New structural insights into the role of TROVE2 complexes in the on-set and pathogenesis of systemic lupus erythematosus determined by a combination of QCM-D and DPI

• Published in: Analytical and bioanalytical chemistry 2019-07, Vol.411 (19), p.4709-4720
• Main Authors: Juste-Dolz, Augusto, do Nascimento, Noelle M., Monzó, Isidro, Grau-García, Elena, Román-Ivorra, Jose A., Lopez-Paz, José Luis, Escorihuela, Jorge, Puchades, Rosa, Morais, Sergi, Gimenez-Romero, David, Maquieira, Ángel
• Format: Article
• Language: English
• Subjects: Analysis; Analytical Chemistry; Antigenic determinants; Autoantibodies; Autoantibodies - immunology; Autoantigens - chemistry; Autoantigens - immunology; Autoantigens - physiology; Autoimmune diseases; Autoimmunity; Belimumab; Biochemistry; Biomarkers; Calcium; Case-Control Studies; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Chronic conditions; Complementarity; Data processing; Epitope mapping; Ethylenediaminetetraacetic acid; Fc receptors; Female; Food Science; Humans; Immunotherapy; Interferometry; Interferometry - methods; Intracellular signalling; Laboratory Medicine; Lupus; Lupus Erythematosus, Systemic - immunology; Male; Medical research; Medicine, Experimental; Microbalances; Monitoring/Environmental Analysis; Pathogenesis; Peptide mapping; Phosphoproteins; Protein Conformation; Protein structure; Proteins; Quartz crystal microbalance; Quartz Crystal Microbalance Techniques; Quartz crystals; Receptors; Research Paper; Ribonucleoproteins - chemistry; Ribonucleoproteins - immunology; Ribonucleoproteins - physiology; RNA, Small Cytoplasmic - chemistry; RNA, Small Cytoplasmic - immunology; RNA, Small Cytoplasmic - physiology; Self-recognition; Systemic lupus erythematosus; Tertiary structure; Young Investigators in (Bio-)Analytical Chemistry
• ISSN: 1618-2642; 1618-2650
• DOI: 10.1007/s00216-018-1407-x

The mechanism of self-recognition of the autoantigen TROVE2, a common biomarker in autoimmune diseases, has been studied with a quartz crystal microbalance with dissipation monitoring (QCM-D) and dual polarization interferometry (DPI). The complementarity and remarkable analytical features of both techniques has allowed new insights into the onset of systemic lupus erythematosus (SLE) to be achieved at the molecular level. The in vitro study for SLE patients and healthy subjects suggests that anti-TROVE2 autoantibodies may undergo an antibody bipolar bridging. An epitope-paratope-specific binding initially occurs to activate a hidden Fc receptor in the TROVE2 tertiary structure. This bipolar mechanism may contribute to the pathogenic accumulation of anti-TROVE2 autoantibody immune complex in autoimmune disease. Furthermore, the specific calcium-dependent protein-protein bridges point out at how the TRIM21/TROVE2 association might occur, suggesting that the TROVE2 protein could stimulate the intracellular immune signaling via the TRIM21 PRY-SPRY domain. These findings may help to better understand the origins of the specificity and affinity of TROVE2 interactions, which might play a key role in the SLE pathogenesis. This manuscript gives one of the first practical applications of two novel functions (−d f /d D and Δ h /molec) for the analysis of the data provided by QCM-D and DPI. In addition, it is the first time that QCM-D has been used for mapping hidden Fc receptors as well as linear epitopes in a protein tertiary structure. Graphical abstract ᅟ