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 common missense mutation P1104A in a protein TYK2 was 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-γ immunity 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 LY9 deficiencies.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. PD-1 is an inhibitory “checkpoint” in T lymphocytes ligated with two known ligands, PD-L1andPD-L2, to maintain self-tolerance.The PD-1-deficient proband had not only TB but also multi-organ autoimmunity and died of autoimmune pneumonitis at age 11 years.His older brother also had type 1 diabetes and died of pneumonitis of undocumented etiology at age 3 years.Moreover,I had an opportunity to study another two siblings with inheritedPD-L1 deficiency, both of whom had early-onset type 1diabetes. Unlike the two PD-1-deficient siblings,neither of the PD-L1-deficient siblings developed any autoimmune phenotypes other than endocrinological autoimmunity. Consistent with their much more severe clinical manifestations, PD-1 deficiency triggered much more severe leukocyte dysregulation than PD-L1 deficiency.The discordant severity in clinical and leukocytic phenotypes in humans with PD-1 and PD-L1 deficiencies suggest that 1) PD-1:PD-L2 interaction can compensate, at least in part,for the absence of PD-1:PD-L1 signal to mitigate unrestrained leukocytic dysregulation in vivo; and that 2) PD-1:PD-L1 signal is nonetheless indispensable in preventing type 1 diabetes in humans. Finally, during these studies, I discovered that PD-1 and PD-L1contribute to optimal memory B cell development and antibody responses.Surprisingly, PD-1:PD-L1 interactions promote immunoglobulin production in a B-cell-autonomous manner,and a newly established B-cell-specific PD-1 KO mouse line showed a severe contraction of almost all B cell compartments. In fact, the B-cell phenotype was much more severe in B-cell-specific PD-1 KO mice than in whole-body KO mice, suggesting that1) PD-1 on B cells has a critically indispensable role in the homeostasis of B cells and 2) PD-1 on leukocytes other than B cells (probably T cells) has a unique role in mitigating the disturbance the B-cell compartment.Thus, the second part of my graduate research provides unique insights into the non-redundant roles of PD-1 and PD-L1 in maintaining self-tolerance and functional oral immunity in mice and 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