| Autor: |
Zhu, Jing, Hay, Alayna N, Potter, Ashley A, Richwine, Madison W, Sproule, Thomas, LeRoith, Tanya, Wilson, John, Hasham, Muneer G, Roopenian, Derry C, Leeth, Caroline M |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
J Immunol |
| Popis: |
Almost a decade has passed since the approval of belimumab, a monoclonal antibody directed against B lymphocyte stimulation and the first targeted therapy approved for systemic lupus erythematous (SLE) in over 50 years. While well tolerated, the efficacy of belimumab remains limited and is not labelled for patients suffering from nephritis, the leading cause of patient mortality. We sought to explore alternative targets of autoreactive B lymphocytes through manipulation of affinity maturation. The BXSB/MpJ mouse, a well-established model of human SLE, develops elevated antinuclear antibodies and immune complex-mediated nephritis along with other manifestations of SLE-like disease. To limit interfering with critical background genetics, we used CRISPR-Cas9 to disrupt Activation Induced Cytidine Deaminase (Aicda, AID) directly in BXSB zygotes. Homozygous null mice demonstrated significantly prolonged survival compared to wildtype. While mice continued to develop plasma cells, splenic follicular structure was restored and renal pathology was reduced. Mice developed expanded germinal center B lymphocyte populations as in other models of AID deficiency as well as increased populations of CD73(+) B lymphocytes. Treatment with the small molecule inhibitor of RAD51, 4,4’-Diisothiocyano-2,2’-stilbenedisulfonic acid, resulted in minimal changes in disease markers in BXSB mice. The prolonged survival in AID-deficient BXSB mice appears attributed primarily to the reduced renal pathology, warranting further exploration as current therapeutics targeting lupus nephritis are limited and thus in great demand. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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