Pharmacology, Snow Lab
Snow Lab

Targeted Approaches to Optimize Immune Responses:
Learning from Primary Immune Disorders

THE PROBLEM

Single gene variants in humans can disrupt normal lymphocyte signaling and homeostasis, resulting in immune deficiency, autoimmunity, and lymphoid malignancy. Mechanistic studies of these disorders can illuminate new targets for regulating abnormal immune responses in many disease scenarios that affect both civilian and military populations, including infections, immunodeficiency, allergy, lymphoproliferative disease, and lymphoma/leukemia.

WHAT WE'RE DOING

The Snow Lab investigates aberrations in signaling, metabolic and cell death pathways in B and T cell lymphocytes within these disease contexts, with the goal of developing therapeutic strategies that rebalance and optimize adaptive immune responses in the broader context of immune deficiency, autoimmunity, lymphoproliferative disease, and cancer. As part of this research, we have also taken a leading role in characterizing novel primary immune disorders caused by mutations in the lymphocyte scaffold molecule CARD11, a crucial regulator of lymphocyte antigen receptor signaling.

OUR FINDINGS

We have pioneered the discovery and characterization of primary immune disorders linked to inherited mutations in CARD11, a critical scaffold molecule that governs antigen receptor signaling in B and T lymphocytes. In partnership with researchers and clinicians around the world, our efforts have illuminated how myriad CARD11 gene variants cause immune dysregulation associated with B cell lymphoproliferation, severe atopic disease, and frequent bacterial and viral infections.

Publications

Nat Genet, 2017 >

Dorjbal, 2018 >

Lu, 2018 >

We previously discovered a profound T cell death defect in patients with X-linked lymphoproliferative disease (XLP-1), who often succumb to a lethal overaccumulation of effector T cells in response to Epstein-Barr virus infection,  We led a multi-laboratory collaboration that demonstrated a pharmacologic inhibitor of diacylglycerol kinase alpha could prevent excessive XLP-1 patient T cell proliferation and associated immunopathology by restoring cell death sensitivity.

Publications

Ruffo, 2016 >

We are currently studying how T cell apoptosis is regulated in healthy individuals, focusing on the role of specific cell membrane receptors, transcriptional regulators, and metabolic programs that control the death of T cells derived from various functional subsets over time. Delineating how T cell death is regulated temporally will inform novel therapeutic strategies for boosting lackluster T cell responses to microbes/tumors, or attenuating overactive responses that drive autoimmunity and immunopathology.

Publications

Larsen, 2016  >

Katz & Voss, 2018 >

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