We use human genetics and immunology to discover mechanisms of immune defense and dysregulation, and to translate these insights into better diagnosis and therapy.
Understanding why only a small subset of individuals develops life-threatening infections, immune dysregulation, or malignancies provides insight into the fundamental principles and nonredundant immune pathways underlying human disease pathogenesis.
Background:
Interindividual variability in susceptibility to infection, immune dysregulation, and malignancy risk remains a fundamental and largely unanswered question in human biology. Even among individuals exposed to the same pathogens, outcomes range from asymptomatic infection to life-threatening disease, highlighting critical gaps in our understanding of protective and pathological immunity.
Extreme clinical variability during infection and immune dysregulation reflects underlying genetic and immunological determinants that are poorly understood (Annu Rev Pathol, 2024; PNAS, 2015).
Despite major advances in sequencing technologies, the diagnostic yield for patients with suspected inborn errors of immunity remains limited, at approximately 30% (Frontiers in Pediatrics, 2024), suggesting that many disease-causing genes, allelic variants, and mechanisms remain undiscovered.
Identifying and characterizing novel IEIs not only enables precise diagnosis for the patients we study, but also uncovers essential immune pathways that govern host defense, immune regulation, and malignancy risk in humans.
Key Questions We Ask:
- Why do some individuals develop severe or life-threatening disease after otherwise common infections?
- Which immune pathways are non-redundant in humans causing or preventing patients from diseases of interests?
- How do monogenic defects predispose to immune dysregulation and cancer?
Disease Phenotypes We Study:
- Life-threatening infections, with a particular focus on Epstein–Barr virus (EBV)
- Immune dysregulation and malignancy in the context of EBV infection
- Broader spectra of immune dysregulation, including autoimmunity and autoinflammation
Our Approach:
- Patient-driven discovery, including deep clinical phenotyping, enrollment, and next-generation sequencing
- Human genetics and immunology, to link genotype to cellular and molecular immune phenotypes
- Deep mechanistic investigation, to establish causal relationships between genetic defects and disease
- Rather than beginning with predefined pathways, we prioritize unbiased discovery in humans, followed by rigorous functional validation in relevant immune systems
Despite widespread use of clinical sequencing - including targeted gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS) - the diagnostic yield for inborn errors of immunity (IEIs) remains limited (~30%) ( Frontiers in Pediatrics, 2024 ). A major barrier is the interpretation of variants of uncertain significance (VUS). Our laboratory leverages multiplexed assays of variant effect (MAVEs) to systematically map genotype-function relationships and generate comprehensive functional atlases for key IEI genes.
Background:
Although sequencing technologies have rapidly advanced, interpretation has become the primary bottleneck in genetic diagnosis. For IEIs in particular, many patients harbor rare or private variants whose functional consequences cannot be inferred from sequence data alone.
- The majority of variants submitted to clinical databases such as ClinVar are classified as variants of uncertain significance (VUS).
- The number of reported VUS continues to grow exponentially as sequencing expands (Nat Rev Genet, 2025).
- Testing variants individually is resource-intensive, time-consuming, and impractical at scale.
- Functional studies performed across different laboratories often yield inconsistent or non-comparable results.
- Together, these challenges limit the clinical utility of sequencing and delay diagnosis for patients with suspected IEIs.
Genes and Pathways of Interest:
- Our group is actively developing MAVEs for several high-yield IEI genes, selected based on clinical relevance, genetic constraint, and unmet diagnostic need.
- These genes span pathways involved in immune activation, regulation, and malignancy risk, and are frequently associated with high rates of VUS in clinical testing.
Our Approach:
- High-throughput variant generation, enabling saturation scale
- Physiologically relevant cellular systems tailored to gene-specific function
- Quantitative functional readouts that directly reflect immune phenotypes
- Rigorous statistical and computational analysis for reproducibility and clinical translation
Human genetics provides a uniquely powerful framework for therapeutic discovery. By identifying non-redundant immune pathways through naturally occurring genetic variation, we aim to develop genetics-informed, mechanism-based therapies for inborn errors of immunity (IEIs), and to extend these insights beyond rare monogenic disorders to patients with more common, modest, or even mild clinical disease arising from dysregulation of the same pathways.
Background:
Human monogenic disorders provide direct causal links between gene function, immune pathways, and disease phenotypes—offering a blueprint for precision therapy.
Naturally occurring human mutations act as in vivo perturbation experiments, revealing which immune pathways are essential, non-redundant, or safely targetable in humans.
Insights from human genetics have repeatedly led to transformative therapies that extend far beyond rare disease. Canonical examples include the discovery of LDLR deficiency informing statin therapy (PNAS, 2013) and the development of PCSK9 inhibition (e.g., evolocumab) for hypercholesterolemia (Circulation, 2024).
Despite this promise, translation from genetic discovery to targeted therapy remains fragmented, and most IEIs still lack mechanism-based treatments.
Guided by a Brown–Goldstein approach, we aim to leverage insights from rare genetic disorders to inform therapies for broader populations who share dysregulation of the same immune pathways.
Therapeutic Areas of Focus:
- CD40–CD40L pathway dysregulation, spanning immune deficiency and immune dysregulation
- Life-threatening Epstein–Barr virus (EBV) disease, including immunodeficiency, lymphoproliferation, and malignancy
Our Approach:
- Human genetic discovery to define causal disease mechanisms
- Functional immunology to identify precise therapeutic leverage
- Pathway-informed intervention, prioritizing specificity, safety, and durability
Background:
Neutralizing anti-cytokine autoantibodies can create an acquired phenocopy of an inborn error of immunity by functionally blocking a cytokine or receptor pathway that is genetically intact. As a result, patients can develop the same narrow infectious susceptibility seen in genetic defects of that pathway, such as anti-IFN-gamma autoantibodies causing MSMD-like mycobacterial disease or anti-IL-17A/F autoantibodies causing chronic mucocutaneous candidiasis.
Our Approach:
We leverage existing autoantibody screening technologies to screen patients with severe unexplained autoimmune and infectious phenotypes who have negative genetic testing.
We are also interested in developing novel autoantibody screening platforms.