Date of Award
Doctor of Philosophy (Medical Science)
Medical Sciences (Molecular Virology and Immunology Program)
Several labs have previously demonstrated that humoral immune responses at one mucosal tissue can disseminate to other mucosal sites, giving rise to the theory of the common mucosal immune system (CMIS). Evidence that demonstrates a similar link between systemic immune responses and mucosal protection is lacking despite indications that both mucosal and systemic memory B cells share common circulatory pathways. The focus of this study is to determine the contribution of blood-borne B cells to mucosal immunity in humans, and how B cells trafficking through blood can be induced to traffic to mucosal tissues.
To address these aims, I have performed several analyses of active and inactive peripheral blood memory B cell (MBC) populations in normal, healthy humans. Analysis of recently activated blood B cells confirmed the revealed that the majority of pre-plasma cells (PPC) in blood of healthy, normal humans secrete IgA, and that the majority of IgA- positive PPC secrete primarily polymeric IgA. A large fraction of blood PPC also express CCR10, and this population contains the highest fraction of IgA-expressing and pIgA-secreting PPC in blood. In contrast, most CCR10- PPC secrete IgG, although a small fraction secretes and stains positive for IgA, and analysis of α4β7expression by blood MBC revealed that CCR10 is more inclusive of IgA-switched and pIgA-secreting PPC in blood. The data presented in this study demonstrate that IgA+/CCR10+ PPC represent the mucosal subset of PPC in the blood of healthy humans, and can be investigated as representative of recent or ongoing mucosal immune responses.
In vitro polyclonal stimulation of blood MBC through CD40 was able to induce CCR10 expression by blood MBC treated with IL-21, IL-2, IL-10 with additions of other germinal center (GC) cytokines such as IL-5 and TGF-β enhancing CCR10 induction. Surprisingly, CCR10 expression by IgG MBC stimulated under these conditions was similar to that of IgA MBC, demonstrating that CCR10 expression is not limited to IgA- switched B cell clones. The results of this study demonstrate that CCR10 expression is inducible by many GC factors, and importantly, is not limited to IgA-switched B cells.
Systemic immunization of healthy volunteers with tetanus toxoid/diphtheria vaccine induced a robust systemic IgG response, but also resulted in a post-immunization mobilization of IgA PPC in blood. These PPC were not specific for tetanus or diphtheria, and in several volunteers showed specificity for mucosal pathogens such as poliovirus (PV) and herpes simplex virus (HSV) glycoproteins. In addition, stimulation of anti-HSV IgG memory was also observed. Thus we have demonstrated that a systemic immune response is capable of inducing antibody relevant to mucosal immunity, possibly exposing a mechanism through which systemic and mucosal humoral immune responses are linked.
The studies presented here demonstrate the presence of mucosal B cell memory in blood and thus provide new insight into ways to assess and manipulate mucosal immunity.
Fernandes, Jason R., "Correlates of Mucosal Humoral Immunity in Peripheral Blood" (2012). Open Access Dissertations and Theses. Paper 7530.
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