title: The H2-Ab gene influences the severity of experimental allergic encephalomyelitis induced by proteolipoprotein peptide 103-116.
abstract: Immunization of H2(p) and H2(q) congenic C3H mouse strains with the PLP 103-116 peptide elicited two distinct experimental allergic encephalomyelitis (EAE) disease courses. C3H.Q (H2(q)) mice developed an acute-phase disease with classical ascending paralytic signs whereas C3H.NB (H2(p)) developed a highly variable disease course with symptoms originating from CNS above the spinal chord. C3H.Q lacks functional H2-E molecules and share H2-Aalpha with C3H.NB. To examine if the differences found at positions 85, 86, 88, and 89 in the Abeta-chains account for disease susceptibility, H2(q) mice were made transgenic with the Ab(p) gene. The Ab(p)-transgenic mice on the C3H.Q background developed a more severe disease course, demonstrating the importance of class II. However, the onset was not affected and the disease showed a classical ascending paralysis similar to the C3H.Q suggesting that the observed brain symptoms were related to nonclass II genes. Inhibition studies performed on affinity purified MHC class II molecules indicated that the PLP 103-116 peptide bound to A(p) with slightly higher affinity than to A(q). Both A(q) and A(p) formed long-lived stable complexes (t(1/2)>24 h) with the PLP 103-116 peptide, but a higher amount of the peptide was loaded on to A(p) compared with A(q). An F2 gene segregation experiment, in which the low PLP 103-116 binding A(r) molecule and the high binding A(p) molecule could be compared for the influence on the disease susceptibility, indicated a role for both peptide binding affinity and non-MHC genes. Based on our results, we conclude that the H2-Ab gene controls severity of EAE but not necessarily the onset or type of disease course and that affinity of the disease-promoting peptide for the class II molecule is a critical pathogenic factor.
authors.affiliation: Section for Medical Inflammation Research, Lund University, Sölvegatan 21, l11 BMC, S-223 62, Lund, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Kjellén
authors.forename: L
authors.initials: L
authors.lastname: Jansson
authors.forename: M
authors.initials: M
authors.lastname: Vestberg
authors.forename: A
authors.initials: A
authors.lastname: Andersson
authors.forename: R
authors.initials: R
authors.lastname: Mattsson
authors.forename: R
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000276:immunology; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D005802:Genes, MHC Class II / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000494:pharmacology*; D010243:Paralysis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D019683:Penetrance; D010446:Peptide Fragments / Q000494:pharmacology*; D010641:Phenotype
chemical_list: D000949:Histocompatibility Antigens Class II; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments