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 more readily be done by the use of inbred rodent strains. With these, genetic heterogeneity is avoided and variation in the environmental influences is minimized. Close mimicking of the human disease characteristics is desirable in such endeavors. Chronic relapsing experimental autoimmune encephalomyelitis (EAE) with MS-like histopathology is achieved after immunization of certain rat strains with myelin oligodendrocyte glycoprotein (MOG) or spinal 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 influences 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 studies of the mechanisms for MHC-controlled autoimmune pathogenicity leading to MS-like disease. Gene mapping of F2 crosses between susceptible and resistant rat strains demonstrated nine genome regions outside the MHC which regulate different phenotypes of rat EAE. Many of these co-localize with genome regions regulating other organ-specific disease such experimental arthritis, 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, subsequent to anterior nerve root avulsion in rats. The genetic dissection of these influences may unravel pathways controlling CNS vulnerability.
Olsson
T
T
Neuroimmunology Unit, Department of Medicine, Karolinska Institute, Center for Molecular Medicine L8:04, Karolinska Hospital, 171 76, Stockholm, Sweden. tomas.olsson@cmm.ki.se
Dahlman
I
I
Wallström
E
E
Weissert
R
R
Piehl
F
F
D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains