Optic Neuritis, A New Variant of Experimental Encephalomyelitis, A Durable Model for All Seasons, Now In Its Seventieth Year

One of the most enduring models of human disease now celebrates the seventieth anniversary of its publication in The Journal of Experimental Medicine . Thomas Rivers, working at the Hospital of the Rockefeller Institute for Medical Research, along with his colleagues D.H. Sprunt and G.P. Berry, submitted the article entitled, “Observations on Attempts to Produce Disseminated Encephalomyelitis in Monkeys,” on Feb. 21, 1933 (1). Rivers established this model to try to understand what caused neurological reactions to certain viral infections like smallpox and in some circumstances to vaccinations like rabies: the very first sentence of this landmark paper reads, “During convalescence from certain diseases notably smallpox, vaccinia and measles, and during or following vaccination against rabies, an occasional patient develops symptoms and signs referable to the central nervous system.” One of the most devastating complications of vaccination and viral infection is acute optic neuritis (2). In the current issue, Bettelli and colleagues have been able to establish a model of acute optic neuritis, without accompanying inflammation elsewhere in the central nervous system (3). The Optic Neuritis Model of EAE. There are multiple forms of autoimmune demyelination. About 10 to 30% of patients with multiple sclerosis have a clinical presentation that starts with an attack of optic neuritis, sometimes accompanied by other findings (4). Rates vary due to ascertainment biases: ophthalmologists may report higher rates of optic neuritis than neurologists, for the obvious reason that patients and referring physicians turn to ophthalmologists first. In some cases there is optic neuritis with no obvious evidence of inflammation outside the visual system. About a third of the time optic neuritis is a harbinger of further attacks elsewhere in the central nervous system leading to a diagnosis of multiple sclerosis. To date there have been no reproducible experimental systems where we have a model of either pure optic neuritis, optic neuritis plus inflammation elsewhere in the central nervous system, or inflammation elsewhere in the central nervous system without optic neuritis. In this issue, Bettelli and colleagues have discovered such models in a transgenic mouse with TCRs recognizing the major encephalitogenic epitope of myelin oligodendroglial glycoprotein (MOG) in H-2b mice (3). 30% of these MOG-specific TCR transgenic mice spontaneously develop pure optic neuritis. The optic nerve interestingly contains more MOG, than elsewhere in the central nervous system. If these transgenic mice are immunized with MOG35–55 plus pertussis toxin, then they develop optic neuritis plus inflammation elsewhere in the central nervous system. The role of an exogenous toxin in this model of genetically determined autoimmunity, provides a brilliant opportunity to assess the interplay of genes and environment in autoimmunity. The Topology of Immunology: Autoimmunity and Allergy Are Joined In EAE. Since its first description by Rivers the model has served as a starting point for our understanding of autoimmunity (Table I and Fig. 1). The “ A ” in the acronym EAE, mutated from experimental allergic to experimental autoimmune encephalomyelitis, sometime in the 70’s (Table II). Now the boundaries between these two seemingly opposite poles of immunity are coming together as if the contour of immunity was more spherical than flat. We are learning from studies on the EAE model that components of the allergic response are critical in the modulation of Th1 autoimmunity (5, 6). The boundary between allergy and autoimmunity can be blurred: it is possible to induce “horror autotoxicus” with anaphylaxis against certain self-antigens, exemplified by myelin peptides (5). Further, Th2 T cells are capable of inducing EAE with features that include eosinophilic inflammation, sometimes also present in MS (7). Furthermore mast cells are present in MS lesions, and PAF-R and tryptase are elevated in the spinal fluid of MS patients (6, 8). Analysis of mRNA from multiple sclerosis (MS) lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase (PGDS), histamine receptor type 1 (H1R), platelet actiAddress correspondence to L. Steinman, Department of Neurology and Neurological Sciences, Stanford University Medical Center, Beckman Center B002, Stanford, CA 94305-5429. Phone: 650-725-6401; Fax: 650-725-0627; E-mail: [email protected] on July 9, 2017 em .rupss.org D ow nladed fom