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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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T cell proliferative responses to rmRo60 in mice of different  haplotypes: SJL/J (• rmRo60, ○ CFA), A/J (▪ rmRo60, □ CFA), and  BALB/c (▾ rmRo60, ▿ CFA). Results are expressed as mean triplicate  ΔCPM. Data for SJL/J strain of mice are represented on the left y-axis.  Data for A/J and BALB/c mice are plotted on the right y-axis.
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Figure 4: T cell proliferative responses to rmRo60 in mice of different haplotypes: SJL/J (• rmRo60, ○ CFA), A/J (▪ rmRo60, □ CFA), and BALB/c (▾ rmRo60, ▿ CFA). Results are expressed as mean triplicate ΔCPM. Data for SJL/J strain of mice are represented on the left y-axis. Data for A/J and BALB/c mice are plotted on the right y-axis.

Mentions: Because of a sequence difference between human and mouse Ro60, the immune response generated by hRo60 immunization could be strongly mediated by these differences between the xenogeneic and autologous forms of this autoantigen. To determine whether responses to autologous Ro60 could be demonstrated, the cDNA encoding mouse Ro60 was cloned and expressed. Our sequence was in agreement with that reported by Wang et al. (14). There is 90% homology at the amino acid level between the mouse and human Ro60, and the amino acid differences scatter throughout the whole sequence. Immunization with purified rmRo60 induced T cell proliferative responses in all strains of mice (Fig. 4). The response in SJL/J mice was much higher than that in BALB/c and A/J. Proliferative responses were not seen in the animals immunized with only CFA, indicating specificity of the response.


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)

T cell proliferative responses to rmRo60 in mice of different  haplotypes: SJL/J (• rmRo60, ○ CFA), A/J (▪ rmRo60, □ CFA), and  BALB/c (▾ rmRo60, ▿ CFA). Results are expressed as mean triplicate  ΔCPM. Data for SJL/J strain of mice are represented on the left y-axis.  Data for A/J and BALB/c mice are plotted on the right y-axis.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: T cell proliferative responses to rmRo60 in mice of different haplotypes: SJL/J (• rmRo60, ○ CFA), A/J (▪ rmRo60, □ CFA), and BALB/c (▾ rmRo60, ▿ CFA). Results are expressed as mean triplicate ΔCPM. Data for SJL/J strain of mice are represented on the left y-axis. Data for A/J and BALB/c mice are plotted on the right y-axis.
Mentions: Because of a sequence difference between human and mouse Ro60, the immune response generated by hRo60 immunization could be strongly mediated by these differences between the xenogeneic and autologous forms of this autoantigen. To determine whether responses to autologous Ro60 could be demonstrated, the cDNA encoding mouse Ro60 was cloned and expressed. Our sequence was in agreement with that reported by Wang et al. (14). There is 90% homology at the amino acid level between the mouse and human Ro60, and the amino acid differences scatter throughout the whole sequence. Immunization with purified rmRo60 induced T cell proliferative responses in all strains of mice (Fig. 4). The response in SJL/J mice was much higher than that in BALB/c and A/J. Proliferative responses were not seen in the animals immunized with only CFA, indicating specificity of the response.

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