Autoimmune diseases can affect most organs of the body including liver, heart, the endocrine system, the musculoskeletal apparatus, and the central nervous system (CNS). They commonly start off at a young age and then last throughout life, often resulting in severe disability. The factors that trigger the onset, modulate the course, and determine the clinical character of autoimmune diseases have remained obscure, a deficit of knowledge which sets limits to the design of specific and efficient therapies.
Yet there is increasing evidence that organ-specific autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes mellitus, and multiple sclerosis (MS), are the result of a pathogenic interaction of autoimmune T and B cells. There is substantial information on the role of T cells in organ-specific autoimmunity. Some act as effector cells attacking self-tissues, either directly or via recruiting accessory cells like macrophages. Other T cells regulate the time course of the response and still others provide help to autoantibody-producing B cells. The contribution of autoimmune B cells to the inflammatory pathogenesis seems to be complex as well. Beyond producing humoral autoantibodies, B cells serve as APCs activating pathogenic T cells, and, through their capacity of releasing cytokines, B cells are involved in shaping local microenvironments favorable to evolving cellular autoimmune responses.
Deciphering the interactions between T and B cells in the spontaneous development of organ-specific autoimmune responses requires suitable animal models. Naturally occurring models are available for type 1 diabetes mellitus and systemic lupus erythematosus but not for autoimmunity in the CNS (1
). Recently, we and others described a double-transgenic mouse model, which simulates opticospinal MS (OSMS) remarkably well, a variant of which is also known as Devic's disease (2
). These mice, termed opticospinal experimental autoimmune encephalomyelitis (EAE [OSE]) mice, express myelin oligodendrocyte glycoprotein (MOG)–specific receptors on T and B cells and spontaneously develop demyelinating inflammatory disease at frequencies >50%. Like in human OSMS (4
), the lesions in affected mice are restricted to optic nerve and spinal cord, and, in most cases, the disease takes a chronic progressive course without remissions and marked relapses. It should, however, be noted that the type of MS that most prevalently affects Caucasian populations differs fundamentally from OSMS (5
). Typically, MS starts out with a relapsing-remitting (RR) course, where disease episodes may completely resolve only to be followed by a subsequent relapse. In this disease variant, the pathogenic lesions, demyelinating plaques, may be located throughout the CNS, thus causing the notoriously varied neurological defect patterns.
In this paper, we describe a new transgenic mouse model that spontaneously develops RR-EAE and, thus, recapitulates the “Western” variant of MS. Furthermore, and most importantly, we found that in these mice transgenic autoimmune T cells expand autoimmune B cells from the endogenous immune repertoire and guide them to produce antibodies against conformational epitopes of the MOG protein, which, together with complement, may initiate the destruction of MOG-expressing target cells.