Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation

Abstract

We describe a double-transgenic mouse strain (opticospinal EAE [OSE] mouse) that spontaneously develops an EAE-like neurological syndrome closely resembling a human variant of multiple sclerosis, Devic disease (also called neuromyelitis optica). Like in Devic disease, the inflammatory, demyelinating lesions were located in the optic nerve and spinal cord, sparing brain and cerebellum, and the murine lesions showed histological similarity with their human correlates. OSE mice have recombination-competent immune cells expressing a TCR-alphabeta specific for myelin oligodendrocyte glycoprotein (MOG) aa 35-55 peptide in the context of I-Ab along with an Ig J region replaced by the recombined heavy chain of a monoclonal antibody binding to a conformational epitope on MOG. OSE mouse B cells bound even high dilutions of recombinant MOG, but not MOG peptide, and processed and presented it to autologous T cells. In addition, in OSE mice, but not in single-transgenic parental mice, anti-MOG antibodies were switched from IgM to IgG1.

Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis

“…Although [ 18 F]FDG PET/CT can detect metabolic changes induced by PTX that precede the onset of neurological manifestations, the relationship between these alterations and the biological mechanisms of autoimmune demyelination needs to be further investigated. The question of whether this imaging technology can be used to ''predict'' disease onset might be better answered by using recently created mouse EAE models characterized by spontaneous development of autoimmune demyelination (37,38). Moreover, we were unable to correlate glycolysis imaged with [ 18 F]FDG PET with disease severity as represented by the clinical score.…”

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

“…First, autoreactive T-cell activation is triggered by MOG-presenting B cells serving as the main source of professional APCs in this particular animal model (3). Second, T-cell responses in these mice are predominantly of a T H 1 phenotype, with a minor role of IL-17A production (3,15). And, third, inflammatory demyelinating CNS lesions are confined to the spinal cord and optic nerves, but not the brain, brainstem, or cerebellum (3,15).…”

“…Several histological MS subtypes have been described with regard to lesion distribution and cellular composition (2). The reasons underlying distinct lesion development at different anatomical sites still remain however largely elusive: Some authors have proposed that the nature and expression pattern of the target autoantigen might play a role (3,4). Others have observed an influence of the HLA complex and its role in shaping antigen presentation, thus suggesting that T-cell antigen specificity might impact the location of inflammation (5).…”

“…However, these models are of limited value for studying the very first steps of disease initiation and lesion development, mainly due to their dependence on microbial adjuvants for artificial breakdown of tolerance and promotion of BBB disruption (12)(13)(14). During the last years, novel models of spontaneous CNS autoimmunity have been developed by crossing myelin-specific T-cell receptor (TCR) transgenic mice and myelin-specific Ig heavy chain knock-in mice (3,15). The offspring of those mice are characterized by spontaneous development of a severe form of EAE.…”

Demyelinating Myelin Oligodendrocyte Glycoprotein-Specific Autoantibody Response Is Focused on One Dominant Conformational Epitope Region in Rodents

“…This leads to the obvious question of why then is the epitope specificity of conformation-dependent MOG ex -specific Abs focused on one main immunogenic region of the protein? Several observations suggest that this may be due to the deletion of certain epitope specificities from the Ab repertoire by components of self proteins that mimic the corresponding MOG epitopes (58,59).…”