Systemic Lupus Erythematosus: Molecular Mimicry between Anti-dsDNA CDR3 Idiotype, Microbial and Self Peptides—As Antigens for Th Cells

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.

Quantification of inter-sample differences in T cell receptor sequences

“…First, both the too high-numbered PAMs and too low-numbered BLOSUMs seemed to lose the intra-cluster structures by trying to compress the clusters into regions that were too small, while both the too low-numbered PAMs and too high-numbered BLOSUMs diminished any inter-cluster differences, resulting in indistinguishable clusters. Second, BLOSUM62 has been the most widely used matrix in analyses of TCRs and antigen peptides to date (Oyarzún et al, 2013; Schwaiger et al, 2014; Hoffmann et al, 2015; Aas-Hanssen et al, 2015).…”

“…The second key merit of our method is the ability to identify the sequences with the greatest contributions to pairwise sample differences. This sequence identification allows for targeted analyses along with the results of other studies such as the simulation modeling for determining the crystal structures of the TCRs encoded by these sequences (Klausen et al, 2015) or establishing alignments between CDR3 sequences and microbial genomes (Aas-Hanssen et al, 2015). Such a closed-loop experimental design may help to achieve a breakthrough in the development of vaccines or immunotherapies (Hou et al, 2016).…”

“…Although these PA models can successfully quantify the inter-sample distances, they are also associated with a major drawback in that some of the sequence information for each sample is lost since these models focus only on the count distribution. This loss of information has hampered the ability to determine the characteristic sequences of each sample, which is a requisite for further investigations of the source of the difference by, for example, evaluations of the interaction with microbial peptides (Aas-Hanssen et al, 2015) and the simulation of TCR crystal structures (Klausen et al, 2015).…”

Quantification of Inter-Sample Differences in T-Cell Receptor Repertoires Using Sequence-Based Information

“…Although these PA models can successfully quantify the inter-sample distances, they are also associated with a major drawback in that some of the sequence information in the samples is lost since these models focus only on the count distribution. This loss of information has hampered the ability to determine the characteristic sequences of each sample, which is a requisite for further investigations of repertoires by, for example, evaluations of the interaction with microbial peptides ( 13 ) and the simulation of TCR crystal structures ( 14 ).…”

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

“…Several conjectures were made for explaining disturbed tolerance to autologous DNA. One of the hypotheses is implication of molecular mimicry, when immune response to autoantigens is induced by exogenous molecules with similar epitopes [24]. Epitope spreading mechanism may also participate in it, subsequently producing antibodies to hidden epitopes after initial reaction to major epitope [25].…”