Beyond spell checking: Adding function to precision medicine

+ See all authors and affiliations

Science Immunology  05 May 2017:
Vol. 2, Issue 11, eaan5141
DOI: 10.1126/sciimmunol.aan5141


Immunoprofiling signaling pathways in rare immunodeficiencies aid design of targeted therapies.

Primary immunodeficiencies (PIDs) are a group of rare genetic diseases that result in altered infection susceptibility and immune dysfunction, such as increased rates of autoimmunity or cancer incidence. In the last 10 years, whole-exome sequencing has led to an explosion in genetic diagnoses and aided the development of targeted therapies for a subset of PIDs. However, even for genetically-defined PIDs, clinical phenotypes can be broadly variable. The phenotype of a particular PID can be dramatically different depending on whether a patient’s mutation leads to increased [gain-of-function (GOF)] or decreased [loss-of-function (LOF)] activity, and sequencing the gene may not help if the patient in question has a previously unreported variant.

A recent paper by Choi et al. wades into this translational frontier with key insights into leveraging immune cell function for mechanistic understanding and patient care. Using mass cytometry, which can simultaneously measure 40 to 50 features, the authors first evaluated the baseline activation states of 9 core signaling pathways in 18 immune cell subsets in healthy controls. They then measured the effect of 12 separate stimuli (including PMA, LPS, and 10 cytokines) on these signaling pathways. They applied this toolkit to define the molecular signature of these signaling cascades in two patients with known genetic PID: STAT1 GOF and autosomal dominant STAT3 (or hyper IgE syndrome). Using limited pediatric blood volumes, the authors went beyond defining the patients’ genetic diagnoses to comprehensively connect individual patient mutations to altered immune functions. Such studies could highlight the causative core pathway(s) in each PID and facilitate the development of more targeted treatment regimens for each patient.

Although this paper studies a very small group of patients and the potential insights into STAT1 GOF and autosomal dominant STAT3 PID mechanisms require validation and extension, this work represents an important step forward in the development of precision medicine approaches for PIDs and other rare diseases.

Highlighted Article

View Abstract

Related Content

Navigate This Article