The H2-Ab gene influences the severity of experimental allergic encephalomyelitis induced by proteolipoprotein peptide 103-116

Immunization of H2(P) and H2(q) congenic OH 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 w ith 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-A alpha w ith C3H.NB. To examine if the differences found at positions 85, 86, 88, an d 89 in the AD-chains account for disease susceptibility, H2(q) mice were m ade transgenic with the Ab(P) gene. The Ab(P)-transgenic mice on the C3H.Q background developed a more severe disease course, demonstrating the import ance of class IL However, the onset was not affected and the disease showed a classical ascending paralysis similar to the C3H.Q suggesting that the o bserved brain symptoms were related to nonclass II genes. Inhibition studie s 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) wi th the PLP 103-116 peptide, but a higher amount of the peptide was loaded o n to A(P) compared with A(q). An F2 gene segregation experiment, in which t he 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, indicat ed 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 di sease-promoting peptide for the class II molecule is a critical pathogenic factor. (C) 2001 Elsevier Science BN. All rights reserved.