Altogether 553 children (195 first graders, mean age 6.8 years, and 358 third graders, mean age 8.7 years) participated in the development of a self-report measure to assess the intensity of children's pain. The first step was the derivation, from children's drawings of facial expressions of pain, of 5 sets of 7 schematic faces depicting changes in severity of expressed pain from no pain to the most pain possible. With the set of faces that achieved the highest agreement in pain ordering, additional studies were conducted to determine whether the set had the properties of a scale. In one study, children rank-ordered the faces on 2 occasions, separated by 1 week. All 7 faces were correctly ranked by 64% (retest 1 week later, 61%) of grade 1 children and by 86% (retest 89%) of grade 3 children. In a second study, the faces were presented in all possible paired combinations. All 7 faces were correctly placed by 62% (retest 86%) of the younger and by 75% (retest 71%) of the older subjects. A third study asked children to place faces along a scale: a procedure allowing a check on the equality of intervals. The fourth study checked on whether pain was acting as an underlying construct for ordering the faces in memory. We asked whether children perceived the set as a scale by asking if memory for an ordered set of faces was more accurate than for a random set. The final study checked, with 6-year-old children, the test-retest reliability of ratings for recalled experiences of pain. Overall, the faces pain scale incorporates conventions used by children, has achieved strong agreement in the rank ordering of pain, has indications that the intervals are close to equal, and is treated by children as a scale. The test-retest data suggest that it may prove to be a reliable index over time of self-reported pain.

Background T follicular helper (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 immunological abnormalities. Objective To determine the signaling pathways and cellular interactions required for the development and function of Tfh cells in humans. 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 Tfh (cTfh) cell subsets, memory B cells and serum Ig levels were quantified and functionally assessed in healthy controls as well as 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 frequencies. STAT3, IL21/R LOF and STAT1 gain-of function mutations skewed cTfh differentiation towards a phenotype characterized by over-expression of IFNγ and programmed death -1 (PD-1). IFNγ inhibited cTfh function in vitro and in vivo, corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1 and IL12RB1 LOF mutations. Conclusion Specific mutations impact the quantity and quality of cTfh cells, highlighting the need to assess Tfh cells in patients by multiple criteria, including phenotype and function. Furthermore, IFNγ functions in vivo to restrain Tfh-induced B cell differentiation. These findings shed new light on Tfh biology and the integrated signaling pathways required for their generation, maintenance and effector function, and explain compromised humoral immunity in some PIDs.

SCID resulting from mutations in