The general aim of this thesis was to elucidate the immune regulation and breach of tolerance towards modified proteins in Rheumatoid Arthritis(RA). Anti-modified protein antibodies are a hallmark... Show moreThe general aim of this thesis was to elucidate the immune regulation and breach of tolerance towards modified proteins in Rheumatoid Arthritis(RA). Anti-modified protein antibodies are a hallmark of disease and are implicated in the pathogenesis of RA. Recent studies have shown that these autoantibodies can serve as diagnostic and prognostic biomarkers. Most research on the role of autoantibodies in RA has focused on ACPA, which are directed against citrullinated proteins. In the past several years it has become clear that the autoantibody response in RA extends to several other modified proteins, such as proteins modified by carbamylation and acetylation. As all these auto-antibodies recognize post-translationally modified proteins, these antibodies are collectively called anti-modified protein antibodies (AMPA). A variety of AMPAs against different protein modifications (anti-citrullinated, carbamylated and -acetylated protein antibodies) have now been described in RA suggesting a shared common ‘developmental’ basis. The studies described in these thesis aim to understand how autoreactive B cell responses are generated to post-translational modified proteins. Show less
Major histocompatibility class II molecules (MHC class II) are one of the key regulators of adaptive immunity because of their specific expression by professional antigen presenting cells (APC).... Show moreMajor histocompatibility class II molecules (MHC class II) are one of the key regulators of adaptive immunity because of their specific expression by professional antigen presenting cells (APC). They present peptides derived from endocytosed material to T helper lymphocytes. Consequently, MHC class II is fundamental in orchestrating both cellular and humoral immune responses. A genetic association of certain MHC class II alleles with autoimmunity has long been established. The molecular mechanisms underlying this association are only poorly understood. An in depth understanding of the antigen presentation pathway by MHC class II is essential for the improvement of current therapies. In this thesis, the tools to arrive at a systems understanding of MHC class II antigen presentation are discussed. What are the advantages and disadvantages of a genome-wide screen? And how can a multi-dimensional, data-integrating approach increase the understanding of the systems biology of MHC class II? Show less
The studies described in this thesis focus on the feasibility of using carcinoembryonic antigen (CEA) as a target for immunotherapy of colorectal cancer and on the balance between anti-tumor... Show moreThe studies described in this thesis focus on the feasibility of using carcinoembryonic antigen (CEA) as a target for immunotherapy of colorectal cancer and on the balance between anti-tumor immunity and autoimmune pathology. The potential of CEA as a target antigen for immunotherapy of cancer is conceivably restricted by the fact that CEA is expressed in several abundant and vital tissues, including intestine and stomach, and is even routinely found in the serum of healthy individuals. We demonstrate that the CEA-specific CD4+ T-cell repertoire in CEA-tg mice is severely limited compared to wild-type mice and that this CD4+ T-cell tolerance for CEA was induced by the thymus. In addition we showed that CEA was expressed in medullary thymic epithelial cells (mTEC) in both mice and human beings. The latter suggests that the CEA-specific T-cell repertoire may also be tolerized in people. In further studies we have focussed on possibilities to overcome tolerance of CEA by reconstituting the T-cell repertoire of CEA-tg mice by adoptive transfer of the T-cell repertoire of CEA-immunized wild-type mice into tumor-bearing CEA-tg mice. Adoptive transfer in combination with immune modulation can result in efficient eradication of CEA-positive tumors. However, in order to prevent hazardous CEA-specific autoimmune reactions, the choice of the right immune modulation protocol is critical. Show less
