Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at ... more Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at all, in nondiseased individuals. Therefore, a tolerance mechanism must exist that prevents pathologic RF B cells from expressing Abs. Surprisingly, it has been shown that pathologic RF B cells are not tolerized by any previously established tolerance mechanism such as deletion, receptor editing, anergy, or prevention of memory establishment. How are pathologic RF cells tolerized? By simulating the RF response with a cellular automaton model immune system, we demonstrate that pathologic RFs can be tolerized by the novel mechanism of "competitive tolerance" with natural, nonpathologic RFs. We then demonstrate that competitive tolerance can be broken when a sequestered pool of expanding B cells are inappropriately subjected to chronic stimulation (as appears to occur in MRL/lpr mice and in patients with rheumatoid arthritis).
Previous studies have demonstrated that mutations at amino acid position 128 of the simian virus ... more Previous studies have demonstrated that mutations at amino acid position 128 of the simian virus 40 large T antigen can alter the subcellular localization of the antigen. A second domain in which mutations can alter localization of the nuclear antigen has been identified by mutations at amino acid positions 185, 186, and 199. Mutations in this region cause the polypeptide to accumulate in both the nucleus and cytoplasm of monkey cells. These T-antigen variants accumulate to near normal levels, but they don't bind to the simian virus 40 origin of DNA replication and are unable to mediate DNA replication. Furthermore, the altered tumor antigens can no longer transform secondary rat cells at normal efficiency, but they retain the ability to transform established mouse and rat cell lines.
The coding region for the structural and nonstructural polypeptides of the type A12 foot-and-mout... more The coding region for the structural and nonstructural polypeptides of the type A12 foot-and-mouth disease virus genome has been identified by nucleotide sequencing of cloned DNA derived from the viral RNA. In addition, 704 nucleotides in the 5' untranslated region between the polycytidylic acid tract and the probable initiation codon of the first translated gene, P16-L, have been sequenced. This region has several potential initiation codons, one of which appears to be a low-frequency alternate initiation site. The coding region encompasses 6,912 nucleotides and ends in a single termination codon, UAA, located 96 nucleotides upstream from a 3'-terminal polyadenylic acid tract. Microsequencing of radiolabeled in vivo and in vitro translation products identified the genome position of the major foot-and-mouth disease virus proteins and the cleavage sites recognized by the putative viral protease and an additional protease(s), probably of cellular origin, to generate primary a...
A comparative sequence analysis of the 5' noncoding region of a subgroup of the picornavi... more A comparative sequence analysis of the 5' noncoding region of a subgroup of the picornaviruses, including the polioviruses, coxsackie B3, and the human rhinoviruses, reveals the conservation of certain features despite the divergence of sequence. In this subgroup, for which nine complete sequences are available, two long stretches of sequence, two pyrimidine-rich regions, and 22 hairpins are conserved. Based on these results, similar secondary structures encompassing the entire 5' noncoding regions of these viruses are predicted. The fact that sequence divergence occurred only in a manner that allowed conservation of these structures implicates a biologically functional role for this region. The possible roles it may have in the picornavirus life cycle are discussed.
Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at ... more Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at all, in nondiseased individuals. Therefore, a tolerance mechanism must exist that prevents pathologic RF B cells from expressing Abs. Surprisingly, it has been shown that pathologic RF B cells are not tolerized by any previously established tolerance mechanism such as deletion, receptor editing, anergy, or prevention of memory establishment. How are pathologic RF cells tolerized? By simulating the RF response with a cellular automaton model immune system, we demonstrate that pathologic RFs can be tolerized by the novel mechanism of "competitive tolerance" with natural, nonpathologic RFs. We then demonstrate that competitive tolerance can be broken when a sequestered pool of expanding B cells are inappropriately subjected to chronic stimulation (as appears to occur in MRL/lpr mice and in patients with rheumatoid arthritis).
Previous studies have demonstrated that mutations at amino acid position 128 of the simian virus ... more Previous studies have demonstrated that mutations at amino acid position 128 of the simian virus 40 large T antigen can alter the subcellular localization of the antigen. A second domain in which mutations can alter localization of the nuclear antigen has been identified by mutations at amino acid positions 185, 186, and 199. Mutations in this region cause the polypeptide to accumulate in both the nucleus and cytoplasm of monkey cells. These T-antigen variants accumulate to near normal levels, but they don't bind to the simian virus 40 origin of DNA replication and are unable to mediate DNA replication. Furthermore, the altered tumor antigens can no longer transform secondary rat cells at normal efficiency, but they retain the ability to transform established mouse and rat cell lines.
The coding region for the structural and nonstructural polypeptides of the type A12 foot-and-mout... more The coding region for the structural and nonstructural polypeptides of the type A12 foot-and-mouth disease virus genome has been identified by nucleotide sequencing of cloned DNA derived from the viral RNA. In addition, 704 nucleotides in the 5' untranslated region between the polycytidylic acid tract and the probable initiation codon of the first translated gene, P16-L, have been sequenced. This region has several potential initiation codons, one of which appears to be a low-frequency alternate initiation site. The coding region encompasses 6,912 nucleotides and ends in a single termination codon, UAA, located 96 nucleotides upstream from a 3'-terminal polyadenylic acid tract. Microsequencing of radiolabeled in vivo and in vitro translation products identified the genome position of the major foot-and-mouth disease virus proteins and the cleavage sites recognized by the putative viral protease and an additional protease(s), probably of cellular origin, to generate primary a...
A comparative sequence analysis of the 5' noncoding region of a subgroup of the picornavi... more A comparative sequence analysis of the 5' noncoding region of a subgroup of the picornaviruses, including the polioviruses, coxsackie B3, and the human rhinoviruses, reveals the conservation of certain features despite the divergence of sequence. In this subgroup, for which nine complete sequences are available, two long stretches of sequence, two pyrimidine-rich regions, and 22 hairpins are conserved. Based on these results, similar secondary structures encompassing the entire 5' noncoding regions of these viruses are predicted. The fact that sequence divergence occurred only in a manner that allowed conservation of these structures implicates a biologically functional role for this region. The possible roles it may have in the picornavirus life cycle are discussed.
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