Although the antimicrobial activity of reactive oxygen species (ROSs) is well defined, the role of ROSs in regulating the immune response of the body is not well understood. We now provide evidence that hydrogen peroxide (H 2 O IntroductionAccumulated damage due to reactive oxygen species (ROSs) has been suggested to occur during aging 1,2 and more clearly demonstrated during the respiratory burst of phagocytes. 3,4 Hydrogen peroxide (H 2 O 2 ), is a primary component of ROSs produced in large amounts by macrophages and granulocytes and is a mediator of innate immunity against the invading pathogens. 5,6 H 2 O 2 is known to function as a second messenger 7,8 and regulates activation of many important transcription factors, such as nuclear factor-B (NF-B) and activator protein-1 (AP-1), 9,10 that control the inducible expression of genes regulating macrophage-effector functions and cytokine signaling. [11][12][13] The macrophage-induced cytokines determine the fate of the subsequent T-cell responses as type 1 14,15 or type 2. 16,17 Thus, the possibility exists that H 2 O 2 may alter the T-cell immune responses by affecting the macrophageeffector responses. The function of ROSs may not be restricted to its antimicrobial activity alone, 18 but ROSs may also play an important role in regulating the immune environment in the body. Such situations may arise during certain pathophysiologic conditions such as tuberculosis. 19,20 We earlier reported that activated macrophages from the Bruton tyrosine kinase (btk)-deficient mice (CBA/N) produced lower levels of ROSs as compared to the wild-type mice (CBA/J). 21 However, in contrast to CBA/J macrophages, the IL-12 induction was significantly higher in macrophages from CBA/N mice with T-cell responses biased toward type 1. 21,22 Although the contribution of btk enzyme in controlling the signal transduction cascades responsible for ROS production independent of IL-12 signal may not be ruled out, it is possible that btk targets the ROS pathway to influence IL-12 production. However, the exact mechanism by which ROSs down-regulate IL-12 production is not well understood. We now provide evidence that H 2 O 2 /ROSs affect the signaling events important for IL-12 production, leading to downregulation of the same in activated macrophages. Materials and methods MiceBALB/c mice were bred and maintained in the animal facility of Indian Immunologicals (IIL; Hyderabad, India). All mice were 6 to 12 weeks old and experimental protocol was approved by the Institutional Review Committee for care and usage of animals of Indian Immunologicals. Macrophage stimulation assayThe peritoneal exudate cells (PECs) were harvested by injecting 4% thioglycolate broth as described elsewhere. 23 The RAW 264.7 macrophages were obtained from NCCS (National Centre for Cell Science, Pune, India) and maintained in Dulbecco minimal essential medium (DMEM; Invitrogen, Grand Island, NY) containing 10% fetal calf serum and antibiotics (DMEM-10). The macrophages were plated at a density of 3 ϫ 10 6 cells/mL and ...
Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/02/15/jimmunol.090043
Nineteen isolates of leptospires recovered from patients during three epidemics that occurred at different places and different times in the Andaman Islands and eight isolates from sporadic cases were characterized using serological and molecular genetic techniques. Group sera and monoclonal antibodies were used for antigenic characterization, whereas fluorescent amplified fragment length polymorphism (FAFLP) was used for genotyping. Of the 27 isolates, 19 were identified as belonging to serogroup Grippotyphosa, 3 belonged to serogroup Australis, 2 belonged to serogroup Icterohaemorrhagiae, and 1 each belonged to serogroups Hebdomadis, Canicola, and Sejroe. Analysis of FAFLP data grouped these 27 isolates into two main clusters of genotypes. One of the clusters, populated by 19 isolates, included 16 outbreak isolates. Seven of these 19 isolates belonged to serovar Ratnapura, 10 belonged to serovar Valbuzzi, and 1 each belonged to serovar Grippotyphosa and serovar Saxkoebing. Of the 27 patients from whom isolates were obtained, 9 had severe illness, and 6 of these 9 patients had pulmonary involvement, 1 had pulmonary and hepatorenal involvement, and the remaining 2 had hepatorenal involvement alone. Two patients out of the nine severe cases died subsequently. The isolates from sporadic cases showed great genetic diversity and were also diverse antigenically. Perhaps the strains belonging to a dominant genotype (the outbreak-associated cluster) possessed epidemic potential and higher virulence with a greater predilection to cause pulmonary complications than strains belonging to other genetic backgrounds.
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