Pertussis Toxin Enhances Th1 Responses by Stimulation of Dendritic Cells (1)
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Pertussis toxin (PTX) is an exotoxin produced by Bordetella pertussis, which has adjuvant properties to induce Th1 response. PTX has been widely used as an adjuvant to induce Th1-mediated autoimmune diseases in animal models, such as experimental autoimmune encephalomyelitis, experimental autoimmune uveitis (EAU), and experimental autoimmune orchitis. PTX associates with induction of proinflammatory cytokines and expression of the costimulatory molecules B7-1 and B7-2 on antigen presentation cells (APCs), which affect T cell differentiation.
Dendritic cells (DC) work as effective APCs for priming naive T cells and induce IL-12 production, initiating autoimmunity.
Since PTX is used for development of EAU, instead, DCs simulated with PTX (PTX-DC) substitute PTX in EAU. EAU with IRBP immunization using PTX-DC showed that high interphotoreceptor retinoid-binding protein (IRBP) related IFN-g and IL-12 production, higher anti-IRBP IgG2a but lower anti-IRBP IgG1. PTX may play a role to activate DC in their adjuvant effect to elicit a Th 1 response.
B10.A mice were immunized s.c. with 50ug of IRBP in 0.2ml emulsion with CFA containing 2.5 mg/ml of M. tuberculosis. In addition, PTX (0.5 ug/0.1 ml) was injected i.p. as an additional adjuvant to induce EAU. PTX-DC (1 x 10^6 cells/0.1ml) was injected instead by IP injection. Eyes were collected on day 21 after immunization, and EAU score was evaluated by histopathology.
The mice received PTX developed EAU. PTX-DC also induced with a similar severity of EAU.
IFN-g and IL-4 serve as switching factors for IgG2a and IgG1, respectively. In the PTX-DC group, IgG2a levels against IRBP were increased and IgG1 levels were decreased as compared with unstimulated the DC, indicating a Th1-dependent isotype switch.
IL-12 is an indicator for switching to Th 1 responses. In fact, PTX-DC received mice have higher serum IL-12 peaked at 4 hour after cell injection, lasting at least for 24 hours. It was reported that the anti-IL-12 treatment during the IRBP-priming phase prevents EAU induction.
PTX activates ERK as cellular signaling to induce IL-12 and TNF production. PD98059, a specific ERK inhibitor, prevented EAU development with PTX-DC injection effectively.
PTX has the A-B architecture type of many bacterial toxins similar to cholera toxin and E. coli heat-labile toxin. Evidence shows that LPS and PTX bind to different domains on the same p73 receptor on murine splenocytes. PTX may share some endotoxin signal pathways with LPS-mediated signaling.