T Cell Repertoire Selection in the Psoriatic Arthritis Thymus
Principal Investigator: Robert Winchester, M.D.
Institution: The Trustees of Columbia University in the City of New York
Grant Mechanism: Discovery Grant
Funding Amount: $75,000
Project Start Date: August 1, 2023
Project End Date: July 31, 2024
Keywords: Psoriatic Arthritis, Genetics, Immunology, Disease Etiology, Cell Biology, Basic Science
Our repertoire of billions of T cells is produced in two stages in the thymus gland from bone marrow stem cells. This proposal uses a method analogous to marrow transplantation to transplant a psoriatic arthritis patient's stem cells into an immune-deficient mouse that contains a fragment of a human thymus HLA-matched to the patient. A replica of the patient's immune system forms in the thymus gland that recapitulates all the stages of thymic development, with the replica patient's immune system essentially at the stage when the patient was newly born. This enables us to study: first how different psoriatic arthritis susceptibility genes act to positively select the initial repertoire without the complicating elements of all the interim immune responses, therapy, etc. that occur throughout our life and second, whether a critical genetic defect in psoriatic arthritis patients is the failure to eliminate positively selected autoreactive clones from their working T cell repertoire in a process of negative selection.
How will your project help improve the lives of the 125 million affected by psoriatic disease?
Psoriatic disease is mediated by particular T cells in our overall repertoire of working T cells that strongly recognize certain self-peptides in the body structures and then this becomes the sites of psoriatic inflammation. Since these highly self-reactive T cells are removed from the working T cell repertoire in healthy people, two fundamental unanswered questions are what are the distinguishing characteristics of the T cell receptor in these cells and what element in the formation of the T cell repertoire in psoriatic individuals allows these self-reactive T cells to remain in their repertoire. Identifying and understanding this root cause of psoriatic disease should lead to its amelioration.
Why is psoriatic disease research important to you, personally? What role will this award play in your research efforts or career development?
As someone who treats patients with psoriatic disease, I see the devastating impact psoriatic inflammation can have on a person's life and I appreciate the immunologic complexities and challenges posed in treating the disease process. Now with the development of human immune system mice, we have the potential to advance understanding of the root cause of the psoriatic process. This should greatly facilitate knowing how particular genes act to result in a highly autoreactive repertoire of T cells that mediate psoriatic inflammation, without the many changes induced in the repertoire by years of exposure to multiple environmental influences.
Dr. Winchester has had a sustained interest in human autoimmune disease His earlier studies defined the molecular importance of rheumatoid factors, other autoantibodies, and immune complexes in human disease. Moreover, Dr. Winchester was involved in the initial identification and tissue expression of human HLA class II molecules. As importantly, his studies of the polymorphisms of MHC molecules have provided the basis of establishing the link between HLA genotype and susceptibility to autoimmunity. Dr. Winchester and colleagues then showed that susceptibility to rheumatoid arthritis was determined by certain amino acid sequences in the beta chain of HLA-DR molecules shared among the different forms of the gene associated with disease susceptibility.
This observation led to the shared MHC 'epitope' hypothesis which provides a molecular basis for susceptibility to rheumatoid arthritis associated with a region on the MHC molecule involved in both binding of the peptide and interacting with the TCR. This seminal discovery has emphasized the importance of the modern means of HLA typing which involves DNA sequencing of the MHC genes and the theoretical basis for the discovery of antigens that initiate autoimmune disease including psoriatic arthritis. In recent years Dr. Winchester has also focused on the relationship between psoriatic arthritis susceptibility genes and the different clinical forms of psoriatic arthritis. More recently he has focused on the effect of these genes on the DNA and peptide sequence of T cell receptor beta chains in order to define the changes in the TCR repertoire associated with autoimmunity.