Joshua Tobin

Program: Immunology

Current advisor: Megan A. Cooper, MD, PhD

Undergraduate university: Georgetown University, 2018

Enrollment year: 2019

Research summary
Enhancer hijacking causing monogenic B cell deficiency and susceptibility to invasive infection

Despite significant advances in sequencing technology, a genetic diagnosis remains elusive in approximately 70% of suspected genetic errors of immunity (GEI). For my thesis work, we are investigating two families with an autosomal dominant pattern of invasive Streptococcus pneumoniae infection associated with specific antibody deficiency (SAD). All 5 individuals reported histories of bacterial infections, significantly reduced memory B cells, and tested patients had normal serum immunoglobulin levels but poor responses to S. pneumoniae vaccination or infection. Whole genome sequencing identified similar tandem duplications encompassing part of the IGH locus and upstream genes, with complete penetrance in affected individuals. Bulk and scRNA-seq revealed B-cell-specific overexpression of one duplicated gene, JAG2, encoding the Notch ligand jagged-2. Hi-C demonstrated the IGH locus interacting with JAG2 due to the duplication, supporting enhancer hijacking leading to overexpression of JAG2. Enhancer hijacking is well-described in cancer but has never been described in GEI. Together, these findings demonstrate a novel genetic mechanism of GEI, a new role for JAG2 in B cell differentiation, and a genetic cause of SAD. Ongoing work is focused on the effects of JAG2 overexpression on B cell function.

Graduate publications
Tobin JM, Cooper MA. 2025 Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management. J Hum Immun, 1(3)::e20250034. PMCID: PMC12365696

Sohn H, Kolicheski A, Poursine-Laurent J, Tran J, Wang Y, Gan K, Tobin JM, Saucier N, Fehniger TA, Payton JE, Cooper MA. 2025 ACLY promotes NK cell effector function by regulating glycolysis and histone acetylation. J Immunol, 214(11):3100-114. PMCID: PMC12380160

Arnold DE, Kaviany S, Aluri J, Calvo KR, Mehta SS, Tobin JM, Schuettpelz L, Saucier N, Schmitz EG, Murguía-Favela L, Wright NAM, De Ravin SS, Rao VK, Holland SM, Bleesing J, Loughran TP, Feith DJ, Powell J, Ratan A, Warren JT, Pai SY, Bednarski JJ, Connelly JA, Cooper MA. 2025 Clinical Characteristics, Management, and Hematopoietic Cell Transplantation of Patients with TLR8 Gain-of-Function. Blood Adv, ():Online ahead of print. PMCID:

Tobin JM, Cooper MA. 2024 PTPN2 deficiency: Amping up JAK/STAT. J Exp Med, 221(9)::e20240980

Mah-Som AY, Keppel MP, Tobin JM, Kolicheski A, Saucier N, Sexl V, French AR, Wagner JA, Fehniger TA, Cooper MA. 2021 Reliance on Cox10 and oxidative metabolism for antigen-specific NK cell expansion. Cell Rep, 35(9):109209. PMCID: PMC8229496