PROJECTS

NEW MONOGENIC IMMUNE DISEASE DISCOVERY

We continue to recruit on a rolling basis patients with rare, inherited immune disorders in order to study the genetic, molecular, and cellular basis of disease.  By understanding the mechanisms of immune dysfunction, we aim to devise precision medicine approaches to treat these patients while at the same time gleaning insights into biology that is fundamental for proper immune function in humans. In addition to our work with primary human samples, we advance our projects using CRISPR-engineered mouse models harboring patient-derived mutations that enable access to sophisticated tools and mechanistic dissection of immune function and potential treatments. 

PI3K-delta in immune REGULATION: APDS

A major research focus has been on PASLI/APDS (Activated PI3Kdelta Syndrome), a primary immunodeficiency caused by germline gain-of-function mutations in the PIK3CD or PIK3R1 gene encoding a subunit of the phosphoinositide 3-kinase delta (PI3Kdelta) complex.  We have identified multiple distinct mutations sites that all result in recurrent sinopulmonary infections, lymphoproliferative disease, and susceptibility to herpesviruses and B cell lymphomas.  Identification of the underlying genetic cause of PASLI/APDS has led to exciting clinical trials of specific PI3Kdelta inhibitors in this disease.

PI3K-gamma in immune regulation: IPGS

We additionally expanded the set of monogenic immune disorders caused by PI3K mutations through discovery of human ‘Inactivated PI3K-gamma Syndrome’ (IPGS). Loss of PI3Kgamma in humans results in recurrent sinopulmonary infections, cytopenias, and lymphocytic pneumonitis (lung inflammation) and colitis (gut inflammation). We could recapitulate these immune defects in PI3Kgamma knockout mice using ‘dirty’ mouse models in which we expose laboratory mice kept in a clean research environment to ‘dirty’ mice exposed to the real world so that their microbiota are transferred to our mouse models. This better emulates the human condition and sets the stage for translationally relevant models of human monogenic diseases.

ELF4 regulation of INFLAMMATion: DEX

A major effort in the laboratory revolves around another human inborn error of immunity we discovered and termed ‘Deficiency in ELF4, X-linked’ (DEX). ELF4 is a transcription factor on the X chromosome, and loss-of-function mutations in ELF4 in male patients causes an autoinflammatory disease resembling inflammatory bowel disease with recurring fevers, canker sores in the mouth, abdominal pain and diarrhea. Studying both patient immune cells and DEX mouse models, we are systematically investigating responses of macrophages, neutrophils, and T cells at the organismal, cellular, and molecular levels to learn how the magnitude of the inflammatory response is regulated directly and indirectly by ELF4.

T cell differentiation

In PASLI/APDS, we discovered an abnormally increased frequency of terminally differentiated, senescent T cells, which may contribute to their poor control of herpesviruses.  T cell senescence occurs when the DNA damage response (DDR) is activated, which can be triggered by direct DNA insult or extreme shortening of telomeres that are recognized as a double-stranded DNA break.  T cells from the blood of PASLI/APDS patients exhibit markedly short telomeres, and our ongoing efforts are directed at better understanding regulation of telomere length by PI3K and related pathways, inflammation associated with senescent T cells, and signal transduction through DDR pathways in T cells. 

In DEX, we discovered that CD4 T cell differentiation into inflammatory IL-17-producing cells is increased. The normal function of ELF4 in restraining inflammatory T cell responses has important implications for better understanding how T cell cytokines contribute to inflammatory diseases such as IBD and Behcet’s Disease. Ongoing efforts are defining these differentiation trajectory mechanisms further.

Antibody responses

The most common feature of immunodeficient patients as a whole is defective antibody responses. Building from our work in PI3K gene defects, we are uncovering new biology of the antibody response to better understand the molecules and pathways that tune healthy and pathological responses. In the long-term, we envision these new insights leading to novel immunomodulatory therapies while also providing a more complete basic understanding of cellular differentiation and cell-cell interactions required for antibody responses.