Genetics of rat neuroinflammation

The definition of genes regulating the pathogenetic pathways of autoimmune neuroinflammation, may provide targets for new therapeutic strategies. This is not easily accomplished in human disease. Such genetic dissection can m ore readily be done by the use of inbred rodent strains. With these, geneti c heterogeneity is avoided and variation in the environmental influences is minimized. Close mimicking of the human disease characteristics is desirab le in such endeavors. Chronic relapsing experimental autoimmune encephalomy elitis (EAE) with MS-like histopathology is achieved after immunization of certain rat strains with myelin oligodendrocyte glycoprotein (MOG) or spina l cord homogenate. The major histocompatibility complex (MHC) regulate the ease by which the environmental trigger in the form of immunisation induces disease. Use of intra-MHC recombinant strains demonstrated major influence s from the MHC class II genome region, but additional influences from both the MHC class I and III regions. These findings now provide a basis for stu dies of the mechanisms for MHC-controlled autoimmune pathogenicity leading to MS-like disease. Gene mapping of F2 crosses between susceptible and resi stant rat strains demonstrated nine genome regions outside the MHC which re gulate different phenotypes of rat EAE. Many of these co-localize with geno me regions regulating other organ-specific disease such experimental arthri tis, suggesting a sharing of disease pathways. Further finemapping can lead to the exact identification of disease regulating genes. Interestingly, we have also demonstrated a non-MHC gene control of the inflammatory response , in the form of glial cell activation, and neuronal degeneration, subseque nt to anterior nerve root avulsion in rats. The genetic dissection of these influences may unravel pathways controlling CNS vulnerability. (C) 2000 El sevier Science B.V. All rights reserved.