Study:   Role of LAMP-2 in tolerance to ANCA antigens
Institution:  Medical University of Vienna, Vienna, Austria
Award:  $50,000, one-year study

Summary:  Despite recent advances in treatment, ANCA-associated vasculitis (AAV) still causes serious morbidity especially after the acute injury has been controlled, emphasizing the need for better ways to monitor disease activity and personalize immunosuppressive therapy. It was thought that antibodies to the classical ANCA targets would be ideal biomarkers, myeloperoxidase (MPO) and proteinase-3 (PR3), because of the overwhelming evidence that they cause injury.

Surprisingly, this is not the case and they correlate badly with disease activity, suggesting either that current assays don’t measure the damaging antibodies or that additional factors are required for injury.  We identified autoantibodies to a protein called LAMP-2 as a potential missing link because they are found together with antibodies to MPO or PR3 in 80-90% of individuals with active AAV. Much of our research is designed to find out why these two types of autoantibody are found so commonly together in AAV.

LAMP-2 is located both in lysosomes inside the cell and on the cell surface and is important for presenting antigens to the T cells that initiate immune responses. We showed recently that LAMP-2 acts as a receptor on the surface of human antigen presenting cells that facilitates internalization of molecules and their targeting to the compartment where antigens are loaded onto the molecules that present them to T cells.

We now propose to use novel techniques to fluorescently label LAMP-2 and so provide a unique opportunity to discover whether it also promotes uptake of MPO and PR3 by antigen presenting cells before transporting them into the antigen loading compartment; and also to determine whether anti-LAMP-2 antibodies interfere with the process. If we are correct, the results will identify the link between antibodies to LAMP-2 and to MPO and PR3 and lead on definitive studies to determine whether anti-LAMP-2 antibodies influence autoimmunity to them.