Scientific Publications by FDA Staff

J Allergy Clin Immunol 2019 Mar;143(3):1176-82.e5

Developmental regulation of type 1 and type 3 IFN production and risk for infant infections and asthma development.

Holt PG, Mok D, Panda D, Renn L, Fabozzi G, deKlerk NH, Kusel MM, Serralha M, Hollams EM, Holt BJ, Sly PD, Rabin RL

BACKGROUND: Virus-associated febrile lower respiratory tract infections (fLRI) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defence capacity during this period, exemplified by production of types 1 and 3 interferons (T1/3IFNs), may be an underlying determinant of risk. OBJECTIVE: To investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze. METHODS: We studied a subset of subjects from a birth cohort at high risk for asthma/allergy, and determined capacity of cord blood cells (n=151) to produce any of a panel of 17 T1/3IFNs in response to the viral mimic poly(I:C), employing a sensitive PCR assay. We investigated relationships between neonatal interferon responses and lower respiratory infection history during infancy, wheezing history to 5Yrs, and ensuing maturation of innate immune capacity by 4Yrs (n=160) and 10Yrs (n=125). RESULTS: While cohort subjects produced on average 2.6+/-0.3 of the 17 innate IFNs tested at birth, 24% showed no T1/3IFN production. This non-producer subgroup showed increased risk for infant fLRI (OR 2.62[1.14-6.06]p=0.024) and persistent wheeze (OR 4.24[1.60-11.24]p=0.004) at age 5Yrs relative to those producing >/=1 T1/3IFNs, whereas risk for infant wheezy LRI or "transient early wheeze" was unaffected. Moreover, infants who experienced fLRI subsequently demonstrated accelerated development of T1/3IFN response capacity between 1Yr and 4Yrs. CONCLUSIONS: T1/3IFN response capacity appears strongly developmentally constrained at birth. Infants in whom this negative regulation is strongest manifest increased risk for severe respiratory infections during infancy and subsequent persistent wheeze.