Impaired Control of Epstein-Barr Virus Infection in B-Cell Expansion with NF-κB and T-Cell Anergy Disease.

B-cell expansion with NF-κB and T-cell anergy (BENTA) disease is a B-cell-specific lymphoproliferative disorder caused by germline gain-of-function mutations in CARD11. These mutations force the CARD11 scaffold into an open conformation capable of stimulating constitutive NF-κB activation in lymphocytes, without requiring antigen receptor engagement. Many BENTA patients also suffer from recurrent infections, with 7 out of 16 patients exhibiting chronic, low-grade Epstein-Barr virus (EBV) viremia. In this mini-review, we discuss EBV infection in the pathogenesis and clinical management of BENTA disease, and speculate on mechanisms that could explain inadequate control of viral infection in BENTA patients.

A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family.

CARD11 is a lymphocyte-specific scaffold molecule required for proper activation of B- and T-cells in response to antigen. Germline gain-of-function (GOF) mutations in the CARD11 gene cause a unique B cell lymphoproliferative disorder known as B cell Expansion with NF-κB and T cell Anergy (BENTA). In contrast, patients carrying loss-of-function (LOF), dominant negative (DN) CARD11 mutations present with severe atopic disease. Interestingly, both GOF and DN CARD11 variants cause primary immunodeficiency, with recurrent bacterial and viral infections, likely resulting from impaired adaptive immune responses. This report describes a unique four-generation family harboring a novel heterozygous germline indel mutation in CARD11 (c.701-713delinsT), leading to one altered amino acid and a deletion of 4 others (p.His234_Lys238delinsLeu). Strikingly, affected members exhibit both moderate B cell lymphocytosis and atopic dermatitis/allergies. Ectopic expression of this CARD11 variant stimulated constitutive NF-κB activity in T cell lines, similar to other BENTA patient mutations. However, unlike other GOF mutants, this variant significantly impeded the ability of wild-type CARD11 to induce NF-κB activation following antigen receptor ligation. Patient lymphocytes display marked intrinsic defects in B cell differentiation and reduced T cell responsiveness in vitro. Collectively, these data imply that a single heterozygous CARD11 mutation can convey both GOF and DN signaling effects, manifesting in a blended BENTA phenotype with atopic features. Our findings further emphasize the importance of balanced CARD11 signaling for normal immune responses.

Communication plays a critical role in web-based monitoring.

BACKGROUND: Patient-health care practitioner (HCP) interaction via a Web-based diabetes management system may increase patient monitoring of their blood glucose (BG) levels. METHODS: A three-center, nonrandomized, prospective feasibility study of 109 Native Americans with poorly controlled type 1 diabetes mellitus and type 2 diabetes mellitus were recruited from Alabama, Idaho, and Arizona. The study intervention included the use of a Web-based diabetes management application (MyCareTeam) that allowed timely interaction between patients and HCPs. Information about diabetes, nutrition, and exercise was also available. Finally, patients were able to provide BG readings to their HCP via the MyCareTeam system. RESULTS: As a result, 59.6% of the patients sent one or more messages to their HCP, 92.67% received one or more messages from their HCP, and 78.89% received one or more person-centered messages from their HCP. Additionally, the number of times a patient logged into the system and the frequency with which they tested their blood sugar were correlated with (a) the number of messages sent to their HCP, (b) the total number of messages received from their HCP, and (c) the number of person-centered messages received from their HCP. Thus patients who sent more messages also tested their BG more frequently, as measured by the number of BG readings uploaded from their meter to the MyCareTeam database. Person-centered messages seem to be particularly important to motivating the patient to monitor their BG levels and use the Web-based system. CONCLUSIONS: These results suggest that patient-HCP interaction and, in particular, more personalized interactions increases patient frequency of BG monitoring.