Induction of Pathogenic Anti-dsDNA Antibodies Is Controlled on the Level of B Cells in a Non-Lupus Prone Mouse Strain

Abstract

The SmD1(83-119) peptide is a main target of autoantibodies and T cells in human and murine lupus, but its role in autoimmunity induction remains elusive. Therefore, female Balb/c mice and (NZW x Balb/c)F1 [CWF1] mice with identical MHC haplotype as lupus prone NZB/W mice were immunized with SmD1(83-119). Immunizations of CWF1 mice with SmD1(83-119), but not with the controls (irrelevant peptide, HEL peptide, or saline), induced anti-SmD1(83-119) and anti-dsDNA antibodies and proteinuria not present in Balb/c mice. DsDNA-specific plasma cell induction after SmD1(83-119) immunizations was confirmed by ELISPOT assays showing that the generation of dsDNA-specific antibody forming cells (AFC) was mainly driven by increased T-cell help. T-cell help for the generation of dsDNA-specific AFC was also present in saline-treated CWF1 mice but was controlled on the levels of B cells preventing autoimmunity.

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

“…These data suggest that the T and B cell responses to SmD are strain dependent and some autoantibodies might not be induced in normal mice (20). The lack of epitope spreading in BALB/c mice immunized with SmD in our model system is supported by recent findings of Langnickel et al (21). BALB/c mice immunized with peptide SmD1 83-119 did not generate anti-SmD or anti-dsDNA autoantibodies.…”

Anti-Nuclear Antibody Production and Autoimmunity in Transgenic Mice That Overexpress the Transcription Factor Bright

“…In this same study, B cells from tolerized mice induced T cell anergy in vitro (64). Others showed that B cells controlled T cell help and autoimmunity in lupus-prone NZB/W mice (65). We showed previously that Bright is expressed in activated mature B cells in response to a number of stimuli (31).…”

Immunization of nonautoimmune mice with DNA binding domains of the largest subunit of RNA polymerase I results in production of anti-dsDNA and anti-Sm/RNP antibodies

“…From the results of the present investigation, RNAPI(S1)-NT (Figure 3a), RNA-PI(S1)-BD ( Figure 3b) and La (Figure 5a) can now be added to the list of proteins and peptides that are capable of inducing an anti-DNA response in nonautoimmune animals. This list includes RNAPI holoenzyme [34], histones [31], the SmD1 83 -119 peptide [32], a SmB/B 0 peptide [33], nRNP A peptides [54] and DNA mimotope peptides [29,30]. Anti-DNA antibodies can, in turn, lead to production of antibodies against a variety of other SLE autoantigens, including anti-RNAPI [35,36] directed against (S1)-NT and -BD (Figure 2a and b), anti-La (Figure 2c), anti-ribosomal P protein (Figure 2d) and anti-Sm/RNP (Figure 2e).…”

“…Immunization of normal mice (Balb/c) with nucleosomes or histones leads to the production of anti-dsDNA, anti-Ro, anti-La and antiSm [31]. Immunization with the SmD1 83 -119 peptide leads to anti-dsDNA in the nonlupus prone mouse strain CWF1 but not in Balb/c mice [32]. Immunization of rabbits with a peptide from the Sm B/B 0 antigen results in anti-dsDNA, anti-RNP and anti-Ro (but not anti-La) in a significant fraction of these noninbred, pedigreed animals [33].…”