Immunogenicity and immunopathogenicity of an autoimmune epitope are potentiated by increasing MHC binding through residue substitution.
We have previously shown that in Lewis rats, peptide 273-283 (TWEGSGVLPCV) of rat interphotoreceptor retinoid-binding protein (IRBP) serves as a "surrogate" epitope for pathogenic lymphocytes sensitized against peptide 1181-1191 (SWEGVGVVPDV) of bovine IRBP. Yet, peptide 273-283 itself causes experimental autoimmune uveoretinitis (EAU) only at 200 nmol/rat, whereas peptide 1181-1191 is pathogenic even at 0.2 nmol. This difference was attributed to the higher affinity of 1181-1191 to MHC molecules. Here we demonstrate that substitution of putative MHC binding-residues of peptide 273-283 with the corresponding ones of 1181-1191 results in increased binding to MHC and in remarkably elevated immunologic capacities. Analogs of 273-283 were synthesized, in which residues 277 and 282 were substituted with one or both the corresponding amino acids of peptide 1181-1191, V and D, respectively. The main findings were: 1) substitutions drastically increased MHC affinity, namely, 273-283(V277,D282) >> 273-283(D282) >>> 273-283; 2) the substituted analogs were much more immunogenic than the native peptide, inducing cellular responses at much lower doses; 3) the analogs were more antigenic in vitro than the native peptide; 4) the analogs were exceedingly pathogenic; peptide 273-283(V277,D282) caused disease even at 0.02 nmol/rat; and 5) the analogs were superior to the native peptide in their capacity to stimulate production of IFN-gamma by sensitized lymphocytes. Thus, enhancement of affinity of an autoimmune peptide for MHC molecules increases both immunogenicity and pathogenicity.
Kozhich
A T
AT
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Caspi
R R
RR
Berzofsky
J A
JA
Gery
I
I
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry*; D001327:Autoimmune Diseases / Q000276:immunology*; D002417:Cattle; D005136:Eye Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D012177:Retinol-Binding Proteins / Q000276:immunology*; D013329:Structure-Activity Relationship; D014605:Uveitis / Q000209:etiology / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D001324:Autoantigens; D005136:Eye Proteins; D007371:Interferon-gamma; D010455:Peptides; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial