Molecular mimicry between insulin and retroviral antigen p73. Development of cross-reactive autoantibodies in sera of NOD and C57BL/KsJ db/db mice.
Enzyme-linked immunosorbent assay (ELISA) was used to study temporal development of murine autoantibodies against insulin and both type C and intracisternal type A retroviral antigens. The nonobese diabetic (NOD) mouse, a model for autoimmune, insulin-dependent diabetes, was compared with a related, but diabetes-resistant, strain, nonobese normal (NON). Similarly, C57BL/KsJ db/db mice (insulin-resistant model of insulin-dependent diabetes and obesity) were compared with diabetes-resistant C57BL/6 db/db mice. NOD mice developed much higher autoantibody titers than did NON mice. Whereas type C autoantibodies in NOD developed to peak titer shortly after mice were weaned, autoantibodies against insulin and p73 (group-specific antigen of the intracisternal type A particle) did not develop until shortly before, or concomitant with, the development of hyperglycemia. Two NOD mice not developing hyperglycemia during the 40-wk study period were distinguished from the mice developing diabetes by a delayed onset of insulin (but not p73) autoantibodies. Our findings suggest that in NOD mice, the appearance of insulin and p73 autoantibodies signifies that extensive underlying necrosis of beta-cells occurred. C57BL/KsJ db/db mice (with extensive beta-cell necrosis and early hyperglycemia) developed much higher autoantibody titers to insulin and p73 than did the diabetes-resistant C57BL/6 db/db mice. However, the presence of autoantibodies in normoglycemic C57BL/KsJ +/db controls demonstrated that elevated autoantibody titers alone were insufficient to produce diabetes in this model. Absorption studies indicated that autoantibodies against p73 recognized a common epitope on insulin and IgE-binding factor. The potential significance of this molecular mimicry is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
Serreze
D V
DV
Jackson Laboratory, Bar Harbor, ME 04609.
Leiter
E H
EH
Kuff
E L
EL
Jardieu
P
P
Ishizaka
K
K
D000375:Aging; D000818:Animals; D000917:Antibody Formation; D000956:Antigens, Viral / Q000276:immunology*; D001323:Autoantibodies / Q000032:analysis*; D003429:Cross Reactions; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015683:Gene Products, gag; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007328:Insulin / Q000276:immunology*; D008222:Lymphokines / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D029584:Prostatic Secretory Proteins; D012191:Retroviridae Proteins / Q000276:immunology*
D000956:Antigens, Viral; D001323:Autoantibodies; D015683:Gene Products, gag; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007328:Insulin; D008222:Lymphokines; D029584:Prostatic Secretory Proteins; D012191:Retroviridae Proteins; C043076:beta-microseminoprotein; C013059:immunoglobulin-binding factors