Project #3

Local breach of tolerance – understanding the process of chronicity in autoimmune disease

Introduction | Chronic inflammation in autoimmune diseases is driven by resident T cells and a breakdown in immune tolerance. Systemic factors often complicate the study of local antigen presentation; however, juvenile idiopathic arthritis (JIA) provides a unique model due to its joint-specific inflammation. While innate immune-driven T-cell activation has been observed in JIA, the roles of autoantibodies and autoreactive lymphocytes remain unclear. Mapping these factors will improve understanding of local tolerance breakdown and support the development of targeted therapies and patient subgroup identification in autoimmune diseases.

Aim | To investigate the mechanisms of local tolerance breach by identifying autoantigens, autoantibodies, and autoreactive lymphocytes.

Methods | We propose that lymphocytes migrate to joints and target local autoantigens, leading to immune activation and a breach of tolerance. To explore this, we aim to identify autoantigens and autoreactive lymphocytes, uncovering mechanisms of activation and their potential as therapeutic targets.

Significance | Local breaches of tolerance play a key role in autoimmune diseases, but systemic influences make them difficult to study. Using JIA as a model with minimal systemic involvement, we seek to identify key immune components involved in disease progression. Our findings will provide insights into localized autoimmunity, refine patient classification, and guide targeted therapies. This approach may also be applicable to other autoimmune diseases, such as diabetes and inflammatory bowel disease, offering novel strategies for personalized diagnosis and treatment.

Main Principal Investigator

• Robin Kahn

Co-supervisors

• Anders Bengtsson         
• Pontus Nordenfelt