Mechanistic elucidation of pathogenic CBM complex mutations associated with atopic disease - PROJECT ABSTRACT
The study of primary atopic disorders (PADs) has provided important and surprising knowledge about
specific genes that control the function of white blood cells involved in driving allergic responses. Over the last
several years, our groups have played a leading role in the discovery and characterization of human immune
disorders linked to mutations in CARD11, which encodes a critical signaling protein in lymphocytes. CARD11
partners with two other proteins (BCL10 and MALT1) to form the “CBM complex”, which communicates key
signals that dictate lymphocyte activation, differentiation and function. Most recently, we described numerous
patients with severe eczema, asthma/food allergies, and skin/respiratory infections that carried debilitating
CARD11 mutations that disrupt normal CBM function. These variants attenuate CBM signaling in patient
lymphocytes and cause them to differentiate abnormally into effector cells associated with allergy/atopy. The
long-term objective of this project is to precisely define which cell signaling processes are disrupted
by mutations in CBM complex genes, and elucidate how these defects adversely affect B and T cell
function to ultimately manifest as in atopy, including assessment of glutamine as a potential treatment
strategy. We will also define the broader scope and burden of pathogenic CBM complex mutations that
influence atopic predisposition in both rare PADs and common cohorts of allergy disease patients.
Built upon an extensive panel of atopy-associated, damaging mutations spanning the CARD11 gene,
and extending to other CBM gene mutations identified from allergic patient cohorts, our studies will better
define how these mutations disrupt normal CBM-dependent signaling pathways in lymphocytes. Using well-
established cell transfection systems AND primary murine and patient cells, we will elucidate the molecular and
cellular mechanisms through which impaired CARD11 signaling drives the preferential production of allergy-
associated cytokines and IgE. Based on compelling preliminary data, our analyses will pinpoint specific
biochemical and metabolic pathways that are disrupted by defective CARD11 signaling directly in primary cells
from affected patients, an invaluable resource that we have unique access to. Defining these molecular
abnormalities will enhance our understanding of disease pathogenesis and illuminate mechanisms by which
simple interventions, such as supplementation with the essential amino acid glutamine, can restore the proper
function of T and B cells harboring CBM mutations. Our innovative approach has the potential to significantly
revise our understanding of how the CBM complex regulates adaptive immune responses. Insights gleaned
from a more thorough investigation of CBM gene mutations, derived from both rare and common allergy
patient cohorts, will better define their contribution to atopic susceptibility and inform new targeted therapeutic
approaches for treating a broader spectrum of patients suffering from allergic disease.
