Transition Program in Clinical Research

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Patients with Congenital Disorders of Glycosylation (CDGs) and other monogenic syndromes presenting with severe allergic disease in association with connective tissue abnormalities are actively being recruited and studied. A number of clinical assays have been developed in the laboratory in order to accomplish these goals: lectin-based flow cytometry is employed to characterize N-glycan abnormalities; ddPCR assays have been developed to perform tryptase genotyping and assay isoform-specific gene expression. Using molecular genetic techniques, we continue to characterize defects we have identified in discrete immune pathways and in glycosylation processes. To do so, we employ a number of techniques including cellular transfection and pathway inhibition with small molecules, gene silencing, and antibody-based inhibition. As we characterize the role that altered glycosylation plays in allergic diseases and reactions, we seek to devise ways to manipulate these pathways to limit or alter disease pathogenesis. Through these efforts, we identified a functional haplotype in the voltage gated calcium channel CACNA1H which is commonly co-inherited with increased TPSAB1 copy number in patients with hereditary alpha tryptasemia. Also, through collaborative work we: 1) expanded our understanding of the clinical phenotypes associated with the first disorder of de-glycosylation (NGLY1 deficiency); 2) described hypomorphic and dominant negative mutations in CARD11 that lead to atopic dermatitis; 3) identified mast cell compartment disruption in patients with Gauchers disease leading to elevated serum tryptase; 4) described a mechanism by which elevated STAT1 signaling due to germline mutations in STAT1 (gain-of-function) or STAT3 (loss-of-function) limits Th17 differentiation via induction of PD-L1.