Pertussis Toxin Inhibits Encephalitogenic T-Cell Infiltration and Promotes a B-Cell-Driven Disease during Th17-EAE

Abstract

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX’s effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.

The Plasticity of Immune Cell Response Complicates Dissecting the Underlying Pathology of Multiple Sclerosis

“…In pertussis toxin (PTX)-induced Th17-EAE, B cell insufficiency reduces paralysis in mice, indicating that B cells are important for inducing demyelination. PTX also promotes an inflammatory B cell phenotype in the periphery, allowing pathogenic B cells to accumulate in the CNS, where they are associated with the duration of disease in animals with milder EAE [ 79 ].…”

“…B cells Located in the meninges and in the large perivascular spaces around the cerebral ventricles. While CD20 + B lymphocytes predominate and may have pro-inflammatory properties in early and active lesions, the number of plasma cells with potential antiinflammatory properties increases in later stages [67][68][69][70][71][72][73][74][75][76][77][78][79][80] Macrophages Major effectors of inflammation and demyelination in both MS and EAE found in MS lesions [7,48,58,[81][82][83][84][85][86][87][88][89] Myeloid Aberrant myeloid function is often observed in MS plaques in the CNS [48,90,91] Microglia/macrophages Shift in M1/M2 balance is important for disease pregression.…”

Non-primate animal models for pertussis: back to the drawing board?

“…pertussis adjuvant effects in animal models was more broadly proposed (Morse 1976 ). Pertussis toxin particularly acts as a co-adjuvant in experimental autoimmune encephalomyelitis (Maria et al 2021 ).…”