Abstract
We previously demonstrated the importance of the RNP1 motif-bearing region 131–151 of the U1-70K spliceosomal protein in the intramolecular T-B spreading that occurs in MRL/lpr lupus mice. Here, we analyze the involvement of RNP1 motif in the development and prevention of naturally-occurring intermolecular T-B cell diversification. We found that MRL/lpr peripheral blood lymphocytes proliferated in response to peptides containing or corresponding exactly to the RNP1 motif of spliceosomal U1-70K, U1-A and hnRNP-A2 proteins. We also demonstrated that rabbit antibodies to peptide 131–151 cross-reacted with U1-70K, U1-A and hnRNP-A2 RNP1-peptides. These antibodies recognized the U1-70K and U1-A proteins, and also U1-C and SmD1 proteins, which are devoid of RNP1 motif. Repeated administration of phosphorylated peptide P140 into MRL/lpr mice abolished T-cell response to several peptides from the U1-70K, U1-A and SmD1 proteins without affecting antibody and T-cell responses to foreign (viral) antigen in treated mice challenged with infectious virus. These results emphasized the importance of the dominant RNP1 region, which seems to be central in the activation cascade of B and T cells reacting with spliceosomal RNP1+ and RNP1- spliceosomal proteins. The tolerogenic peptide P140, which is recognized by lupus patients' CD4+ T cells and known to protect MRL/lpr mice, is able to thwart emergence of intermolecular T-cell spreading in treated animals.
Highlights
Longitudinal studies of spontaneously lupus-prone inbred mouse strains and patients with systemic lupus erythematosus (SLE) consistently show an ordered appearance of typical auto-antibodies in the serum of individuals [1,2,3,4]
Owing to the well-documented accumulation of CD4-CD8- double negative (DN) T cells in peripheral blood lymphocytes (PBLs) of MRL/lpr mice (80% of DN T cells at 17 weeks of age, data not shown), we focused our measurement of specific CD4+ T cells proliferation in a window ending at week 14
U1-A peptide 35–54, which contains a part of the RNP1 motif (Figure 1a), induced proliferation of MRL/lpr PBLs that was similar in intensity to the proliferative response to P140 peptide (Figure 2a), and was at its maximum at week 12
Summary
Longitudinal studies of spontaneously lupus-prone inbred mouse strains and patients with systemic lupus erythematosus (SLE) consistently show an ordered appearance of typical auto-antibodies in the serum of individuals [1,2,3,4]. With time the fine specificity of the antibody response initially focused against one or few autoepitopes diversifies to other epitopes of the same protein (intramolecular spreading) and to other components that are physically associated within the same antigenic macromolecular particles, such as nucleosome, spliceosome, and Ro particle (intermolecular spreading). Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon is not limited to autoimmunity; it has been described in experimental and natural situations as a consequence of acute or persistent infection. Recent studies suggest that autoreactive B cells are important cellular mediators contributing to autoreactive T-cell response diversification via their functions that mediate antigen processing and presentation [6,7]
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