Academisch Medisch Centrum Universiteit van Amsterdam

Research in our group focuses on the identification of key intracellular signalling pathways which mediate the switch from acute to chronic inflammation, and perpetuate established inflammation, in complex autoimmune diseases such as rheumatoid arthritis (RA).  These studies provide a fundamental understanding of the pathophysiological mechanisms of chronic inflammation, identify new targets in the treatment of RA and other autoimmune diseases, and apply a translational pre-clinical and clinical approaches to understanding the efficacy (or lack of efficacy) of novel and established therapeutic compounds in RA.

Much of our work is centered around the regulation and function of Ras superfamily small GTPase signalling pathways in immune and stromal cells in the RA synovium.  Specific research questions that we are currently exploring include:

How do functional interactions between Ras family GTPases regulate qualitative T cell immune responses?

How do Ras family GTPase-dependent proliferative and survival signals integrate with inflammatory signals in the RA synovium to perpetuate cellular hyperplasia and promote joint destruction?

Can changes in Ras family GTPase signaling pathways be used as biochemical fingerprints to predict or detect the development of erosive inflammatory arthritis?

Overexpression of prototypical Ras family members (H-, K-, and N-Ras) has been proposed to drive synovial hyperplasia and joint destruction in RA patients.  In defining the expression patterns and activation status of Ras signaling components in RA synovial tissue, we find that the guanine nucleotide exchange factor RasGRF1 is overexpressed and constitutively activated in RA stromal cells, and compounds selectively targeting H-Ras signaling are protective in animal models of arthritis.  Consequent selective signalling to the PI3-kinase/PKB pathway promotes cell survival in RA via inactivation of FoxO transcription factors, and accelerates joint erosion through enhancement of NF-kappaB signalling.  We have also identified a critical link between MAP kinase activation and engagement of the Ang/Tie2 angiogenic signaling pathway, particularly in synovial macrophages, which even in patients with undifferentiated arthritis, appears to be predictive of the development and progression of RA.  In this part of the program, we are using prospective clinical studies, gene array analysis, cellular biology, and animal models to understand how these signaling pathways lead to the onset and perpetuation of RA.

In attempts to understand molecular mechanisms altering T lymphocyte behavior in rheumatoid arthritis (RA), we found that chronic oxidative stress in these cells is due to inactivation of Rap1.  CTLA4-Ig, which has shown clinical success in the treatment of RA, restores Rap1 function in T cells and alleviates T cell oxidative stress.  Constitutive activation of Rap1 in T cells decreases interferon production, and protects mice against collagen-induced arthritis.  This may be due in part to effects on regulatory T cell function and trafficking.  We are currently attempting to define the cellular and molecular mechanisms by which Rap1 suppresses autoimmune T cell responses, and examining of Rap1 inactivation can be used to enhance autoimmune T cell responses in tumor rejection.

Theme: Infection and Immunity