Antibody-mediated immunity to Borrelia burgdorferi

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Antibody-Mediated Immunity to Borrelia burgdorferi Summary There is an urgent need to better understand mechanisms of immune protection and pathogenesis of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. This proposal aims to advances understanding of anti-Bb immunity and its failure to clear Bb infections in its natural reservoir hosts. Antibodies control Bb infection, although they cannot clear the infection. Binding of IgG to host cells via activating Fcg receptors (FcgR) and complement receptors (CR1/2) supports innate cell-mediated destruction of pathogens and antigen presentation for adaptive immune response induction. In contrast, engagement of the inhibitory FcgRIIb suppresses immune cell activation. It heightens B cell receptor-signaling thresholds, causing enhanced B cell apoptosis and reduced GC and plasma cell development, but also supporting somatic hypermutations. Quantitatively strong antibody responses to Bb infection are generated by plasmablasts in extrafollicular foci, while GC responses are short-lived and non-functional. They fail to generate long-lived plasma cell and memory B cells, and to sustain antibody affinity maturation to Bb and to co-administered antigens. The mechanisms underlying this humoral immune deficiency are unknown, a key gap in knowledge this proposal aims to fill. Recent data demonstrated changes to the ability of IgG from Bb-infected mice to bind to B cells and other APC, in part via the inhibitory FcgRIIb as well as changes to the glycan profile of serum IgG collected over the course of Bb infection. FcgRIIb-deficient mice had prolonged GC responses after Bb infection, while transfer of serum from Bb-infected, but not non-infected mice, induced GC collapse in recipients. The objective of the proposal is to define critical IgG-immune cell interactions and their effects on Bb infection, and to identify mechanisms of their regulation. The hypothesis will be tested that ineffective and/or altered interactions of IgG with FcgRs reduce effective immunity to Bb. Aim 1 is to identify the mechanisms of IgG- mediated B cell response regulation in Bb infection by studying FcgR-IgG interactions that regulate B cell responses, assess humoral immunity in their presence and absence, and measure their effects on the course of Bb infection. Aim 2 is to assess the effectiveness of IgG-B cell interaction for antigen-presentation and T-B interaction. Aim 3 is to identify the mechanisms of altered FcgR binding by Bb-IgG, probing immune complex formation and IgG glycans modifications and their effects on the passive protective capacity of anti-Bb IgG and/or the course of Bb-infection. Expected results would identify changes to IgG-B cell interactions, as causes of suboptimal anti-Bb IgG immunity, enhancing understanding of the pathogenesis of Bb and providing potential therapeutic targets for Lyme disease.