Inoculation with BK virus may break immunological tolerance to histone and DNA antigens.

Abstract

BK virus particles contain histones ofhost cell origin that combine with viral DNA to form minichromosomes. Data from earlier immunoblotting experiments demonstrated that rabbits inoculated i.v. with purified infectious BK virus produced antibodies not only to the viral structural protein VP1 but also to migrating polypeptides of a molecular mass ranging from 14-16 kDa. These proteins were believed to represent certain histone classes. To examine this hypothesis, sera from five rabbits inoculated with BK virus were analyzed by ELISA for antibodies against polynucleosomes, the individual histone classes, and double-stranded DNA, as well as against antigens carried by the structural viral proteins. Antibodies against polynucleosomes and also against histones H1 and H3 were found in sera from two offive inoculated rabbits. The same sera contained antibodies reacting with double-stranded DNA, whereas no antibodies against H2A, H2B, and H4 were detected. BK virus inoculation may thus lead to a break of tolerance, resulting in autoantibody production against hihly conserved antigens that, in this context, may be regarded as "self-antigens", irrespective of the species in which they originate.

Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A).

“…Immune self-tolerance after immunization with purified intracellular self-antigens such as cytochrome c (21) and histones (22) is well established, though immunity to these molecules can be elicited under some circumstances (22)(23)(24). Our data confirm the lack of immune reactivity to purified histones in normal mice and highlight the incomplete nature of tolerance to the La and Ro polypeptides, which can initiate autoimmunity in their own right.…”

In vivo expression of a single viral DNA-binding protein generates systemic lupus erythematosus-related autoimmunity to double-stranded DNA and histones.

“…This has also been indicated by using polyoma virus BK (BKV) or its genomic DNA for induction of such antibodies. Inoculation of animals with BKV has been shown to result in selective production of anti-dsDNA and anti-histone autoantibodies in both rabbits (4,5) and mice (6). The induced anti-DNA antibodies have recently been shown to be serologically and structurally similar to antidsDNA antibodies present in SLE (7).…”

“…Although the origin of anti-dsDNA antibodies remains controversial (3), results from recent experiments have indicated that DNA itself may be an immunogen (4)(5)(6)(7)(8). This has also been indicated by using polyoma virus BK (BKV) or its genomic DNA for induction of such antibodies.…”

“…Microtiter plates (Nunc) were coated with 5 jig of calf thymus (CT) dsDNA per ml, 1 ,tg of BKV T-ag as a T-ag-maltose-binding fusion protein (23) per ml, 1 ,tg of luciferase (Sigma, St. Louis, Mo, USA) per ml, or 1 ,ug of chicken erythrocyte core histones (24) per ml in PBS. CT dsDNA, T-ag fusion protein, and chicken erythrocyte histones were prepared as described (4,23,24). Titers of the induced serum antibodies to the T-ags, DNA, and histones were determined from 2-fold dilution curves.…”

Immunoglobulin Variable-Region Structures in Immunity and Autoimmunity to DNA.

“…Complexes of native bacterial DNA and mBSA (Gilkeson et al 1989) are immunogenic; however, the antibody induced with those complexes binds poorly if at all to mammalian nDNA. Likewise, the anti-DNA antibody induced by BK virus inoculation binds to dsDNA but has specificity for dsDNA that is different from the dsDNA specificity of antoimmune anti-DNA antibody (Flaegstad et al 1988;Fredriksen et al 1990Fredriksen et al , 1991.…”