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Immune regulation and development in chronic inflammation

Thursday 2 July 2015

Femke van Wijk

Immune regulation and development in chronic inflammation

Juvenile idiopathic arthritis (JIA) is one of the most common childhood autoimmune diseases and a major cause of chronic disease with serious disability and loss of quality of life. JIA is the result of an exaggerated and abnormal immune response directed against self-tissue, which leads to chronic inflammation in the joints. Current treatments are not curative and rely on generalized immune suppression that has considerable side effects. Under normal conditions immune regulatory cells, such as regulatory T cells (Treg), control and down-regulate immune responses to prevent excessive tissue damage. There is still a fundamental gap however in our understanding of immune regulation in (autoimmune) inflammatory settings and this gap represents a major obstacle in the development of therapeutic strategies that aim to interrupt the self-sustaining loop of uncontrolled autoimmune inflammation. One of our key findings has been that not intrinsic Treg defects, but instead, T effector (Teff) cells that become resistant to suppression by Treg are the main reason for impaired T cell regulation at the site of inflammation (Blood 2011, Nature Reviews Rheumatology 2013, Arthritis & Rheumatology 2014), leading to a paradigm shift. We have also found that inflammatory antigen presenting cells (APC) play a crucial role in the impairment of immune regulation. We now aim to delineate the mechanisms of impaired immune regulation under inflammatory conditions with a focus on the APC-Teff-Treg triangle. Specific aims:

I Identify functional characteristics of monocyte and DC subsets in the inflamed joint
II Elucidate the mechanisms of T cell resistance induction by inflammatory APC
III Unravel the interplay between inflammatory APC and regulatory T cells
IV Delineating functional specialization of regulatory T cells under inflammatory conditions
V Elucidate myeloid development and epigenetic regulation under chronic inflammatory conditions

Techniques: Human cell culture, Flow cytometry, RNA-seq, Chip-seq, Functional T cell/APC assays