# Leveraging a novel human inborn error of immunity to understand B cell development and function

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $523,622

## Abstract

PROJECT SUMMARY
Lower respiratory tract infections are the leading cause of mortality for children under 5 years old1,2. Although
exposure to respiratory pathogens is common, very few children have severe or life-threatening disease3. A
better understanding of this inter-individual variability may allow us to more effectively prevent or treat serious
infections in those most at-risk. Inborn errors of immunity (IEI) are rare monogenic diseases that serve as
‘experiments of nature’ to pinpoint genes and immune pathways critical to defense against specific pathogens.
However, despite the clear value that IEI research offers, IEI are vastly underdiagnosed. We investigated a
consanguineous family with two children affected by severe and recurrent bacterial respiratory infections
including Streptococcus pneumoniae. By whole exome sequencing we discovered these patients were
homozygous for the novel mutation N10Kfs*17 in TANK. We showed that this mutation leads to a complete loss
of TANK protein expression, indicating that we identified the first ever reported cases of TANK deficiency. TANK
is an adaptor protein assumed to participate in signaling pathways downstream of several immune receptors4,5.
However, its function in the human immune system remains largely unknown. To tackle this knowledge gap, we
performed in depth immunophenotyping of these patients’ samples. We found that TANK is critical for B cell
activation and differentiation, and production of immunoglobulins. Thus, we hypothesize that TANK is critical for
B cell activation and that genetic variants altering its pathway cause human diseases. Capitalizing on the unique
scientific opportunity that these patients offer we will characterize in depth the immunological consequences of
TANK deficiency (Aim 1). TANK has been implicated in the non-canonical NF-κB pathway and mutations that
cause similar clinical and immunological consequences affect this pathway6–8. Hence, Aim 2 will focus on
deciphering the role of TANK in non-canonical NF-κB pathway signaling4,5. We have shown that we can leverage
knowledge from rare and high-impact genetic variants that cause IEI to understand how more frequent genetic
variants contribute to common immunological and infectious diseases9,10. Therefore, in Aim 3 we will take
advantage of our access to several large biorepositories of genetic data linked to de-identified electronic health
records to ascertain the impact of genetic variants in the TANK pathway on human disease phenotypes. The
work proposed in this application has far reaching clinical and immunological implications. We will characterize
the function of TANK in the human immune system, particularly its role in B cell activation and differentiation.
Our findings will showcase a novel mechanism of non-canonical NF-κB activation mediated by TANK. Finally,
we will unravel the consequences of genetic variants in TANK and its pathway in human diseases. In summary,
by studying a rare genetic disease we have...

## Key facts

- **NIH application ID:** 10938668
- **Project number:** 1R01AI184471-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Janet G Markle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $523,622
- **Award type:** 1
- **Project period:** 2024-07-02 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938668

## Citation

> US National Institutes of Health, RePORTER application 10938668, Leveraging a novel human inborn error of immunity to understand B cell development and function (1R01AI184471-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10938668. Licensed CC0.

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