodies, Viral immunology, Autoantibodies immunology, COVID-19 immunology, COVID-19 virology, COVID-19 complications, Cross Reactions immunology, Epitopes immunology, Epitopes chemistry, Molecular Mimicry immunology, SARS-CoV-2 chemistry, SARS-CoV-2 immunology, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity, Systemic Inflammatory Response Syndrome immunology, Systemic Inflammatory Response Syndrome pathology, Systemic Inflammatory Response Syndrome virology
Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection 1,2 , yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases., (© 2024. The Author(s).)

Published
2024
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2. Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity.

Author

Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Saloner R, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, and DeRisi JL

Subjects
Humans, Female, Autoimmune Diseases immunology, Autoimmune Diseases therapy, Male, Immunotherapy, Adoptive methods, B-Cell Maturation Antigen immunology, B-Cell Maturation Antigen metabolism, Adult, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, Antigens, CD19 immunology, Middle Aged, Proteome, Autoantibodies immunology, Autoimmunity
Abstract

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.

Published
2024
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3. Unveiling the autoreactome: Proteome-wide immunological fingerprints reveal the promise of plasma cell depleting therapy.

Author

Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, and DeRisi JL

Abstract

The prevalence and burden of autoimmune and autoantibody mediated disease is increasing worldwide, yet most disease etiologies remain unclear. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leverage advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of proteome-wide autoantibody profiles in both health and disease. We demonstrate that each individual, regardless of disease state, possesses a distinct set of autoreactivities constituting a unique immunological fingerprint, or "autoreactome", that is remarkably stable over years. In addition to uncovering important new biology, the autoreactome can be used to better evaluate the relative effectiveness of various therapies in altering autoantibody repertoires. We find that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly alter an individual's autoreactome, while anti-CD19 and CD-20 therapies have minimal effects, strongly suggesting a rationale for BCMA or other plasma cell targeted therapies in autoantibody mediated diseases., Competing Interests: Competing Interest Declaration Potential Conflicts J.D.R. reports being a founder and paid consultant for Delve Bio, Inc., and a paid consultant for the Public Health Company and Allen & Co. M.A.S. receives unrelated research funding from the NIH, the CDC, Cepheid and Merck and unrelated Honoria from UpToDate, Inc. M.R.W. reports being a founder and paid consultant for Delve Bio, Inc. and receives unrelated research grant funding from Roche/Genentech and Novartis, and received speaking honoraria from Genentech, Takeda, WebMD, and Novartis. C.J.T. reports being on the Scientific Advisory Boards for Caribou Biosciences, T-CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics, Celgene/BMS Cell Therapy; is a member a DSMB member of Kyverna; is on Ad hoc advisory boards/consulting (last 12 months) for Nektar Therapeutics, Legend Biotech, Prescient Therapeutics, Century Therapeutics, IGM Biosciences, Abbvie; has Stock options in Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics; and reports the right to receive payment from Fred Hutch as an inventor on patents related to CAR T-cell therapy. J.A.H. reports research funding from Merck and Takeda and consulting fees from Takeda, Gilead, SentiBio, and Century Therapeutics. J.G. reports research funding from Sobi, Juno Therapeutics (a BMS company), Celgene (a BMS company), Angiocrine Bioscience; is an Ad hoc consultant for Sobi, Legend Biotech, Janssen, Kite Pharma, MorphoSys. D.J.G. has received research funding, has served as an advisor and has received royalties from Juno Therapeutics, a Bristol-Myers Squibb company; has served as an advisor and received research funding from Seattle Genetics; has served as an advisor for GlaxoSmithKline, Celgene, Janssen Biotech, Ensoma and Legend Biotech; and has received research funding from SpringWorks Therapeutics, Sanofi, and Cellectar Biosciences. K.C.O. received unrelated research funding from, and is an equity shareholder of Cabaletta Bio, and receives unrelated research funding from Seismic, argenx, and Viela Bio/Horizon (now Amgen). R.J.N. reports unrelated research support from the National Institutes of Health, Genentech, Inc., Alexion Pharmaceuticals, Inc., argenx, Annexon Biosciences, Inc., Ra Pharmaceuticals, Inc. (now UCB S.A.), the Myasthenia Gravis Foundation of America, Inc., Momenta Pharmaceuticals, Inc. (now Janssen), Immunovant, Inc., Grifols, S.A., and Viela Bio, Inc. (now Horizon Therapeutics plc). R.J.N. has also served as a consultant/advisor unrelated to research in this manuscript for Alexion Pharmaceuticals, Inc., argenx, Cabaletta Bio, Inc., Cour Pharmaceuticals, CSL Behring, Grifols, S.A., Ra Pharmaceuticals, Inc. (now UCB S.A.), Immunovant, Inc., Momenta Pharmaceuticals, Inc. (now Janssen), and Viela Bio, Inc. (now Horizon Therapeutics plc). J.L.D., C.M.B. and M.R.W. receive licensing fees from CDI Labs.

Published
2023
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4. Further description of two patients with biallelic variants in NADSYN1 in association with cardiac and vertebral anomalies.

Author

Kortbawi H, Ames E, Pritchard A, Devine P, van Ziffle J, and Slavotinek A

Subjects
Abnormalities, Multiple, Anal Canal abnormalities, Child, Esophagus abnormalities, Hernia, Diaphragmatic, Humans, Kidney abnormalities, NAD, Spine abnormalities, Trachea abnormalities, Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor, Heart Defects, Congenital complications, Heart Defects, Congenital diagnosis, Heart Defects, Congenital genetics, Limb Deformities, Congenital genetics
Abstract

Congenital nicotinamide adenine dinucleotide (NAD) deficiency disorders are associated with pathogenic variants in the genes NADSYN1, HAAO, and KYNU. These disorders overlap with the anomalies present in vertebral, anal, cardiac, tracheoesophageal, radial and renal, and limb anomalies (VATER/VACTERL) association and often result in premature death. Children who survive typically have developmental delays or intellectual disability. Here, we describe two patients with compound heterozygous variants in NADSYN1 who presented with cardiac and vertebral defects overlapping with the VATER/VACTERL association, although the patients did not satisfy criteria for the diagnosis of VATER/VACTERL due to their lack of limb anomalies and significant renal anomalies. One patient survived into childhood with developmental delays and may represent an expansion of the survival data for NADSYN1-associated NAD deficiency disorders. Interestingly, one patient had hypoplastic left heart syndrome (HLHS) and one had an aortic coarctation and transverse hypoplasia of the aortic arch, suggesting that NADSYN1 sequencing should be performed in children presenting with congenital anomalies related to VATER/VACTERL association and with HLHS and aortic arch abnormalities., (© 2022 Wiley Periodicals LLC.)

Published
2022
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