Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. Retrospective study. Medical and surgical wards or intensive care units of two university hospitals. Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. None. We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.

Objective: To determine the cellular mediators of antigen‐induced arthritis (AIA) and the relative contribution of members of the interleukin‐6 (IL‐6) family and tumor necrosis factor (TNF) in AIA.Methods: AIA was induced in mice deficient in T and B lymphocytes, IL‐6 (IL‐6^−/−), TNF (TNF^−/−), IL‐11 receptor, and oncostatin M receptor, by immunization with methylated bovine serum albumin (mBSA) followed 7 days later by intraarticular injection of mBSA. Arthritis severity was assessed histologically, and T lymphocyte responses were assessed in vitro. Anti‐TNF neutralizing antibody was administered to wild‐type mice during AIA. Bone marrow osteoclasts were generated in vitro via culture with RANKL and macrophage colony‐stimulating factor.Results: AIA was dependent on CD4+ T lymphocytes, but not CD8+ T lymphocytes or B cells. IL‐6^−/− mice had reduced AIA severity and fewer osteoclasts at sites of bone erosion. This protective effect was not seen with a deficiency of other IL‐6 family members and was similar to that in TNF^−/− mice or wild‐type mice receiving TNF blockade treatment. IL‐6^−/− CD4+ T lymphocytes from draining lymph nodes had reduced antigen‐induced proliferation and produced less IL‐17 and less RANKL, relative to osteoprotegerin, than cells from wild‐type mice. Bone marrow from IL‐6^−/− mice generated fewer osteoclasts in vitro than bone marrow from either wild‐type or TNF^−/− mice.Conclusion: AIA is driven by CD4+ T lymphocytes. IL‐6 is an important mediator of bone destruction in AIA because it regulates T lymphocyte production of key osteoclastogenic cytokines and inflammation‐induced bone marrow osteoclast differentiation. These findings have implications for reducing bone and joint damage in rheumatoid arthritis.

Granulocyte colony-stimulating factor (G-CSF) is a well known regulator of granulopoiesis, but the role of endogenous G-CSF in inflammatory joint disease has not been explored. We studied the response of G-CSF-deficient mice in experimental models of joint inflammation. We show that G-CSF deficiency protects mice from acute and chronic arthritis. Reduced severity was associated with blunted mobilization of granulocytic cells from the bone marrow and less cellular infiltrate and cellular activation in inflamed joints. We also demonstrate that G-CSF blockade in established collagen-induced arthritis in WT mice markedly reduces disease manifestations and is as effective as tumor necrosis factor blockade. Our results reveal a critical role for G-CSF in driving joint inflammation and highlight G-CSF as a potential therapeutic target in inflammatory joint diseases, such as rheumatoid arthritis.

Resident CD8⁺ DCs perform several functions, including cross‐presenting antigen and rapidly engulfing the Gram‐positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8⁺ DCs are modulated. Here, we show that granulocyte‐macrophage CSF (GM‐CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross‐presentation and rapid uptake of L. monocytogenes by resident CD8⁺ DCs. This previously unrecognized functional enhancement of CD8⁺ DCs by GM‐CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM‐CSF was also marked by CD103 expression on CD8⁺ DCs that was strongly regulated by GM‐CSF. Our findings not only identify GM‐CSF as a key molecule regulating CD8⁺ DC function, but also as a factor responsible for functional heterogeneity of CD8⁺ DCs that is at least substantially demarcated by CD103 expression.

Objective: To investigate the kinetics of nucleosome leakage from apoptotic cells in an in vitro system and extrapolate the results to autoimmune disease, in particular systemic lupus erythematosus. Methods: A sensitive nucleosome enzyme linked immunosorbent assay (ELISA) was developed, using a monoclonal antibody (mAb) against histone 3 and an mAb against nucleosomes. Nucleosome release during apoptotic cell death was studied in Jurkat cells. AnnexinV binding (early apoptosis) and propidium iodide positivity (late apoptosis) of the cells were compared with nucleosome release at different times after apoptosis induction. Results: Nucleosomes appeared in culture supernatant of Jurkat cells 24 to 48 hours after apoptosis induction, when the cells had been late apoptotic for more than 12 hours. Conclusion: Nucleosomes are released from late apoptotic Jurkat cells, with a 12 hour delay from the appearance of AnnexinV binding cells. This result suggests that in vivo scavenger mechanisms have 12 hours to remove apoptotic material from the circulation.