T cell exhaustion in AAV

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a heterogeneous group of potentially life-threatening autoimmune diseases with a wide range of clinical presentations and relapsing/remitting disease courses. Death from any cause and infection rates remain increased in these patients compared to the general population. Immune system suppressing treatments are used to control disease activity and abrogate inflammation, but potentially have detrimental effects, such as serious infections. A person`s "immunocompetence" is their ability to maintain a functioning immune system capable of responding to and clearing infections with no or minimal disease activity. Defining the state of "immunocompetence" is particularly important in people receiving immune system suppressing therapies and finding a balance between reducing disease recurrence and risk of infections seems desirable. T cells are essential parts of the immune system and help protect the body from infections and cancer. In chronic viral infections and response to tumours, these cells are exposed to persistent external signals (i.e., inflammation or pathogen substances), often associated with the deterioration of their function called "T cell exhaustion". Exhausted T cells lose their capability among others - to control infections, while a certain T cell exhaustive signature is associated with a reduced disease recurrence rate in patients with AAV. In this context, the deeper characterisation of exhausted T cells may allow the identification of new biomarkers that predict the clinical course of AAV. At the same time, its manipulation may be a possible therapeutic mechanism to suppress autoreactivity in AAV patients. In transplantion, viral infections such as cytomegalovirus infections are often a sign of overimmunosuppression, and the density of immunosuppression is often adjusted to allow for clearance of such viruses from circulation, but on the flipside poses risk of kidney allograft rejection. Monitoring of a certain non-pathogenic (unable to cause disease) virus has been used in transplant medicine to predict the risk of organ rejection and infectious complications. Such a viral load could potentially be a reliable and easily applicable measure and can be used to tailor immunosuppression in patients with AAV. In this project, we will conduct a comprehensive analysis of T cells to further characterize T cell dysfunction and establish their distinct contribution to the clinical course in patients with AAV. Moreover, a novel approach investigating the role of a non-pathogenic virus as a surrogate marker of "immunocompetence" for predicting disease course will be tested. The characterisation of T cells may help identifying new biomarkers and therapeutic targets, while the measurement of such a viral load may affect the care of patients with AAV by becoming a part of routine laboratory investigations.