Jennifer Malcolm: C-term citrullinated peptide alters APC-CD4 T cells leading to breach of tolerance
Full title: C-terminal citrullinated peptide alters APC-CD4 T cell interactions leading to breach of immune tolerance
Patients with rheumatoid arthritis harbour autoreactive T and B cells that target self-proteins containing a post-translational modification known as citrullination. This physiological modification regulates the structure and function of numerous proteins, and in health is not overtly immunogenic. Autoimmunity to citrullinated self-epitopes is associated with the interaction between certain HLA-alleles with environmental insults, such as smoking or microbial dysbiosis, at mucosal surfaces. However, the molecular mechanisms leading to the activation of autoreactive T and B lymphocytes in patients with RA remain ill-defined. Porphyromonas gingivalis is an immune subversive oral pathogen associated with microbial dysbiosis and chronic inflammation of oral gingival tissues. P. gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination. Using a synthetically generated C-terminally citrullinated model antigen (peptide ovalbumin), we demonstrate that this modification alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. Our data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Together, our data reveal a novel mechanism demonstrating how non-endogenous C-terminal citrullination can activate peripherally tolerised T cells to target native antigens.
Dr. Jennifer Malcolm completed her BSc/Hons in Microbiology at Glasgow Caledonian University, where she first sparked an interest in host-pathogen interactions in health and disease. She pursued this interest during her PhD at the University of Glasgow, School of Medicine, Dentistry and Nursing, where she identified how oral biofilm development in young children is accompanied by maturation of salivary immune responses. Following her PhD, she worked as a Post-Doctoral Research Associate at the University of Glasgow, School of Infection and Immunity. Here she identified novel therapeutic targets for the treatment of periodontitis and began her work investigating mechanisms driving autoimmunity in rheumatoid arthritis. In 2018, she took up a teaching position at the University of Glasgow Dental School. Here, she presents data exploring how oral bacteria exploit innate immunity to subvert adaptive immune responses, and how this impacts the maintenance of immune tolerance in the oral mucosa.