MOG-Specific T Cells Lead to Spontaneous EAE with Multilocular B Cell Infiltration in the GF-IL23 Model

Abstract

Although IL-23 and downstream signal transduction play essential roles in neuroinflammation, the local impact of IL-23 in multiple sclerosis is still not fully understood. Our previous study revealed that the central nervous system (CNS)-restricted expression of IL-23 in a mouse model with astrocyte-specific expression of IL-23, called GF-IL23 mice, leads to spontaneous formation of infiltrates in the brain, especially in the cerebellum. To further investigate the impact of CNS-specific IL-23-expression on neuroinflammation, we studied the GF-IL23 model in mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (GF23-2D2 mice). The GF23-2D2 mice developed a chronic progressive experimental autoimmune encephalomyelitis with myelitis and ataxia without requiring additional immunization. CNS-production of IL-23 alone induced pronounced neuroinflammation in the transgenic MOG-specific T cell receptor model. The GF23-2D2 mice spontaneously developed multilocular infiltrates with a high number of B cells, demyelination and a proinflammatory cytokine milieu indicating that the interaction of encephalitogenic T cells and B cells via co-stimulatory factors seemed to be crucial.

Delimiting MOGAD as a disease entity using translational imaging

“…(3) Is there a relevant portion of MOGAD patients developing a clinically progressive disease course and do we need a disease-specific definition of neuropathological progression? and (4) Should current treatment regimens for MOGAD be reevaluated because (A) no adverse events to, e.g., Fingolimod/Natalizumab (as seen in AQP4-IgG seropositive NMOSD) were observed in MOG-IgG seropositive patients ( 217 ) and (B) many treatments have been shown to be beneficial in MOG-induced EAE that are less used in or have been unsuccessful in MS ( 160 , 423 – 425 ). In the future, translational and advanced imaging might provide answers to these questions and support the development of biomarkers for the diagnosis and monitoring of MOGAD.…”

“…The GF-IL23 model, with astrocyte-specific IL-23 secretion on a 2D2 background (most CD4+ have TCR specific for MOG 35−55 ), showed a spontaneous EAE induction with chronic disease course, clinical affection (ataxia/paraparesis), and a high proportion of B cells. A pronounced B cell accumulation and B cell follicle-like infiltrates have not been reported as such in MOGAD yet ( 160 ).…”

IL-17A facilitates entry of autoreactive T-cells and granulocytes into the CNS during EAE

“…In the context of EAE, astrocyte-speci c expression of IL-23 results in a particular accumulation of B cells and γδ T cells, demonstrating that the CNS-speci c effects of IL-23 are much more extensive than local IL-17A synthesis (Nitsch et al, 2021). Similar to IL-17A, local IL-23 induces spontaneous in ltration of MOG-speci c T-cells, interestingly also displaying high numbers of in ltrating B cells again (Nitsch et al, 2022). These results again show that IL-23 mediates its effects further upstream compared to IL-17A and that blocking IL-17A could lead to a more targeted MS therapy than blocking IL-23, which failed in a phase II clinical trial to treat patients with relapsing remitting MS (Havrdová et al, 2016;Segal et al, 2008).…”

Role of autoreactive Tc17 cells in the pathogenesis of experimental autoimmune encephalomyelitis

“…6 This is a major drawback for research on CD8 + T cells, particularly Tc17 cells, in EAE. In addition, studies on different types of EAE models-such as myelin antigen-specific TCRtransgenic mouse EAE models, 6,[61][62][63][64] spontaneous EAE models, 61,65,66 humanized mouse EAE models, 63,[67][68][69] and nonhuman primate EAE models 70-72 -might provide new insights into the pathogenesis of the disease.…”