Dendritic cells (DCs) are antigen-presenting cells (APCs) which play a key role in the regulation of immune responses. DCs are often referred to as __professional__ APCs, since their primary... Show moreDendritic cells (DCs) are antigen-presenting cells (APCs) which play a key role in the regulation of immune responses. DCs are often referred to as __professional__ APCs, since their primary function is to present antigens from pathogens or malignant cells. Consequently, there is a great deal of interest in how DCs might be exploited as a form of immunotherapy e.g. to induce immunity to cancers. However, DCs are also thought to play an important role in directing regulatory immune responses to innocuous antigens, which are targeted in autoimmune disease or during transplantation. Soluble factors secreted by DCs are crucial mediators in determining this balance between the immunogenic and regulatory arms of the immune system. One such group of factors is cytokines and one family which is gaining increasing attention is the IL-12 family. It is composed of four members; two are immunogenic and their expression has been very well characterised in DCs. The other two are regulatory, but relatively little is known about their regulation and expression in DC populations. In this thesis we aim to give a comprehensive overview of the expression and regulation of IL-12 family members in human DCs, with a particularly emphasis on IL-12, IL-27 and IL-35. Show less
Xu, W.; Zhao, X.W.; Daha, M.R.; Kooten, C. van 2013
Due to their abilities to eliminate pathogens and modulate host__s immune responses, antimicrobial peptides are considered as potential alternatives for the treatment of infections with (multi-drug... Show moreDue to their abilities to eliminate pathogens and modulate host__s immune responses, antimicrobial peptides are considered as potential alternatives for the treatment of infections with (multi-drug resistant) pathogens. In this thesis the immunomodulatory actions of two peptides have been investigated in order to gain insight in their mechanism of antimicrobial action; human lactoferrin-derived antimicrobial peptide hLF1-11 and the human cathelicidin LL-37. As hLF1-11 is active against infections in animals within a short period, we hypothesized immunomodulatory effects of hLF1-11 on innate immune cells. Results described in this thesis show that hLF1-11 enhances the inflammatory response of monocytes and modulates monocyte-macrophage differentiation resulting in macrophages that display enhanced antimicrobial effector functions. In addition, hLF1-11 drives monocyte-dendritic cell differentiation toward DCs that promote antifungal responses and induce Th17 polarization. Myeloperoxidase was identified as the intracellular target of hLF1-11 mediating immunomodulatory effects of this peptide. We also found that LL-37 was able to modulate monocyte-macrophage differentiation, however different than hLF1-11 as this resulted in macrophages with a pro-inflammatory phenotype. Together, these data underscore the bright future of antimicrobial peptides with immune modulating activity as these peptides might be developed further into a novel class of anti-infectives to which microbial drug-resistance is unlikely to develop quickly. Show less
MHC class II antigen presentation by B cells is important to activate CD4+ T cells that stimulate the B cell to produce antibodies. Besides this, disruption of MHC class II antigen presentation... Show moreMHC class II antigen presentation by B cells is important to activate CD4+ T cells that stimulate the B cell to produce antibodies. Besides this, disruption of MHC class II antigen presentation could play a role in immune escape by tumor cells. This thesis describes MHC class II antigen presentation by B cells during bacterial infections and leukemia. We show that, in contrast to the current dogma, human B cells are able to phagocytose whole, living Salmonella bacteria via their B cell receptor (BCR). Salmonella survives intracellular and is transported by the B cell to the spleen where Salmonella can infect other cells. Although Salmonella uses the B cell to disseminate and escape the immune system, uptake of Salmonella by B cells also results in a good immune response consisting of specific antibody production, antigen presentation and activation of both CD4+ T helper cells and cytotoxic CD8+ T cells that are able to eliminate infected cells. Many leukemic cells express MHC class II. For AML (acute myeloid leukemia) we show that expression of the self-peptide CLIP could be a measure for immune escape because a high percentage of HLA-DR+/CLIP- blasts correlates with a longer disease-free survival. In B-CLL (chronic lymphocytic leukemia), the percentage of activated CD4+ and CD8+ T cells is enhanced and inversely correlated to CLIP. In addition, transcription of all MHC class II genes is increased and B-CLL patients with high HLA-DOA mRNA levels have a less favorable prognosis. Show less
Endocytosis can be conceptually broken down into two stages: The formation of the nascent vesicle containing the ingested proteins and lipids, and its subsequent maturation into a degradative... Show moreEndocytosis can be conceptually broken down into two stages: The formation of the nascent vesicle containing the ingested proteins and lipids, and its subsequent maturation into a degradative compartment. During this maturation process proteins can be recycled back to the plasma membrane to prevent degradation. The vesicular membrane and the luminal contents undergo considerable remodeling to transform this compartment into a degradative one. This stops signal transduction by degrading the receptors within the vesicle and also generates antigens for presentation on MHC class II molecules in order to elicit an adaptive immune response. The engulfment of large particles and microorganisms (e.g. pathogens) is referred to as phagocytosis. The vesicle created by phagocytosis is called the phagosome. Phagosome maturation is considered to involve a complex sequence of fusion and fission events with the sub compartments of the endocytic pathway. In many ways, phagosome maturation recapitulates the progression of cargo along the endocytic pathway. In this thesis we have described molecular mechanisms that regulate the endocytic route and how pathogens explore this endocytic route to ensure survival. Show less
The major targets in Systemic lupus erythematosus (SLE, a systemic autoimmune disease) are nuclear components (DNA, histones, ribonucleoproteins), which are mainly derived from dying cells ... Show moreThe major targets in Systemic lupus erythematosus (SLE, a systemic autoimmune disease) are nuclear components (DNA, histones, ribonucleoproteins), which are mainly derived from dying cells (apoptotic and necrotic cells). Defective clearance of dying cells by phagocytes may lead to the breakdown of peripheral tolerance and initiation of autoimmune SLE. I have investigated the role of the innate immune system in the processing of dying cells and its immunological consequences. I found that a subset of macrophages driven by M-CSF have intrinsic anti-inflammatory properties and are potent phagocytes that have the unique capacity to preferentially bind and ingest early apoptotic cells in a silent manner. I also identified that human peritoneal macrophages freshly isolated from patients on peritoneal dialysis resemble functionally the in vitro-generated M-CSF-driven macrophages. I further showed that the anti-inflammatory and pro-inflammatory macrophages co-exist but can re-differentiate towards opposing phenotype depending on the local cytokine environment. Next to the phagocyte system, I investigated the role of components of the innate immune system in the processing of dying cells. I found that one of the complement regulators called properdin, binds predominantly to late apoptotic and necrotic cells independently of C3b, resulting alternative pathway complement activation. Show less
