DETERMINANT SPREADING - LESSONS FROM ANIMAL-MODELS AND HUMAN-DISEASE

Spreading of the immune response is a common theme in organ-specific a nd systemic autoimmune diseases. We evaluated whether some of the mixe d antinuclear antibody patterns characteristic of systemic autoimmunit y might be the result of determinant spreading from a single initiatin g event. Immunisation of healthy mice with individual protein componen ts of the La/Ro ribonucleoprotein (RNP) targeted in systemic lupus ery thematosus and primary Sjogren's syndrome induced autoantibodies recog nising Ro60 (SS-A), Ro52 (SS-A) and La (SS-B) and in some cases the mo lecular chaperones calreticulin and Grp78. The endogenous antigen(s) d riving determinant spreading might be derived from physiological apopt osis which could explain the involvement of some chaperone proteins in the autoimmune response. Diversified anti-La/Ro antibody responses we re initiated by challenge with a single subdominant T epitope of La ev en though some self epitopes of La were efficiently tolerised. The pat tern of autoantibody responses in primary Sjogren's syndrome was stron gly influenced by HLA class II phenotype which we speculate controls a ctivation of T cells recognising defined peptides from the La/Ro RNP I n this way, HLA class II alleles may be critical in influencing initia tion and spreading of systemic autoimmune reactions. Molecular mimicry of such determinants by exogenous agents might readily initiate sprea ding of an autoimmune response in genetically susceptible hosts.