Genetic regulation of nerve avulsion-induced spinal cord inflammation.
In the animal model for multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), genetic loci correlating with incidence or severity of disease are located both within and outside of the major histocompatibility complex (MHC). Whereas polymorphisms within MHC class I and II molecules are likely to be a major determinant of MHC gene influence in rat EAE, it is still unclear how non-MHC gene regions influence disease. Genetic control of inflammation can hypothetically be either general or specific for a particular target tissue. For the latter, gene regulation of pathomechanisms in the CNS could affect reactivity of microglia or astrocytes, local cytokine/chemokine production, or even neuronal vulnerability. We have obtained strong support for this notion by observations of rat strain-dependent variation in the inflammatory response after ventral root avulsion, a model in which mainly non-antigen-specific elements of the immune system promote inflammation. A comparison of strains with similar MHC haplotypes on different backgrounds and strains with different MHC haplotypes on the same background, respectively, demonstrates that the inflammatory phenotype is regulated mainly by non-MHC genes. Interestingly, different features of the inflammatory response, such as induction of MHC class II expression, glial activation, cytokine expression, and neuronal vulnerability, varied between rat strains and were largely independent of each other. The genetic control of several basic features of inflammation in the CNS is of great relevance not only for MS/EAE, but also for several other neurological conditions with inflammatory components such as cerebrovascular and neurogenerative dieases and trauma.
Olsson
T
T
Neuroimmunology Unit, Department of Medicine, Karolinska Institute, CMM L08;04, Karolinska Hospital, S-171 76 Stockholm, Sweden. Tomas.Olsson@cmm.ki.se
Lundberg
C
C
Lidman
O
O
Piehl
F
F
D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000235:genetics; D015213:Neuroimmunomodulation; D011843:Radiculopathy / Q000235:genetics* / Q000276:immunology; D051381:Rats; D013122:Spinal Diseases / Q000235:genetics* / Q000276:immunology