In that mystifying land I learned meditation and began my introspective journey. I decided to go to India and see for myself, embarking upon an adventurous overland trip soon after completing secondary school. The author talks about barely believable stories of gurus being in two places at the same time, of reading people’s minds like a book, and so on. Since then I have been seeking out the “deep.” Soon after my bus epiphany I came across a book written by the Indian sage Paramahansa Yogananda called Autobiography of a Yogi. I was gazing out at the busy streets wondering: “Is that all there is to life: a predictable and repetitive march from cradle to grave? There has to be something deeper.”
These studies allow us to determine how targeting Tfh and Tfr cells can be used clinically to alleviate disease.My current journey in life started on the top deck of a London bus in 1972. We use a combination of novel genetic mouse models and human clinical samples to study the contribution of Tfh and Tfr cells to a number of disease states (such as multiple sclerosis, lupus, transplant rejection and allergic inflammation). How do alterations in Tfh and Tfr cells contribute to disease? Dysregulation of Tfh and Tfr cells are thought to lead to progression of autoimmune diseases. These studies allow us to elucidate strategies to enhance vaccine effectiveness. We use novel genetic mouse models to perturb Tfh and Tfr cells to understand how these cell types regulate B cell responses at distinct stages during vaccination and infection. How do Tfh and Tfr cell subsets control long term B cell responses? By understanding how Tfh and Tfr cells contribute to B cell responses, strategies can be developed to augment vaccines and limit viral infection.
In addition, we recently elucidated the Tfr transcriptional program, and how alterations in this program can lead to cellular dysfunction and altered B cell responses (Hou J. These studies have helped us understand how inhibitory receptors such as PD-1 and CTLA-4, as well as immunometabolism, have multifaceted roles in modulating antibody responses. We use genomics strategies (bulk RNAseq, single cell RNAseq, ATAC-seq) and functional assays to uncover pathways essential for the stimulation or regulation of B cell responses. The lab is elucidating immunoregulation of B cell responses using three approaches:How are Tfh and Tfr cells transcriptionally programmed to regulate B cell responses? By understanding the machinery Tfh and Tfr cells use to perform their functions, we can develop novel therapeutics to modulate these cells. Therefore, the outcome of humoral immunity is a delicate balance between stimulatory Tfh and inhibitory Tfr function. At the same time, T follicular regulatory (Tfr) cells interact with B cells and inhibit antibody responses. In this reaction, T follicular helper (Tfh) cells interact with B cells to stimulate antibody responses.
The vast majority of antibody responses originate from a highly organized process called the germinal center reaction. By understanding these pathways, therapeutics can be developed that can optimize vaccine responses and treat systemic autoimmunity. Therefore, the immune system has developed intricate regulatory machinery to ensure that antibody responses are both appropriate and tightly controlled. However, dysregulation of antibody responses can result in systemic autoimmunity. Antibodies clear harmful pathogens and mediate protection elicited by vaccination. Research in the Sage Lab focuses on understanding how the immune system regulates B cell responses and antibody production.
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