title: Repetitive pertussis toxin promotes development of regulatory T cells and prevents central nervous system autoimmune disease.
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.
authors.affiliation: Department of Neurology, Technische Universität München, Munich, Germany. m.weber@lrz.tu-muenchen.de
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.forename: Mahdia
authors.initials: M
authors.lastname: Benkhoucha
authors.forename: Klaus
authors.initials: K
authors.lastname: Lehmann-Horn
authors.forename: Deetje
authors.initials: D
authors.lastname: Hertzenberg
authors.forename: Johann
authors.initials: J
authors.lastname: Sellner
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Santiago-Raber
authors.forename: Michel
authors.initials: M
authors.lastname: Chofflon
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002493:Central Nervous System Diseases / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin / Q000737:chemistry* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D037342:Pertussis Toxin