Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

Figure 1. Classes and examples of transposable elements. Abbreviations: TIR, terminal inverted repeats; LTR, long terminal repeats (transcriptional control sequence); Gag, group antigen; Prt, protease; Pol, polymerase; Env, envelope; UTR, untranslated region; ORF, open reading frame; HR, hexamer repeat; VNTR, variable number tandem repeats; SINE-R, Alu right monomer; SVA, SINE-R/VNTR/Alu composite; L, left monomer; R, right monomer.

Figure 2. The L1 retrotransposition process. A similar figure is in [40].

Figure 3. How the L1-containing stress granule may participate in driving SLE-related autoimmunity. The initial priming of T cells likely occurs by dendritic cells, which can take up stress granules, process their contents, and present peptides on class II MHC. The production of autoantibodies against ORF1p and Ro60 likely involves T cells primed by DC, followed by differentiation into follicular or peripheral helper T cells. CD8 T cells derived by cross-priming likely can recognized L1-expressing cells by virtue of ORF1p (and Ro60) derived peptides on class I MHC. Intracellularly, the reverse transcription of L1 transcripts into DNA will trigger IFNβ production and secretion. The secreted IFNβ will further stimulate monocyte differentiation to myeloid DC, plasma cell differentiation, and the differentiation and activation of CD8 T cells to become cytotoxic. Some cells do not express cGAS, but instead have other DNA sensors, such as Z-DNA binding protein 1, ZBP1, which also induce IFNβ production. Lastly (and not specifically illustrated), immune complexes that contain ORF1p, Ro60, and RNA (i.e., stress granules) will be taken up by plasmacytoid dendritic cells and B cells to trigger…