Elicitation of experimental allergic encephalomyelitis (EAE) in mice with the aid of pertussigen

Pertussis toxin (PTx) is a bacterial toxin used to enhance the severity of experimental autoimmune diseases such as experimental autoimmune encephalomyelitis. It is known to promote permeabilization of the blood-brain barrier, maturation of APC, activation of autoreactive lymphocytes and alteration of lymphocyte migration. In this study, we show that i.v. injection of PTx in mice induces a decrease in the number of splenic CD4+CD25+ regulatory T cells (Treg cells). Furthermore, PTx not only induces a depletion of the dominant CD4+CD25+Foxp3+ subpopulation of splenic Treg cells, but also reduces to a similar extent the CD4+CD25−Foxp3+ subpopulation. On a per cell basis, the suppressive properties of the remaining Treg cells are not modified by PTx treatment. The reduction in splenic Treg cells is associated with preferential migration of these cells to the liver. Additionally, Treg cells exhibit a high sensitivity to PTx-mediated apoptosis in vitro. Finally, in vivo depletion of Treg cells by injection of an anti-CD25 Ab, and PTx treatment, present synergistic experimental autoimmune encephalomyelitis exacerbating effects. Therefore, we identify a new effect of PTx and provide an additional illustration of the influence of microbial components on the immune system affecting the balance between tolerance, inflammation and autoimmunity.

Section: P Ertussis Toxin (Ptx)mentioning

confidence: 99%

Pertussis Toxin Reduces the Number of Splenic Foxp3+ Regulatory T Cells

Cassan

Piaggio

Zappulla

et al. 2006

“…RNA (10 g), SuperScript II Reverse Transcriptase (Invitrogen Life Technologies) and oligo(dT) [12][13][14][15][16] were used for first-strand cDNA synthesis as previously described (33). Real-time 5Ј-nuclease fluorogenic RT-PCR analysis was performed on an ICycler iQ Real-Time PCR Sequence Detection System (Bio-Rad).…”

Section: Real-time Rt-pcr Analysismentioning

confidence: 99%

“…This multifunctional molecule has been used for its capacity to promote pathogenic autoimmunity; PTX was found to enhance a variety of immune responses (13)(14)(15)(16)(17)(18)(19)(20) and to be essential for induction of experimental autoimmune diseases in the CNS (13,21) and the eye (22,23). The mode of action of PTX in promoting autoimmune diseases has been attributed to several different mechanisms, including its effect on blood-tissue barriers (5,14), increased cytokine production (24,25), or selective enhancement of Th1 immune response (26).…”

mentioning

confidence: 99%

Pertussis Toxin Is Superior to TLR Ligands in Enhancing Pathogenic Autoimmunity, Targeted at a Neo-Self Antigen, by Triggering Robust Expansion of Th1 Cells and Their Cytokine Production

Fujimoto¹,

Yu²,

Shi³

et al. 2006

“…However, such mice developed EAE when housed in a conventional animal facility, or if they were administered pertussis toxin (PTx), which apparently can act as a surrogate for the environmental microbial effects (2,3). PTx is a well-known microbial component with immunoadjuvant effects and the capacity to enhance the severity of EAE in permissive strains, and renders resistant strains susceptible to disease induction (4,5). In addition to inducing CNS autoimmunity, PTx has been used widely to induce autoimmune diseases in other animal models, such as orchitis (6), uveitis (7), and inflammatory myopathy (8).…”

mentioning

confidence: 99%

Pertussis Toxin by Inducing IL-6 Promotes the Generation of IL-17-Producing CD4 Cells

Chen

Howard

Oppenheim

2007

Compelling evidence has now demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to autoimmune pathogenesis, whereas CD4+CD25+ T regulatory cells (Treg) play a major role in suppression of autoimmunity. Differentiation of proinflammatory Th17 and immunosuppressive Treg from naive CD4 cells is reciprocally related and contingent upon the cytokine environment. We and others have reported that in vivo administration of pertussis toxin (PTx) reduces the number and function of mouse Treg. In this study, we have shown that supernatants from PTx-treated mouse splenic cells, which contained IL-6 and other proinflammatory cytokines, but not PTx itself, overcame the inhibition of proliferation seen in cocultures of Treg and CD4+CD25− T effector cells. This stimulatory effect could be mimicked by individual inflammatory cytokines such as IL-1β, IL-6, and TNF-α. The combination of these cytokines synergistically stimulated the proliferation of CD4+CD25− T effector cells despite the presence of Treg with a concomitant reduction in the percentage of FoxP3+ cells and generation of IL-17-expressing cells. PTx generated Th17 cells, while inhibiting the differentiation of FoxP+ cells, from naive CD4 cells when cocultured with bone marrow-derived dendritic cells from wild-type mice, but not from IL-6−/− mice. In vivo treatment with PTx induced IL-17-secreting cells in wild-type mice, but not in IL-6−/− mice. Thus, in addition to inhibiting the development of Treg, the immunoadjuvant activity of PTx can be attributable to the generation of IL-6-dependent IL-17-producing CD4 cells.