Bone marrow plasma cells require P2RX4 to sense extracellular ATP.

Plasma cells produce large quantities of antibodies and so play essential roles in immune protection1. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals1. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.

Congenital Langerhans cell histiocytosis presenting in a 27-week-gestation neonate.

Langerhans cell histiocytosis is exceedingly rare in premature infants, and the few cases reported suggest a poor prognosis with systemic involvement. We present a case of Langerhans cell histiocytosis limited to a single cutaneous lesion, presenting in a 27-week-gestation infant, which is the youngest gestational age of reported Langerhans cell histiocytosis cases. The lesion showed spontaneous resolution by 41 weeks corrected gestational age, and systemic involvement was absent, demonstrating a mild course of skin-only Langerhans cell histiocytosis in a premature infant.

A Trial Online Educational Melanoma Program Aimed at the Hispanic Population Improves Knowledge and Behaviors.

BACKGROUND: Hispanic individuals who suffer from melanoma are diagnosed later and have a worse prognosis. Because the Hispanic population is one of the fastest growing in the United States, it is important to spread awareness of melanoma. OBJECTIVE: The study aimed to evaluate whether an online educational video about skin cancer could improve knowledge about melanoma and encourage self-skin examinations (SSE). METHODS: The authors directed Hispanic patients to an online survey, which assessed for knowledge about melanoma risk factors and prevention. This was followed by a 5-minute online video about melanoma. A second survey was sent immediately after the video, and a third survey was sent 1 month later. All project materials were in Spanish and available online. RESULTS: Eighty-six participants completed the full experiment. After watching the online video, a significantly higher proportion of participants provided correct answers for melanoma risk factors and prevention techniques. A similar increase was seen in the number of individuals who reported performing SSEs. CONCLUSION: This study provides evidence that an online educational video targeted at the Hispanic population has potential to improve melanoma awareness. This type of intervention may lead to earlier diagnosis and better prognosis for Hispanic individuals.

Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation.

Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naive B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell-cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundance for numerous mTORC1- and Myc-regulated genes. Myc loss compromised plasma cell differentiation for MZ B cells, and reciprocally induced ectopic mTORC1 signaling in follicular B cells enabled division-independent differentiation and plasma cell-affiliated gene expression. We conclude that ongoing in situ Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state that enables rapid division-independent plasma cell differentiation.