Definition of Autoimmune Disease Physiology Versus Pathology

Identification of genes controlling autoimmune diseases requires that we have a clear definition of what an autoimmune disease is. Over the years, this definition has been shifting and also varies depending on whether it is seen from a clinical point of view or from a basic science point of view.

From a clinical point of view, these diseases are inflammatory diseases of unknown origin, which cannot be explained by any obvious cause such as infection or allergen exposure. To strengthen the classification they should be chronic, i.e. they should last for a period that exceeds a normal acute inflammatory phase of usually 3-4 weeks. The occurrence of autoantibodies targeting some relevant tissue antigen is often, but not always, included as an additional criteria . However, the pathogenic relevance of such antibodies is not always clear. These definitions have led us to classify a number of commonly occurring chronic diseases as classical autoimmune, for example MS, RA, T1D, and systemic lupus erythematosus (SLE). Aborderline group is made up of inflammatory diseases with a possible but not proven infectious cause such as spondyloarthropathies and inflammatory bowel diseases. Another borderline group comprises diseases in which an inflammatory component has emerged as one of the major driving factors, for example, psoriasis and atherosclerosis. It is obvious that from this perspective autoimmune diseases compose a highly heterogeneous group, even within each disease classification, as there are not yet means to link diagnosis with disease mechanisms. Rather we are bound to description of the more obvious pathologic end-result, such as the lack of insulin in T1D or the neurological deficit in MS.

From the basic science standpoint, autoimmune recognition is often the phenomenon of interest for definition of autoimmune diseases. It stems from a tradition of viewing autoimmunity as forbidden self or "horror autotoxi-cus," as Burnett described it. The view has been broadened over the years with inclusion of innate immune recognition, more colorfully expressed as "danger," as a factor not only in combat of infections but also in playing a role in the development of autoimmunity. The immune recognition is seen as the essential key for understanding both regulatory/suppressor and helper/effector mechanisms. Autoimmunity is defined through autoimmune recognition by lymphocytes, an event that is physiologic but results in an autoimmune disease when such lymphocytes are pathogenic. Proof for autoimmunity can be tested in animal models but not in humans, which has led to the development of animal models for autoimmune diseases. The models are mainly of two types: one that is induced and one where the disease develops spontaneously. Of the induced models, many are induced through immunization with an autoantigen, and the pathogenicity of autoreactive lymphocytes can be clearly shown. In general, only the acute phase of the first inflammatory response is studied. Examples of induced models are collagen-induced arthritis (CIA) as a model for RA [1, 2] and experimental autoimmune encephalomyelitis (EAE) as a model for MS [3]. Other models develop "spontaneously" due to genetic aberrations. In the spontaneous models, as in humans, the pathogenicity of specific autoimmune recognition is often difficult to document and the disease course is often chronic. But in contrast to human disease, these models are often monogenic, highly penetrant and less influenced by environmental factors. Examples of spontaneous models are the transgenic models for arthritis (TNFa [4], IL1Ra deficiency [5], anti-glucose-6-phosphoisomeras T cell receptor [6]), various spontaneous lupus models (NZB xNZW, MRL/lpr, BXSB) [7] and diabetes in the NOD mouse [8].

Clearly, discrepancies between results from studies of autoimmune diseases between human and mouse are not only influenced by the species differences but are in most cases due to different disease definitions and methods. A better definition of the human diseases and also more appropriate, well-characterized animal models are therefore needed.

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