Abstract
We have previously described that boosted natural xenoantibodies in rats cross-react to bacteria by targeting carbohydrate antigens. This type of immunization is associated with reduced survival after cecal ligation and puncture (CLP). In the present study, we investigated further this phenomenon by immunizing Lewis rats with three intraperitoneal injections, every other day, of hamster blood compared to saline-injected control animals. One day after the last injection, CLP was performed to produce a low-grade sepsis. Induction of xenoantibodies was associated with a reduction in animal survival after CLP relative to controls (45% vs. 90%, p<0.01). No bacterial blood load was observed after CLP in this model either with or without xenoantibody enhancement, indicating that the augmented mortality was not mediated by a direct effect of boosted xenoantibodies over blood bacteria. Nevertheless, the xenoimmunization produced a systemic inflammatory response in all rats. Additionally, a lack of weight gain at the time of CLP was present in animals that died after the procedure, which was not observed in surviving rats and controls. The cytokine profile at the time of CLP in animals that died after the procedure was characterized by an increase in the serum level of several cytokines, particularly adipokines. In contrast, the cytokine profile at CLP of xenoimmunized rats that survived the procedure was characterized by a reduction in the level of cytokines. In conclusion, this study failed to show a direct effect of boosted xenoantibodies over blood bacterial isolates as cause for the decreased survival after CLP. However, it evidenced that non-infectious systemic inflammation may lead to a pattern of augmented cytokines, particularly adipokines, which impairs survival after subsequent CLP. Therefore, the profile of cytokines existing before the infectious insult appears more crucial than that resulting from the condition for the outcome of sepsis.
Highlights
Natural antibodies are characterized by their recognition of antigens in the absence of any evidence of exogenous exposure to them
Natural IgM antibodies play a critical role in bacterial clearance [2], making mice lacking this isotype of antibodies more susceptible to cecal ligation and puncture (CLP) [3]
No differences were observed in the levels of anti-hamster IgM and IgG xenoantibodies before CLP between rats that died after the procedure and those that did not (Fig 1C)
Summary
Natural antibodies are characterized by their recognition of antigens in the absence of any evidence of exogenous exposure to them. These antibodies are mainly IgM, are polyreactive, exhibit modest antigen binding affinity, are directed against carbohydrate antigens, and are due to the direct stimulation of antibody production by T-cell-independent (TI) pathways involving B-1 lymphocytes [1]. Natural antibodies recognize self, altered-self and foreign antigens, comprising an important first line of defense against invading pathogens. Natural IgM antibodies contribute to the removal of apoptotic and transformed cells through a complement-dependent pathway, suppression of inflammation, elimination of altered proteins, and control of autoreactive IgG and antibody-producing B cells capable of causing diseases [5]
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