Prkcdg510s/g510s mice – preclinical model of lupus

We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of SLE in the mouse genome, by means of CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulate the human phenotype, presenting with glomerulonephritis, splenomegaly, and various serum autoantibodies, including anti-nuclear, and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell autonomous role of PRKCD in immune regulation. The penetrance of the lupus phenotype is 100% in this mouse model.

Interest / Relevance: Systemic lupus erythematosus (SLE) is a devastating autoimmune disease whose symptoms may include joint pain, fever, skin rash and organ damage. SLE is currently incurable and the therapeutic arsenal to treat SLE remains very limited, without specific treatment for the different clinical forms of the disease. Autosomal recessive PRKCD deficiency has previously been associated with the development of severe forms of systemic lupus erythematosus (SLE) in human patients. PrkcdG510S/G510S mice recapitulate the human phenotype, presenting with glomerulonephritis, splenomegaly, and various serum autoantibodies, including anti-nuclear, and had reduced lifespan. Treatment of mice with rapamycin, a specific mTORC1 inhibitor, significantly improves autoimmune symptoms. This demonstrates the role of the mTOR pathway in the lupus phenotype in PrkcdG510S/G510S mice and shows that this mouse model can be used to test the efficacy of novel lupus therapies.

Keywords: Lupus mouse model, autoimmunity mouse model, preclinical model of lupus

Publications:

1. Moreews M, Mathieu AL, Pouxvielh K, Reuschlé Q, Drouillard A, Dessay P, Meignien M, Zhang J, Fallone L, Rousseaux N, Ainouze M, Rey A, Omarjee O, Decembre E, Lenief V, Djebali S, Thaunat O, Dreux M, Genestier L, Defrance T, Soulas-Sprauel P, Marçais A, Walzer T*, Belot A*. mTOR activation underlies enhanced B cell proliferation and autoimmunity in PrkcdG510S/G510S mice. Submitted

2. Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, Szynkiewicz M, Zabot MT, Rouvet I, Bhaskar SS, Daly SB, Dickerson JE, Mayer J, O'Sullivan J, Juillard L, Urquhart JE, Fawdar S, Marusiak AA, Stephenson N, Waszkowycz B, W Beresford M, Biesecker LG, C M Black G, René C, Eliaou JF, Fabien N, Ranchin B, Cochat P, Gaffney PM, Rozenberg F, Lebon P, Malcus C, Crow YJ, Brognard J, Bonnefoy N. Protein kinase c? deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation.Arthritis Rheum. 2013 Aug,65(8):2161-71. doi: 10.1002/art.38008.

Reference:

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