Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: High-speed technologies for genome sequencing have completely changed the study of disease genetics, but with limited knowledge of the functional value of most genetic changes. Using an innovative individual approach by studying tissue samples from a young woman with an unusual association of breast cancer, polycythemia vera and rheumatoid arthritis (RA), we identified hypothetic mutations involved in her cancer and autoimmune diseases then used a mice model to validate the implication of these mutations both in cancer and autoimmune diseases. We here present a new model of autoimmune disruption displaying RA features for studying pathophysiological pathways of articular dysimmunity.
Methods: Using whole genome analyses, we identified one cMET point mutation common to the breast cancer cells and to the CD34+ bone-marrow progenitors of the patient. We established a Knock-in transgenic mice using CRISPR-Cas9 technology and obtained MET-mutated transgenic mice.
Results: MET-mutated transgenic mice show a cancer skin disease and myeloproliferative disorders. Moreover they develop a 90% of penetrance arthritis, with autoantibodies (both ACPA, and auto-SSA and anti-SSB) and histological signs of Sjögren disease. Using ELISA, serum levels of anti-SSA and anti-SSB murine antibodies are significantly higher in the mutated mouse than in the wild-type mouse. Histological signs of synovial hyperplasia of a distal joint are observed in the mutated mouse concomitantly with high serum levels of ACPA. Transgenic mice also display signs of thyroiditis with lymphocyte infiltrate between abnormal thyroid follicles. Using an anti-MET drug, we were able to modulate the biological signs of auto-immunity and myeloproliferation, and the occurrence of skin cancers. We finally demonstrated for the first time a genetic link between myeloproliferative disorders, rheumatoid arthritis, and cancers.
Conclusion: Our study opens a large field of application in the domain of constitutional genetics but above all describes a new model for studying autoimmunity in mice through a non destructive RA model with ACPA. This non-destructive RA model is of major interest to decipher pathways that could lead from articular autoreactivity to autoimmunity. Furthermore, anti- immune-regulatory checkpoint molecules are now currently used in metastatic cancers and enlighten the close relation between cancers and autoimmune diseases because new autoimmune disorders can rise out in anti-PD1 treated cancer patients. This new arthritis model observed because of a cancer gene mutation could be an original approach to explore the autoimmune disruption in the context of cancer disease.
GF and MEB are first co-authors. AF et GB are co-authors
To cite this abstract in AMA style:Falgarone G, El Bouchtaoui M, Do Cruzeiro M, Leboeuf C, Loisel-Ferreira I, Frédonie C, Ferreira C, Ait El Far R, Espié M, Cassinat B, Kiladjian JJ, Feugeas JP, Janin A, Bousquet G. From Cancer to Autoimmunity : A New Model of Rheumatoid Arthritis Emerging from a Constitutional Genetic Approach Used in Low Penetrance Cancers [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/from-cancer-to-autoimmunity-a-new-model-of-rheumatoid-arthritis-emerging-from-a-constitutional-genetic-approach-used-in-low-penetrance-cancers/. Accessed February 16, 2020.
« Back to 2018 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/from-cancer-to-autoimmunity-a-new-model-of-rheumatoid-arthritis-emerging-from-a-constitutional-genetic-approach-used-in-low-penetrance-cancers/