Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Ro60/TROVE2 is a clinically important member of the nuclear antigen family. It binds synergistically YRNAs, allowing the formation of a stable complex with exoribonuclease polynucleotide phosphorylase. The main known function of TROVE2 is so to perform a quality control of misfolded ncRNA (such as Alu RNAs and pre-5S rRNAs), enhancing the cell survival. For that, anti-TROVE2 antibodies are major targets of the immune system in SLE patients and can be identified years before the disease manifestation, providing advantage of an early diagnosis. Epitope mapping studies showed that TROVE2 has an immunodominant epitope between 169-190 a.a. These amino acids reside in a loop involved in binding single-stranded RNA, so anti-TROVE2 antibodies target a key part for its functional mechanism. Hence, although the underlying cause of the disease is not fully defined, SLE is related to the cellular function of the TROVE2 protein. In this work, we analyze the host-guest binding of the TROVE2-autoantibody system in SLE patients and healthy subjects.
Methods: Cross-sectional prospective study of 20 SLE patients diagnosed according to the SLICC-ACR2012 criteria, from the Rheumatology Department of La Fe Hospital. All patients showed high anti-Ro Ab (SSA) concentrations (>200,0 U/mL). We have also taken 8 healthy individuals as negative controls, who had anti-Ro Ab concentrations <15 U/mL. A sensitive TROVE2-based QCM-D biosensor was developed.
Results: Pre–steady–state analysis revealed an antibody bipolar bridging mechanism for the host-guest binding of the TROVE2-autoantibody system, for the first time. Although Fc receptors (such as Fc-gamma receptors) do not exist on the protein surface, its MIDAS motif is the Fc receptor exposed when the epitope-paratope binding takes place initially. In this molecular recognition, the protein hydration shell dynamics plays also an important role. Furthermore, we demonstrate that the TRIM21a:TROVE2 association is a calcium-dependent adhesion system. Thus, the ‘bridging’ role in the TROVE2 bound, a feature of pathogenic superantigens, leads to the inhibition of the biological function of the Ro/SSA ribonucleoprotein. The MIDAS motif acts as a YES logic gate, having a key role in the intracellular antibody signaling, activating, or deactivating, the innate immune system.
Conclusion: Our results suggest a distinct pathway of induction of anti–TROVE2 autoimmunity in SLE patients. The different interaction mechanism of autoantibodies in SLE patients would suggest a majority necrosis-induced specificity, and not apoptosis as in healthy subjects. Anti-TROVE2 cell-penetrating autoantibodies will so induce the inhibition of degradative activity of the TROVE2 autoantigen in SLE disease. This one would imply the accumulation of the Alu RNAs, stimulating intracellular RNA sensors to induce inflammatory responses. The originated increase of calcium intracellular level favors the TRIM21a-TROVE2 binding through the PRYSPRY domain and therefore, an inhibitory effect on the TRIM21 physiological function. Financial support by GVA (PROMETEO II 2014/040 and GV15/83 project) and from MINECO and FEDER (CTQ2013-42914-R project) is acknowledged
To cite this abstract in AMA style:Vicens Bernabeu E, Grau Garcia E, Juste A, Monzo I, Tejero R, Morais S, Lopez Paz JL, Puchades R, Maquieira A, Roman Ivorra JA, Gimenez Romero D. Autoantibody Response to TROVE2 in Systemic LUPUS Erythematosus Patients [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/autoantibody-response-to-trove2-in-systemic-lupus-erythematosus-patients/. Accessed November 23, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibody-response-to-trove2-in-systemic-lupus-erythematosus-patients/