한빛사 인터뷰
- 등록2024-07-15
- 조회1,355
1. Can you please briefly summarize the paper?
In brief, we found that a chemical imbalance that mechanistically explains a cellular imbalance in patients with lupus (compared to healthy controls). Correcting this chemical imbalance appears to be a useful therapeutic approach for this disease.
Through mass cytometry, we found an increase in B-helper T cells (T follicular helper and T peripheral helper T cells) and a decrease in a CD96+ Th22 cell. Interestingly, these cells appear to be in epistasis with each other. Molecules that promote the Th22 phenotype inhibit the B-helper T cell phenotype and vice versa. Utilizing CRISPR screens, we found that aryl hydrocarbon receptor controls this differentiation axis. Activation of this ligand-gated transcription factor pushes cells to the Th22 pathway and diminishes expression of CXCL13 and the T peripheral helper/T follicular helper cell type. Conversely, inhibitors of this pathway does the opposite. Interestingly, patients with lupus have a chemical imbalance such that they have circulating inhibitors of the AHR pathway, one of which we identify to be type I interferon, which is a cytokine known to be upregulated in patients with lupus.
Through a series of genetic screens, biochemical/epigenetic assays, and pharmacology, we describe detailed molecular mechanisms including the co-operation of AHR and JUN to support the Th22 pathway and suppress expression of CXCL13, a B cell chemoattractant. Ex vivo exposure to AHR agonists reduces the number of B-helper T cells from the blood of patients with lupus and reduces their ability to support B cell differentiation/antibody production. Lastly, patients who are on anifrolumab have the expected reversal of the cellular imbalance found in lupus. After IFN blockade, they have a decrease in CXCL13, an increase in CD96+ Th22 cells, and a concomitant decrease in Tph cells.
Collectively, we found a potentially targetable “root cause” of the disease that appears to control the cascades of cellular dysfunction that controls the production of pathogenic antibodies in autoimmune diseases like lupus and rheumatoid arthritis.
2. Can you please tell us the main difficulties you had in the laboratory work and how you overcame them?
There were many technical hurdles. Through hard work and creativity, my students overcame them and found interesting new biology.
3. Please introduce your laboratory, university or organization to bio-researchers in Korea.
My laboratory is a human T cell biology lab wherein we utilize human disease to understand the circuitry of T cells with the goal of designing novel therapeutics. We have studied T cell lymphomas to identify novel mechanisms of increasing the potency of CAR-T cells and have now utilized the lessons from lupus to understand B-helper T cells. Our goal is to publish high impact papers and potentially start companies related to our work to translate our findings to developing novel drugs.
4. Please tell us your experiences and your thoughts related to research activities abroad.
I enjoy the American scientific culture of co-operation, creativity, and independent thought.
5. Can you provide some advice for younger scientists who have plans to study abroad?
Find a mentor that is a good person and does transformative science.
6. Future plan?
We are hoping to develop novel drugs related to our work for autoimmune disease and cancer.
7. Do you have anything else that you would like to tell Korean scientists and students?
Please consider applying to my lab for a post-doctoral position.
#Lupus
#autoimmune disease
#T cell biology
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