Epitope spreading in systemic lupus erythematosus: Identification of triggering peptide sequences

Monneaux, Fanny; Muller, Sylviane

doi:10.1002/art.10263

Cited by 93 publications

(87 citation statements)

References 79 publications

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“…This pathway has been invoked in other studies of epitope spreading using synthetic peptides from SmB, La, and Ro60 for immunization (reviewed in Ref. 10). In all these studies, immunization with the peptide epitope induced autoantibodies to the protein from which the peptide was derived, some of it through intramolecular epitope spreading.…”

Section: Discussionmentioning

confidence: 92%

“…Based on the serological analyses of patient sera and mouse models, different snRNP proteins have been proposed to be the Ags responsible for initiating the epitope spreading cascade (7,9). Experimental model systems, using immunization of mice and rabbits with recombinant RNP or synthetic peptides, have provided evidence for this hypothesis (10). Despite these observations, molecular mechanisms for intermolecular epitope spreading have not been clearly defined (11,12).…”

mentioning

confidence: 99%

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A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

Deshmukh

Bagavant

Sim

et al. 2007

The Journal of Immunology

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Autoantibody response against the small nuclear ribonucleoprotein (snRNP) complex is a characteristic feature of systemic lupus erythematosus. The current investigation was undertaken to determine whether activation of SmD-reactive T cells by synthetic peptides harboring T cell epitopes can initiate a B cell epitope spreading cascade within the snRNP complex. T cell epitopes on SmD were mapped in A/J mice and were localized to three regions on SmD, within aa 26–55, 52–69, and 86–115. Immunization with synthetic peptides SmD31–45, SmD52–66, and SmD91–110 induced T and B cell responses to the peptides, with SmD31–45 inducing the strongest response. However, only SmD52–66 immunization induced T cells capable of reacting with SmD. Analysis of sera by immunoprecipitation assays showed that intermolecular B cell epitope spreading to U1RNA-associated A ribonucleoprotein and SmB was consistently observed only in the SmD52–66-immunized mice. Surprisingly, in these mice, Ab responses to SmD were at low levels and transient. In addition, the sera did not react with other regions on SmD, indicating a lack of intramolecular B cell epitope spreading within SmD. Our study demonstrates that T cell responses to dominant epitope on a protein within a multiantigenic complex are capable of inducing B cell responses to other proteins within the complex. This effect can happen without generating a good Ab response to the protein from which the T epitope was derived. Thus caution must be taken in the identification of Ags responsible for initiating autoimmune responses based solely on serological analysis of patients and animals with systemic autoimmune disorders.

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

Deshmukh

Bagavant

Sim

et al. 2007

The Journal of Immunology

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“…21,34,35 Intramolecular B cell epitope spreading may also present a clinical correlate for pathogenesis in human autoimmune disease. 24,25,36 The process may be most relevant to disease when autoAb have a direct role in mediating tissue injury or cytotoxicity, as is the case in AHN; however, it could also have a role in amplifying cellmediated immunity through unique antigen-processing capacity of B lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Intramolecular Epitope Spreading in Heymann Nephritis

Shah¹,

Tramontano²,

Makker³

2007

Journal of the American Society of Nephrology

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Immunization with megalin induces active Heymann nephritis, which reproduces features of human idiopathic membranous glomerulonephritis. Megalin is a complex immunological target with four discrete ligand-binding domains (LBDs) that may contain epitopes to which pathogenic autoantibodies are directed. Recently, a 236-residue N-terminal fragment, termed "L6," that spans the first LBD was shown to induce autoantibodies and severe disease. We used this model to examine epitope-specific contributions to pathogenesis. Sera obtained from rats 4 weeks after immunization with L6 demonstrated reactivity only with the L6 fragment on Western blot, whereas sera obtained after 8 weeks demonstrated reactivity with all four recombinant fragments of interest (L6 and LBDs II, III, and IV). We demonstrated that the L6 immunogen does not contain the epitopes responsible for the reactivity to the LBD fragments. Therefore, the appearance of antibodies directed at LBD fragments several weeks after the primary immune response suggests intramolecular epitope spreading. In vivo, we observed a temporal association between increased proteinuria and the appearance of antibodies to LBD fragments. These data implicate B cell epitope spreading in antibody-mediated pathogenesis of active Heymann nephritis, a model that should prove valuable for further study of autoimmune dysregulation.

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“…Diversification and augmentation of the autoimmune response is believed to occur via epitope spreading, a process whereby distinct and non-cross-reactive epitopes are created (9,10). Two types of epitope spreading have been described: intramolecular spreading, in which the autoimmune response spreads in epitopes within the same protein, and intermolecular spreading, which also involves other protein components physically associated within the same antigenic complex, such as a spliceosome and Ro/La particles.…”

mentioning

confidence: 99%

RNA Recognition Motif (RRM) of La/SSB: The Bridge for Interparticle Spreading of Autoimmune Response to U1-RNP

Routsias

Kyriakidis

Latreille

et al. 2009

Mol Med

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Epitope spreading in systemic lupus erythematosus: Identification of triggering peptide sequences

Cited by 93 publications

References 79 publications

A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading

Intramolecular Epitope Spreading in Heymann Nephritis

RNA Recognition Motif (RRM) of La/SSB: The Bridge for Interparticle Spreading of Autoimmune Response to U1-RNP

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