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 of DIDS did not strikingly alter the course of SLE in either BXSB mice or MRL/lpr mice. These findings demonstrated that affinity maturation could be a potential target for T1D and SLE, while further explorations into targeting other components in the repair pathway are warranted for SLE. Lastly, we assessed the effect of maternal AID modulation on the SLE development in the offspring using BXSB mouse model. Interestingly, the absence of maternal AID resulted in offspring that developed significantly more severe lupus nephritis compared to control. The offspring born to AID-deficient dams also exhibited elevated levels of pathogenic autoantibodies and exacerbated disease features. Therefore, the modulation of maternal AID could influence the SLE development in the offspring, and future investigations are needed to determine the underlying mechanisms responsible for the disease acceleration. / Doctor of Philosophy / The failure of the immune system to differentiate self from non-self leads to the development of autoimmune diseases. Type 1 diabetes (T1D) and systemic lupus erythematosus (SLE) are complex autoimmune diseases affecting millions of people in the world. Despite intensive research regarding these two diseases, no known cure is available indicating an imperative need for the development of novel therapies. With the importance of B cells in the pathogenesis of these two diseases, intensive research focused on whole B cell depletion therapies. However, these therapies exhibited high risks of infections as a result of depleting all the B cells. In this dissertation, we sought to selectively target specific B lymphocyte subsets that are crucial contributing factors in the development of T1D and SLE. While the effect of therapeutic treatment varied among different mouse models, the genetic manipulation of specific B cells successfully retarded the progression of both T1D and SLE and extended the lifespan of the mice. Further studies shed light on the possible mechanisms that are responsible for the disease inhibition. These data proved that targeting specific B cell compartment could be a potential disease management in T1D and SLE patients. In addition, using the established mouse model, we demonstrated the modulation of maternal factors significantly impact the SLE development in the offspring. Future experiments to identify the underlying mechanisms could provide more targets for the therapeutic development.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/100945 |
| Date | 25 November 2020 |
| Creators | Zhu, Jing |
| Contributors | Animal and Poultry Sciences, Leeth, Caroline M., Luo, Xin, Johnson, Sally E., Li, Liwu |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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