The immunological role of IRA B cells in the immunosuppressive phase of sepsis
Zusammenfassung der Projektergebnisse
My initial project described an effector B cell population that protects against microbial sepsis. In the published work I characterized the new Innate response activator (IRA)-B cells. IRA-B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern recognition receptors, and produce GM-CSF. Specific deletion of IRA-B cell activity impaired bacterial clearance, elicited a cytokine storm, and precipitated septic shock. These observations enrich our understanding of innate immunity, position IRA-B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases. In a second project I characterized the role of IRA B cells in pneumonia. Pneumonia is a major cause of mortality worldwide and a serious problem in critical care medicine, but the immunophysiological processes that confer protection or morbidity are incompletely understood. Ongoing studies show that in response to lung infection, B1a B cells migrate from the pleural space to the lung parenchyma to secrete emergency immunoglobulin-M (IgM). The process requires innate response activator (IRA) B cells, a transitional, B1aderived inflammatory subset that controls IgM production via autocrine granulocytemacrophage colony stimulating factor (GM-CSF) signaling. The strategic location, coupled with the capacity to produce GM-CSF-dependent IgM, ensures effective early frontline defense against bacteria invading the lungs. The study describes a previously unrecognized GM-CSF-IgM axis and positions IRA B cells as orchestrators of protective IgM immunity. In a third project I concentrated my work on the initial phase of sepsis and the role of Interleukin(IL)-3. Sepsis is a frequently fatal condition characterized by an uncontrolled host reaction to microbial infection. Human studies have shown that sepsis is associated with excessive production of inflammatory cytokines – an event known as a cytokine storm. Clinical trials targeting inflammatory mediators have failed, however, creating an urgent need for a better fundamental understanding of sepsis’ pathophysiology. Ongoing studies show that IL-3 is an essential inducer of inflammation in sepsis. Although almost undetectable in the steady state, IL-3 expression was pronounced in response to microbial infection in a mouse model. Within hours, IL-3 amplified hematopoiesis in the bone marrow and spleen, generating monocytosis and neutrophilia. Among the leukocytes, Ly-6Chigh monocytes contributed substantially to the ensuing cytokine storm by producing abundant IL-1β, TNFα, and IL-6. As a consequence, IL-3 precipitated multi-organ damage, septic shock, and death. The cellular source of IL-3 were the innate response activator (IRA) B cells which arose from peritoneal B1 cells via direct recognition of bacteria at the site of infection. Injection of antibodies against the IL-3-specific receptor in mice reduced morbidity and mortality. Altogether, this study enriches our understanding of immune activation, and identifies IL-3 as an orchestrator of emergency hematopoiesis and a potential therapeutic target for the treatment of sepsis.
Projektbezogene Publikationen (Auswahl)
- Protective function of pleural B cells in pneumonia depends on a GM-CSF-IgM axis. Keystone Meeting “B cell Development and Function”, Keystone, Colorado, USA
Weber GF
- Extramedullary hematopoiesis generates Ly-6Chigh monocytes that infiltrate atherosclerotic lesions. Circulation. 2012 Jan 17;125(2):364-74
Robbins CS, Chudnovskiy A, Rauch PJ, Figueiredo JL, Iwamoto Y, Gorbatov R, Etzrodt M, Weber GF, Ueno T, van Rooijen N, Mulligan-Kehoe MJ, Libby P, Nahrendorf M, Pittet MJ, Weissleder R, Swirski FK
- Innate response activator B cells protect against microbial sepsis. Science. 2012 Feb 3;335(6068):597-601
Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I, Tiglao E, Figueiredo JL, Iwamoto Y, Theurl I, Gorbatov R, Waring MT, Chicoine AT, Mouded M, Pittet MJ, Nahrendorf M, Weissleder R, Swirski FK
(Siehe online unter https://doi.org/10.1126/science.1215173)
