We aim to understand the biology of the immune system response by studying lymphocytes that are responding to vaccination or infection. Our work advances our understanding of antibody protection, auto-immunity and the ageing immune system. In particular we study the processes that happen in lymph nodes and other lymphoid tissues, when B cells interact with incoming antigens to produce antibody responses specific to these antigens.
Understanding how vaccines work, how we become immune in the long term, and how the immune system is triggered to produce highly specific antibodies may lead to better understanding on how to improve vaccines and long-term immunity to pathogens. Understanding the biology of antibody responses is relevant for a number of reasons. Vaccination inducing long term antibody-mediated protection to a number of pathogens is an important health intervention, providing the general population with immunity to old and new infectious agents. Vaccination is also a necessary first step in the generation of new monoclonal antibody drugs and therefore of interest for biotech industry.
Occasionally, our immune system can spontaneously start antibody responses against parts of our own body. Understanding how such autoimmune disease is triggered, is important for a range of different autoimmune diseases. Particularly the ageing immune system has trouble regulating the antibody response: vaccination in aged people to many vaccines is not working as efficiently as in young people, and autoimmunity becomes more prevalent.
We study antibody responses of B cells by following their migration and differentiation in lymphoid tissues. Developing antibody responses involve complex and repeated interactions between B cells and other accessory cells. While they interact, cells exchange signals that activate, regulate, and select cells on both sides of these interactions. We study these responses in mice that have genetic deletions of genes involved in these interactions, or that express fluorescent reporter genes that label specific cells while they undergo interactions.
Our main interests are signals that induce activation and selection of B cells, feedback on Tfh responses, the roles of antibody in selecting B cells, antigen entry and interactions of B cells with macrophages, the regulation of antibody affinity maturation, signals inducing the generation of antibody forming cells, and the functions and roles of memory B cells.
In the twenty years since extrafollicular B cell responses were originally described, much has been learned about B cell biology. With this progress, the term "extrafollicular" has expanded beyond its initial use to describe a variety of B cell processes, resulting in ambiguity over the term. Extrafollicular responses are often not identified by location, convoluting the criteria being used to define the pathway. Here, we discuss the current understanding of B cell responses as relevant to the current uses of the term "extrafollicular." In this context, we propose a framework to classify evolving concepts in B cell biology. The use of this framework moving forward is expected to help harmonize and clarify the discussion in the field.
Vaccines are less immunogenic in older adults, partly due to immunosenescence. Having previously shown that morning influenza vaccination may be more immunogenic in older adults (mean age 71), we assessed if this could be replicated in a younger cohort (mean age 57) and with a T-cell independent vaccine. This study examined whether diurnal timing of a single dose of Pneumovax® (PPV-23) and seasonal influenza vaccine influenced antibody responses in 140 healthy adults over the age of 50. Pneumococcal serotype-specific (PnPS) antibodies and Haemagglutination Inhibition Assays (HAI) were used to characterize antibody responses at Baseline, 1, 4, and 52 weeks post-vaccination. Protective thresholds were set at 0.35 μg/mL for two-thirds of PnPS tested (WHO) and a titre of ≥40 HAI for H1N1, H3N2, and B/Victoria strains. Both AM and PM cohorts showed increased Pn-specific antibodies to one PPV-23 dose at weeks 1, 4, and 52; however, time of day did not significantly influence antibody responses. Baseline immunity for pneumococcus was high (57.1 % AM, 50.0 % PM had WHO), and immunity was maintained with at least 7/12 serotypes elevated at 52 weeks. Time of day did not alter short- or long-term influenza antibody responses. H1N1 had the highest baseline immunity (67.6 % AM, 48.6 % PM had ≥40 HAI) and the most increased responses at week 4 post-vaccination (92.8 % AM, 94.1 % PM) that were maintained at 52 weeks post-vaccination (91.7 % AM, 89.3 % PM). The poorest serotype immunity was for the B/Victoria strain at all time points. Although time of day did not influence vaccine immunogenicity in AM and PM cohorts, sustained cohort-wide antibody responses were demonstrated in an older population. Identifying 18 % of the total cohort exhibited suboptimal responses to pneumococcal or influenza vaccines underscores the imperative for enhancing vaccine efficacy within this age group to reduce morbidity and mortality.
The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG B cells over IgM B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1 GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1 GC B cell survival during positive selection, whereas IgM GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)-mediated calcium (Ca) mobilization downstream of B cell receptor (BCR) signaling in IgG1 B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction-induced IgG1 GC cell death caused by excessive Ca accumulation. This study uncovers a unique Ig isotype-specific dependency on a hitherto unidentified mechanism in GC-positive selection.