15 research outputs found
Effect of Feeding Thyroprotein to Dairy Cattle in a Subtropical Environment on Milk Composition and Production, Rumen Metabolism, and Fatty Acid Composition of Milk Fat
“Don't Eat Anything That Can Play Videogames”: Deleuze-Guattarian Alternatives to Corporate Capitalism in Scarlett Thomas's PopCo
The correlation between education, engineering, enforcement, and self-reported seat belt use in Tennessee: Incorporating heterogeneity and time of day effects
Bayesian Approach Based on Geographic Information System to Identify Hazardous Roadway Segments for Traffic Crashes
A home-based approach to understanding seatbelt use in single-occupant vehicles in Tennessee: Application of a latent class binary logit model
The Economic Impact of Payer Policies after the Rx-to-OTC Switch of Second-Generation Antihistamines* *Preliminary results of this analysis were presented at the 9th annual HMO Research Network Conference April 1-2, 2003
Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.
Background: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Methods: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function invitro and invivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions invivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs