Abstract
Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4+CD25+FoxP3+ regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4+CD25+FoxP3+ Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation.
Highlights
Evidence suggests that in the pathogenesis of multiple sclerosis (MS), viral or bacterial agents may trigger or mislead activation of an immune system with the general potential to generate a selfreactive immune response [1,2,3]
Continuous pertussis toxin (PTx) treatment is not immunosuppresive and does not induce tolerization First, we investigated whether continuous PTx pre-treatment may exert an unspecific immunosuppressive effect or may have tolerized mice for PTx, possibly hindering subsequent EAE induction using this particular adjuvant
We examined whether continuous PTx treatment may have generated myelin-specific T cell responses due to its presumed ability to increase permeabilization of the blood-brainbarrier
Summary
Evidence suggests that in the pathogenesis of multiple sclerosis (MS), viral or bacterial agents may trigger or mislead activation of an immune system with the general potential to generate a selfreactive immune response [1,2,3]. Pro-inflammatory activity of PTx is mainly attributed to an increased permeabilization of the otherwise cell-restrictive blood-brain barrier leading to an influx of immune cells into the CNS [13,14]. This assumption may not be conclusive as recent data suggest that PTx increases expression of cerebrovascular adhesion molecules [15,16], proposing an alternative mechanism by which PTx may facilitate leukocyte migration into the CNS. PTx may utilize multiple mechanisms to promote development of EAE
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