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Immune responses to Ro60 and its peptides in mice. I. The nature of the immunogen and endogenous autoantigen determine the specificities of the induced autoantibodies.

Deshmukh US, Lewis JE, Gaskin F, Kannapell CC, Waters ST, Lou YH, Tung KS, Fu SM - J. Exp. Med. (1999)

Bottom Line: With human Ro60316-335 as the immunogen, additional autoantibodies reactive with the Golgi complex were found.These results show that both the nature of the immunogen and the immunogenicity of the related endogenous antigen are important in determining the specificities of the autoantibodies generated.They have significant implications for proposed mechanisms on the generation of complex patterns of autoantibodies to a diverse group of autoantigens in SLE patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

ABSTRACT
Anti-Ro60 autoantibodies are found in a variety of autoimmune disorders including systemic lupus erythematosus (SLE), Sjögren's syndrome, primary biliary cirrhosis, and active hepatitis. They are the most prevalent autoantibodies in normal individuals and in asymptomatic mothers of infants afflicted with neonatal lupus. In the present study, immune responses to recombinant human Ro60 (rhRo60) and recombinant mouse Ro60 (rmRo60) and selected Ro60 peptides in non-SLE-prone mice were investigated. Multiple T and B cell epitopes were identified in Ro60. Immunizations with either xenogeneic or autologous Ro60 induced autoantibodies to a diverse group of autoantigens. In addition to La and Ro52, proteins in the small nuclear ribonucleoprotein (snRNP) particles such as SmA, SmB, SmD, and 70-kD U1-RNP were unexpectedly identified as targeted antigens. In the studies involving synthetic Ro60 peptides, both human and mouse Ro60316-335 peptides, which differ in three amino acids, were found to contain dominant cross-reactive T cell determinants. Immunizations with these peptides induced autoantibodies to Ro60, La, SmD, and 70-kD U1-RNP without autoantibodies to Ro52, SmA, or SmB. With human Ro60316-335 as the immunogen, additional autoantibodies reactive with the Golgi complex were found. In contrast to the immunodominance of both human and mouse Ro60316-335 peptides, the T cell determinant in human Ro60441-465 was dominant, whereas that in the mouse peptide was cryptic. Immunization with human Ro60441-465 induced primarily anti-peptide Abs. Mouse Ro60441-465 failed to induce an antibody response. These results show that both the nature of the immunogen and the immunogenicity of the related endogenous antigen are important in determining the specificities of the autoantibodies generated. They have significant implications for proposed mechanisms on the generation of complex patterns of autoantibodies to a diverse group of autoantigens in SLE patients.

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Recall of in vitro  LNC proliferative responses by  rmRo60 (open bars) and peptides,  mRo60316–335 (cross bars) and  mRo60441–465 (hatched bars), in mice  immunized with rmRo60. Results  are expressed as mean triplicate SI.  And an SI > 2.0 was considered  positive.
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Figure 13: Recall of in vitro LNC proliferative responses by rmRo60 (open bars) and peptides, mRo60316–335 (cross bars) and mRo60441–465 (hatched bars), in mice immunized with rmRo60. Results are expressed as mean triplicate SI. And an SI > 2.0 was considered positive.

Mentions: The possibility that the difference observed between the immune responses to the two immunodominant T cell peptides on hRo60 might be due to lack of presentation of the autologous mRo60441–465 was suggestive from data shown in Fig. 5 A. Peptide mRo60311–330 (overlaps hRo60316–335) was able to recall the LNC proliferative response in mice immunized with rmRo60, whereas peptides mRo60441–430 and mRo60451–470 failed to do so. This was further explored. Peptides mRo60316–335 and mRo60441–465 were made and used to recall the LNC proliferative responses in mice immunized with rmRo60. Fig. 13 shows representative results from one of three experiments. While peptide mRo60316–335 could recall the proliferative response, mRo60441–465 could not, indicating that the T cell epitope in the latter peptide is cryptic.


Immune responses to Ro60 and its peptides in mice. I. The nature of the immunogen and endogenous autoantigen determine the specificities of the induced autoantibodies.

Deshmukh US, Lewis JE, Gaskin F, Kannapell CC, Waters ST, Lou YH, Tung KS, Fu SM - J. Exp. Med. (1999)

Recall of in vitro  LNC proliferative responses by  rmRo60 (open bars) and peptides,  mRo60316–335 (cross bars) and  mRo60441–465 (hatched bars), in mice  immunized with rmRo60. Results  are expressed as mean triplicate SI.  And an SI > 2.0 was considered  positive.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192918&req=5

Figure 13: Recall of in vitro LNC proliferative responses by rmRo60 (open bars) and peptides, mRo60316–335 (cross bars) and mRo60441–465 (hatched bars), in mice immunized with rmRo60. Results are expressed as mean triplicate SI. And an SI > 2.0 was considered positive.
Mentions: The possibility that the difference observed between the immune responses to the two immunodominant T cell peptides on hRo60 might be due to lack of presentation of the autologous mRo60441–465 was suggestive from data shown in Fig. 5 A. Peptide mRo60311–330 (overlaps hRo60316–335) was able to recall the LNC proliferative response in mice immunized with rmRo60, whereas peptides mRo60441–430 and mRo60451–470 failed to do so. This was further explored. Peptides mRo60316–335 and mRo60441–465 were made and used to recall the LNC proliferative responses in mice immunized with rmRo60. Fig. 13 shows representative results from one of three experiments. While peptide mRo60316–335 could recall the proliferative response, mRo60441–465 could not, indicating that the T cell epitope in the latter peptide is cryptic.

Bottom Line: With human Ro60316-335 as the immunogen, additional autoantibodies reactive with the Golgi complex were found.These results show that both the nature of the immunogen and the immunogenicity of the related endogenous antigen are important in determining the specificities of the autoantibodies generated.They have significant implications for proposed mechanisms on the generation of complex patterns of autoantibodies to a diverse group of autoantigens in SLE patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

ABSTRACT
Anti-Ro60 autoantibodies are found in a variety of autoimmune disorders including systemic lupus erythematosus (SLE), Sjögren's syndrome, primary biliary cirrhosis, and active hepatitis. They are the most prevalent autoantibodies in normal individuals and in asymptomatic mothers of infants afflicted with neonatal lupus. In the present study, immune responses to recombinant human Ro60 (rhRo60) and recombinant mouse Ro60 (rmRo60) and selected Ro60 peptides in non-SLE-prone mice were investigated. Multiple T and B cell epitopes were identified in Ro60. Immunizations with either xenogeneic or autologous Ro60 induced autoantibodies to a diverse group of autoantigens. In addition to La and Ro52, proteins in the small nuclear ribonucleoprotein (snRNP) particles such as SmA, SmB, SmD, and 70-kD U1-RNP were unexpectedly identified as targeted antigens. In the studies involving synthetic Ro60 peptides, both human and mouse Ro60316-335 peptides, which differ in three amino acids, were found to contain dominant cross-reactive T cell determinants. Immunizations with these peptides induced autoantibodies to Ro60, La, SmD, and 70-kD U1-RNP without autoantibodies to Ro52, SmA, or SmB. With human Ro60316-335 as the immunogen, additional autoantibodies reactive with the Golgi complex were found. In contrast to the immunodominance of both human and mouse Ro60316-335 peptides, the T cell determinant in human Ro60441-465 was dominant, whereas that in the mouse peptide was cryptic. Immunization with human Ro60441-465 induced primarily anti-peptide Abs. Mouse Ro60441-465 failed to induce an antibody response. These results show that both the nature of the immunogen and the immunogenicity of the related endogenous antigen are important in determining the specificities of the autoantibodies generated. They have significant implications for proposed mechanisms on the generation of complex patterns of autoantibodies to a diverse group of autoantigens in SLE patients.

Show MeSH
Related in: MedlinePlus