Human Inborn Errors of Immunity: Tuberculosis, Autoimmunity, and Beyond

Author

Masato Ogishi

Date of Award

2024

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Casanova Laboratory

Abstract

Tuberculosis (TB), a multi-organ infectious disease caused by virulent mycobacteria, most predominantly M. tuberculosis,remains one of the deadliest infectious diseases in human history.Bacillus Calmette-Guérin (BCG) vaccine,first implemented medically in1921,has remained the only available vaccine for TB, although its protective effect is moderate.TB occurs in 5-10% of individuals exposed to those pathogens, while 90-95% remain asymptomatic (i.e.,latent infection or spontaneous clearance). This surprisingly large inter-individual variability has long attracted the attention of human geneticists.Classical twin-based genetic studies have demonstrated the presence of a substantial genetic risk of developing TB disease between monozygotic twins.Later,the clinical and genetic characterization of a rare and severe disease caused by weakly virulent and normally harmless mycobacteria, such as the BCG vaccine substrain, now recognized as Mendelian Susceptibility to Mycobacterial Disease (MSMD),demonstrated that IFN-γ is indispensable for antimycobacterial immunity in humans.Moreover, homozygosity for a commonmissense mutationP1104Ain a protein TYK2was discovered as the first genetic predisposing factor to TB in humans. TYK2 P1104A selectively impairs IL-23-dependent IFN-γ production by lymphocytes.In light of these findings,I hypothesized that a partial impairment of IFN-γimmunity due to known or novel genetic defects underlies vulnerability to TB in humans.I characterized three rare genetic etiologies of TB in children and young adults: inherited ITK, PD-1, and LY9deficiencies.These rare genetic defects partially impair IFN-γ production by diverse T cell subsets through distinct mechanisms such as development, exhaustion, and epigenetic imprinting.Thus,the first part of my graduate research demonstrates that even partial impairment of T-cell IFN-γ production can underlie TB in young humans.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Ogishi, Masato, "Human Inborn Errors of Immunity: Tuberculosis, Autoimmunity, and Beyond" (2024). Student Theses and Dissertations. 770.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/770