Journal of Autoimmunity (1992) 5 (Supplement A), 11-26 The Forces Driving Autoimmune Disease Ivan M. Roitt, Patricia R. Hutchings, Kim I. Dawe, Nazira Sumar, Katherine B. Bodman and Anne Cooke* Dept. of Immunology, University College & Middlesex School of Medicine, London, and *Dept. of Pathology, University of Cambridge, UK There are two classes of autoimmune disease, organ-specific and non- organ specific or systemic. That cells producing autoantibodies are selected by antigen is strongly suggested by the presence of mutations and high affinity antibody. T-cells are pivotal in all forms of autoimmunity as evidenced by the therapeutic benefit of anti-T-cell monoclonals such as anti-CD4, and the frequent development of high affinity IgG autoanti- bodies. The production of anergic T-cells by the use of non-depleting anti-CD4 in the presence of antigen is discussed with particular reference to its potential for immunological intervention in autoimmune disease. It is possible to identify T-cell epitopes in organ-specific autoimmunity using pathogenic T-cell clones or hybridomas to identify the peptide sequences which are reactive. Antigen-specific therapy may ultimately be based on such peptide epitopes. The specificity of the T-cells in systemic autoimmunity is still obscure, but there is some evidence that reactivity with certain germ-line idiotypes can lead to the development of systemic autoimmunity. The possibility of stimulating Blcells specific for auto- antigens such as DNA becomes feasible if a complex of antibody and DNA is taken up by these specific B-cells and processed idiotype is presented to T-helpers specific for those idiotype epitopes. Evidence is presented that there may be pre-existing defects in the target organ in certain organ-specific disorders, and the evidence for a glycosylation defect in the IgG in patients with rheumatoid arthritis is explored. It is noted that the spouses ofprobands with rheumatoid arthritis also tend to have this glycosylation defect and this raises the possibility of an effect due to an environmental factor, such as a microbial infection. Molecular mimicry of autoantigens by microbes can stimulate auto- reactive cells by their cross-reactivity. It is emphasized that cross-reaction which gives rise to the priming ofautoreactive T-cells could give rise to the establishment of a chronic autoimmune state. In animals with normal regulatory immune systems, such induced autoimmunity is ultimately corrected and it is only in animals where there are defects in regulation, Correspondence to: Professor I. M. Roitt, Dept. of Immunology, University College & Middlesex School of Medicine, Arthur Stanley House, 40-50 Tottenham Street, London W1P 9PG, UK. 11 0896-8411/92/0A0011 + 16 $03.00/0 © 1992 Academic Press Limited