التفاصيل البيبلوغرافية
العنوان: |
The modulation of autoimmune disease progression in mouse models |
المؤلفون: |
Zhu, Jing |
المساهمون: |
Animal and Poultry Sciences, Leeth, Caroline M., Luo, Xin, Johnson, Sally E., Li, Liwu |
بيانات النشر: |
Virginia Tech |
سنة النشر: |
2020 |
المجموعة: |
VTechWorks (VirginiaTech) |
مصطلحات موضوعية: |
Type 1 diabetes, systemic lupus erythematosus, affinity maturation, activation-induced cytidine deaminase, DNA double strand breaks, maternal antibodies |
الوصف: |
B cells play crucial roles in the development of the two human autoimmune diseases, type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). In the past decade, numerous studies showed positive responses of B cell depletion therapies in these two diseases. However, the beneficial effects are temporary and accompanied with adverse events. In this dissertation, we aimed to identify novel targets for a better modulation of disease development using mouse models. These diseases have circulating autoantibodies that are mostly mutated with an IgG isotype, indicating B cells that are producing them have been through the process of affinity maturation. Activation-induced cytidine deaminase (AID) is a core enzyme that regulates somatic hypermutation (SHM) and class switch recombination (CSR), the two key mechanisms in affinity maturation. We showed that genetic ablation of AID significantly inhibited the development of TID in NOD mice. Homologous recombination (HR) pathway is important for the repair of AID-induced DNA double strand breaks during CSR. 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, also known as DIDS, is a small molecule that inhibits HR pathway and subsequently leads to apoptosis of class switching cells. DIDS treatment remarkably retarded the progression of TID, even when started at a relatively late stage, indicating the potential of this treatment for disease reversal. In both approaches, we observed a notable expansion of CD73+ B cells, which exerted an immunosuppressive role and could be responsible for T1D resistance. Next we examined the effect of targeting affinity maturation through these two approaches in lupus-prone mice. The genetic abrogation of AID in BXSB mice significantly ameliorated lupus nephritis and prolonged their lifespan. AID-deficient mice also exhibited improvement on disease hallmarks with increased marginal zone B cells and more normal splenic architecture. DIDS treatment notably reduced class switching when B cells were stimulated in vitro. However, the administration ... |
نوع الوثيقة: |
doctoral or postdoctoral thesis |
وصف الملف: |
ETD; application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document |
اللغة: |
English |
العلاقة: |
vt_gsexam:27595; http://hdl.handle.net/10919/100945Test |
الإتاحة: |
http://hdl.handle.net/10919/100945Test |
حقوق: |
In Copyright ; http://rightsstatements.org/vocab/InC/1.0Test/ |
رقم الانضمام: |
edsbas.73A9315C |
قاعدة البيانات: |
BASE |