Abstract Body: Introduction: Hypertension and systemic lupus erythematosus (SLE) lead to modification of self-peptides by isolevuglandin (isoLG) lipid oxidation products. These self-peptides are presented by class 1 major histocompatibility complexes and drive CD8⁺ T cell activation. We have identified self-peptides from the sodium/glucose cotransporter2 (SGLT2); cadherin 16; Kelch domain-containing protein 7A and solute carrier family 23 that are IsoLG-adducted and cause CD8⁺ T cell activation in both ang II and L-NAME/high salt models of hypertension. These prime hypertension in response to low dose ang II.
Hypothesis: We hypothesized that the same immunogenic peptides responsible for experimental hypertension contribute to systemic lupus erythematosus.
Methods: A fluorescent probe made of recombinant IgG and the murine class 1 MHC H2-D^b was loaded with either unadducted SGLT2 peptide or an isoLG-adducted SGLT2 peptide. This probe was used in flow cytometry to detect CD8⁺ T cells specific for this peptide antigen in 12-week-old C57Bl/6 and female B6SLE1.2.3 mice.
Results: The unadducted SGLT2 probe recognized < 1% of CD8⁺ T cells (Figure). In contrast, ang II-infusion caused a striking increase in IsoLG-SGLT2 specific CD8⁺ T cells in C57Bl/6 aortas (Figure panels A and D). In C57Bl/6 very few CD8⁺ T cells recognizing IsoLG-SGLT2 were observed in the spleen (Panel B and E). Importantly, from 5 to 20% of CD8⁺ T cells in spleens of female B6SLE1.2.3 mice recognized the IsoLG-SGLT2 peptide (Figure panels C and E). Image 1.
Conclusions: These findings strongly suggest that IsoLG-adducted peptides responsible for ang II-induced hypertension contribute to SLE and suggest that these conditions share similar immunogenicity.