Abstract
Systemic lupus erythematosus (SLE) is marked by a T helper (Th) cell-dependent B cell hyperresponsiveness, with frequent germinal center reactions, and gammaglobulinemia. A feature of SLE is the finding of IgG autoantibodies specific for dsDNA. The specificity of the Th cells that drive the expansion of anti-dsDNA B cells is unresolved. However, anti-microbial, anti-histone, and anti-idiotype Th cell responses have been hypothesized to play a role. It has been entirely unclear if these seemingly disparate Th cell responses and hypotheses could be related or unified. Here, we describe that H chain CDR3 idiotypes from IgG+ B cells of lupus mice have sequence similarities with both microbial and self peptides. Matched sequences were more frequent within the mutated CDR3 repertoire and when sequences were derived from lupus mice with expanded anti-dsDNA B cells. Analyses of histone sequences showed that particular histone peptides were similar to VDJ junctions. Moreover, lupus mice had Th cell responses toward histone peptides similar to anti-dsDNA CDR3 sequences. The results suggest that Th cells in lupus may have multiple cross-reactive specificities linked to the IgVH CDR3 Id-peptide sequences as well as similar DNA-associated protein motifs.
Highlights
The initiation of autoimmune responses is associated with infection and the development of a gradually evolving T cell and B cell autoreactive response toward self-proteins
CDR3 Sequences from Anti-DNA B Cells from Lupus Mice Show Multiple Similarities with Microbial Sequences We have previously described IgVH sequences from lupus prone mice suffering from Id-driven lupus [33]
We found that IgVH CDR3 from the mutated repertoire of lupus mice had a surprisingly high rate of matches toward the microbial proteomes, eukaryotic pathogens, as well as self-proteins
Summary
The initiation of autoimmune responses is associated with infection and the development of a gradually evolving T cell and B cell autoreactive response toward self-proteins. Molecular mimicry is the concept that similarities of microbial peptides to self-peptides can allow expansion of microbial specific T cells that can cross react to similar self-peptides [1, 2]. It was originally believed that TCR binding to peptide:MHC (pMHC) was dependent upon stringent requirements for amino acid (aa) identity of the T cell contact residues. It is increasingly clear that degeneracy in both the TCR [3, 4] and MHC [5] peptide-binding motifs as well as interchangeable aa with similar properties in the TCR-exposed aa motifs [4, 6, 7] reduce this sequence-specific requirement [1].
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