Dentritic cells and the battle against arthritis
Duivenvoorde, L.M. van
Citation
Duivenvoorde, L. M. van. (2007, October 10). Dentritic cells and the battle against arthritis. Retrieved from https://hdl.handle.net/1887/12372
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Introduction
Chapter 1
Arthritis
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an autoimmune disease which is characterized by chronic inflammation and infiltration of the synovium with activated immune cells. Approximately 0.5-1% of the adult population in Europe and North America suffers from RA (1,2).
Since symptoms of RA have a very heterogeneous presentation, early symptoms of the disease may not be so explicit to establish the diagnosis RA. In clinical practice, rheumatologists base their diagnosis by attributing specific characteristics (e.g. the appearance of several episodes of symmetrical swollen joints, morning stiffness, erosions on X-rays and detection of circulating rheumatoid factor) to RA, thereby making the diagnosis. Furthermore, if the first presentation of arthritis is not clear-cut to support the diagnosis of RA, other causes of arthritis need to be excluded, such as other arthritis-related autoimmune diseases (systemic lupus erythematodes (SLE), psoriasis) and malignancies.
For scientific purposes, the American College of Rheumatology (ACR) has generated classification criteria, which are depicted in table 1. When a patient fulfils 4 of the 7 criteria for at least 6 weeks, he or she is acknowledged as a RA-patient (3).
Unfortunately, there is still no cure available for RA, and patients are mainly treated to decrease the disease-symptoms using anti-inflammatory drugs, disease modifying anti- rheumatic drugs (DMARDs) and/or biologicals like tumor necrosis factor (TNF) inhibitors.
As these drugs are all non-specific and inhibit many aspects of the immune system, they are associated with side effects.
Immunopathology of rheumatoid arthritis
Although various features of RA are well-defined and characterized (like morning stiffness and the presence of rheumatoid factor (RF)), the underlying pathology and cause of RA is still unknown. Many association- and linkage-studies are performed to investigate the role of both genetic and environmental components that might play a role in the development and/or in the progression of RA (4-7).
Table 1: Criteria for having RA, according to the American College of Rheumatologists (ACR). If a patient is positive for at least 4 out of the 7 criteria, the patient can be diagnosed RA positive.
ACR-criteria for the classification of Rheumatoid Arthritis
1.
Morning stiffness for at least 1 hour2.
Simultaneous arthritis in 3 or more joint-structures3.
Arthritis in at least 1 joint of the hand4.
Symmetric involvement of joints5.
Rheumatoid nodule-formation6.
Rheumatoid Factor positive7.
Radiographic changes, including erosion and bone decalcificationStudies in families showed that first-degree relatives of RA patients have a higher risk to develop RA than individuals from the “general” population (8). This implies that there is a genetic contribution to RA.
Genetic and environmental risk factors
The most important genetic risk factor is the human leukocyte antigen (HLA) complex.
The first to show a correlation between certain HLA-genes and RA was Peter Stastny in 1976 (9). He showed that lymphocytes of RA patients reacted less pronounced against stimulators of other RA patients in a mixed lymphocyte reaction (HLA-mismatched) as compared to healthy individuals. Ruling out possibilities that drugs or autoantibodies inhibited proliferation, he concluded that there must be a genetic element which regulated this decrease in proliferation. Later, others have shown that also other HLA-DRB1 alleles were associated with RA (10-12). These HLA-DRB1 molecules contain a conserved sequence, the “shared epitope” (SE), which is proposed to play a role in the presentation of antigens which are important for the induction and/or progression of RA (13).
A few other examples of genetic risk factors are PTPN22 and PADI4.
A single-nucleotide polymorphism (SNP) in a gene encoding protein tyrosine phosphatase N22 (PTPN22) is associated with RA in RF seropositive individuals. PTPN22 functions as a negative regulator of T cell activation and is expressed by several hematopoietic cells, like T cells, B cells, NK cells, monocytes, neutrophils and NKT cells. Individuals carrying the risk-allele of PTPN22 have a higher change to develop RA as compared to individuals carrying the other allele (14,15).
Another example is the association between PADI4 (peptidylarginine deiminase type 4) and RA. PAD enzymes mediate the modification of arginine into citrulline in proteins.
Post-translational modifications of proteins, including peptidyl citrullination, are related to autoimmunity, and peptidyl citrulline is a known target of one of the most specific autoantibodies for RA. The PADI4 gene-variant has been implicated in RA in Japanese and Korean populations, but not in Caucasions and it’s expression in synovial tissue is associated with levels of anti-cyclic citrullinated peptides/proteins antibodies (ACPAs) (16).
The genes mentioned above are found in association with RA on several occasions and therefore have been replicated well. There are also other genetic associations found in RA, indicating that multiple genetic factors contribute to the development and/or progression of RA. However, these await further replication.
There is less information on environmental factors that might play a role in the induction and/or progression of RA. Smoking is one of the few conventional environmental factors that has been linked to an increased risk of developing RA (17-19). The explanation for smoking as a risk factor is not known. One possible mechanism is the anti-estrogenic effect, which reduces the protective effect of estrogen (18). Another possibility is that smoking enhances the production of ACPAs, especially in the context of SE-positive individuals, because cells from bronchoalveolar lavage from smokers contained large amounts of citrullinated proteins in contrast to bronchoalveolar lavages from non-smoking controls (20).
Autoantibodies
A classical autoantibody, which is also one of the seven ACR-criteria, is Rheumatoid Factor (RF). RFs are directed against the Fc-tails of immunoglobulin G (IgG) (21). Although the name suggests differently, RFs are not specific for RA. They are also detectable in patients with other autoimmune diseases, like SLE and Sjögrens disease, and in healthy persons (especially elderly) these RF’s can be measured (22).
More recently, another autoantibody, which is more specific for RA, has been identified.
These autoantibodies are directed against proteins and/or peptides containing a citrulline instead of an arginine residue. Citrullination is a normal occurring process, in which the arginine residue is posttranslational modified into a citrulline residue. It is mediated by the enzyme peptidylarginine deiminase and results in the loss of a positive charge. Although the role of this process is still unclear, it has been proposed that it plays a role in preparing intracellular proteins for degradation during apoptosis (23,24) and in the regulation of transcription through citrullination of histones (25). Even though, the citrullination process itself is not specific for inflammation or disease, the presence of antibodies against these citrullinated peptides and proteins seem to be highly RA-specific (90-97%) (26,27).
Recently, several groups showed an association of the “shared epitope” from the HLA- DRB1 and the presence of ACPAs (20,28-30). It was concluded that the genetic risk factor of HLA-DRB1 is actually associated with the presence of ACPAs, and not with the development of RA. Furthermore, Hill et al. demonstrated that mice, transgenic for the HLA-DRB1 alleles, containing the shared epitope, were able to induce specific CD4+ T cell responses to citrullinated peptides from vimentin, whereas they were not able to initiate specific T cell responses against the same peptide, containing an arginine residue instead of the citrulline residue (31). This indicated that HLA-DRB1 alleles, containing the SE, are, most likely, important for the induction of cyclic citrullinated protein (CCP)-specific T-helper cells, which can help the B cell to produce specific antibodies directed against the same citrullinated antigen.
Even more intriguingly is the observation that these ACPAs can be detected many years before a patient develops clinical symptoms of RA (32-34). These autoantibodies have therefore a predictive value for the development for RA. For that reason it might be relevant to develop a vaccine, which can be used as prophylactic treatment, before the induction of the clinical symptoms of RA in individuals at risk to develop RA (i.e.: ACPA positive subjects). It is not necessary to vaccinate all people against RA, but it might be beneficial to test people with a higher risk for developing RA for the presence of ACPAs. For this purpose, one might consider to examine women above 50 and perhaps relatives of RA patients. If these individuals are ACPA-positive, it could be beneficial to treat them before they actually develop clinical symptoms of RA.
In this thesis we have investigated the effect and efficacy of a cellular vaccine against arthritis. For this purpose, we made use of the mouse model collagen-induced arthritis (CIA).
Collagen-Induced Arthritis
To study the immunopathology underlying RA, researchers make use of animal models.
There have been several experimental animal models developed to study RA as mice
and other rodents do not develop RA (35-39). One of the best described and well-studied models is collagen-induced arthritis (CIA) (40,41). CIA can be induced via immunization with heterologous type II collagen (CII) of genetically susceptible mice, leading to the development of a severe polyarticular arthritis that is mediated by an autoimmune response.
Although CIA is certainly not similar to RA, many characteristics, such as the systemic nature of the arthritis, the production of autoantibodies, the chronic and destructive inflammation of joints, as well as the association with the MHC class II molecules highly resembles important features of RA.
Immunopathology of collagen-induced arthritis
The immunopathological processes underlying CIA are nicely described in a review by Luross and Williams (42). This model is depicted in figure 1 and shortly described below.
Susceptible DBA/1 mice (H-2q) are injected with bovine CII in complete Freund’s adjuvant (CFA) in the base of the tail. Locally, endogenous DCs will take up and process the CII- protein and mature in the presence of heat-killed Mycobacterium tuberculosis which is present in the CFA. These activated, CII-presenting DCs will migrate into the draining lymph nodes and activate naïve CD4+ T cells to become primarily CII-specific, IFN-γ producing Th1 cells. These Th1 cells will help the DC to become more activated (2nd signal) and help the B cells to produce anti-CII-specific antibodies, mainly of the IgG2a isotype.
These IgG2a antibodies can migrate into the joint and bind to murine CII (cross-reactivity), thereby activating complement. Complement activation leads to the release of complement proteins, like C3a, C4a and C5a, which can cause a local inflammatory response by activating endothelial cells from the blood vessel. This activation would facilitate the early entry of activated T cells, monocytes and neutrophils. The activation of macrophages by CII-specific antibodies, complexed to articular cartilage via Fc-receptors will lead to tumor necrosis factor (TNF) production. Locally produced IL-1 (by both monocytes and neutrophils) acts as the primary factor to trigger tissue destruction by infiltrating cells and resident synoviocytes, fibroblasts and chondrocytes.
Destruction of joints will lead to the release of more antigens and a continuation of the disease.
The presence of CII-specific antibodies is crucial for the disease induction, as B cell- deficient mice are not able to develop arthritis (43) and as transfer of CII-specific antibodies is already sufficient to induce arthritis (44,45). Furthermore, recently it is shown that within this model also ACPAs are measurable in blood of DBA/1 mice after induction of CIA (46). In this article they also demonstrated that tolerizing mice with a citrulline-containing peptide resulted in a significant reduction of disease severity and incidence compared to non-tolerized controls. Unfortunately, these findings are not yet reproduced and confirmed by other groups, but that may be due to a range of variations in the experimental set-up.
Nonetheless, this model is a good tool to investigate the potential effect of a cellular vaccine to treat arthritis. For the development of such a cellular vaccine, we chose to use dendritic cells (DCs) as these are pivotal key players in initiating an immune response.
Dendritic Cells
Dendritic cells (DCs) were first described by Ralph Steinman and Zanvil Cohn (47). Although the function was not known, they were morphologically described and differentiated from phagocytes, granulocytes and lymphocytes. Nowadays, DCs are known to be professional antigen-presenting cells (APCs) that are present in low numbers in all body tissues (48).
In the 1990s there was a model proposed in which two different subsets of DCs were described, the immature and mature DCs (49). Immature DCs are capable of antigen- Figure 1. The hypothesized model for CIA.
DCs will take up the collagen-protein, get activated by the mycobacterial components of the CFA, thereby efficiently present the Ag to naïve T cells, which become activated Th1 cells. These Th1 cells will produce a lot of IFN-G and thereby help the B cell to produce A-CII specific antibodies, mainly of the IgG2a isotype. These antibodies can migrate through the blood vessels and bind murine CII in the joint, thereby activating the complement system. Complement activation will lead to endothelial cell activation, and cells, like T cells, macrophages and neutrophils, can migrate into the joint. These will, on their turn, get activated, produce more cytokines, like TNF and IL-1 and processes of tissue destruction will occur.
uptake. After an activation stimulus from the innate immune system through, for example TLR-triggering, DCs become activated and upregulate the expression of MHC molecules and co-stimulatory molecules, like B7.1 and B7.2. Upon maturation DCs will lose their ability to take up antigen, but can present the antigen to T cells and thereby initiate an antigen-specific immunogenic response.
Recently, this model and the nomenclature of DCs are under discussion (50). At first it was suggested that mature DCs induce an immunogenic immune response, whereas immature DCs were able to initiate a tolerizing immune response, by the induction of regulatory T cells; anergy or ignorance of T cells or even deletion of immunogenic T cells (51-53).
Currently, several groups showed that also semi-mature or mature DCs are able to induce tolerance as expression of MHC molecules and (low-)expression of costimulatory molecules are necessary to induce antigen-specific tolerogenic T cells (54-57).
Induction of different T-helper cell-populations by dendritic cells.
The DC is a highly plastic cell type, which can drive immune responses into the desired direction. DCs are able to acquire and present antigens to T cells in different conditions, thereby directing the outcome of the T cell response into the preferred track (figure 2).
Figure 2. Thelper cell differentiation.
Prompted by different types of cytokines produced by DCs and other sources, naïve CD4+ T cells can differentiate into different lineages of T cell-subsets, which produce different types of cytokine themselves. Furthermore these T cell-subsets are also able to suppress the development of other T cell-subsets. Regulatory T cells suppress the initiation of all three other types of CD4+ T cells; Th1 cells and their cytokines suppress the induction of both Th2 and Th17 cells; Th2 cells and their cyto- kines suppress the activation of Th1 and Th17 cells and Th17 and their cytokines probably suppress the induction of Th1 and Th2 cells.
Although the mechanisms employed by DCs to orchestrate the immune system are less clear, it is generally accepted that the environment provides DCs with essential signals that are instrumental to the decision which type of immune response will be mounted (58). For example, the induction of Th1 cells is important to combat intracellular pathogens, like bacteria and viruses. Th1 cells will help to activate cytoxic T lymphocytes (CTLs) and B cells to produce for example IgG2a antibodies, while the induction and activation of Th2 cells is requested for the defense against extracellular parasites, like helminthes and protozoa (figure 3).
Importantly, Th2 cells enhanced IgE and IgG1 synthesis, whereas Th1 cells promoted IgG2a production by B cells (59). This was in line with the finding that the Th2-cytokine IL-4 controls class-switching to IgE and IgG1 and the Th1-cytokine IFN-γ controls switching to IgG2a (60).
Another set of CD4+ T cells are the so-called “regulatory” T cells. These T cells can arise directly from the thymus as a distinct T cell population (the “naturally occurring”
regulatory T cells), but can also be induced after a trigger in the periphery, most likely from DCs. Regulatory T cells are selected on their expression of CD25 (the IL-2R-α chain) and their production of either IL-10 or TGF-β. As these characteristics are not exclusively for regulatory T cells, it is difficult to discriminate these cells from normal, activated CD4+
T cells. In mice, the transcription factor Fox-p3 is specific for Treg cells (i.e. it is not yet Figure 3. Environmental factors decide the outcome of the immune response induced by DCs.
The presence of, for example, Mycobacterium tuberculosis leads to the maturation of DCs that are endowed with the capacity to activate Th1 cells that helps macrophages to clear the bacterial infection. In contrast, the presence of parasites, like helminthes, instructs DCs to activate Th2 cells, which helps the induction of IgE-secreting B cells and mast cells for the clearance of the helminthes infection.
observed that it is also expressed on other cells) (61,62). For humans, it is different, as also activated effector T cells are able to express Fox-p3 (63). The main function of these regulatory T cells is to suppress or regulate other immune responses.
A new lineage of effector CD4+ T cells, which is distinct in development and function compared to Th1- and Th2 subsets, is recently described. These so-called Th17 cells are characterized by the production of IL-17.
This new lineage is in vitro induced after activation in the presence of both IL-6 and TGF-β (64,65). IL-23 (produced by DCs, among others) is an important cytokine for the expansion of these Th17 cells, but it does not instruct naïve CD4+ T cells to become Th17 cells, as naïve T cells do not express the IL-23 receptor. In vivo, it is not yet known under which circumstances naïve CD4+ T cells become Th17 cells and what cells (probably DCs) are responsible for this initiation.
Th17 cells appear to be important in the defense against extracellular bacteria and in mediating inflammation, but it also seems to play a pivotal role in autoimmune diseases, like RA and multiple sclerosis, because depletion of IL-17 decreases experimental arthritis and encephalomyelitis (66,67).
In conclusion, the immune system is equipped with a highly plastic cell type, the DC. The DC will take up antigens and present them to T cells. The pathogen or bacteria and the environment in which DCs will take up the pathogen or bacteria will decide which immune response is directed and what type of T cells will be induced.
Aim and outline of this thesis.
As DCs are the main antigen-presenting cells and key players in setting immune responses and connecting innate with adaptive immunity, it is favorable to use these cells to manipulate the immune system to circumvent autoimmunity, in this case CIA.
Because CIA is still implicated as a Th1-mediated disease, the aim was to skew the immune system towards a more Th2-like phenotype or to induce a T cell with a regulatory capacity.
Therefore, several ways to stimulate DCs and subsequently the evolving T cell response were selected, to analyze whether Th2 cells or regulatory T cells were activated, resulting in inhibition of arthritis.
In chapter 2, we show that partially activated DCs (TNF modulated DCs) were able to suppress CIA in a prophylactic setting. The DCs were infused prior to immunization with type II collagen. The protective effect observed was related with the induction of IL-5 producing T cells (Th2-like T cells) and a decrease in production of specific anti-collagen IgG2a antibody titers.
In chapter 3, different modulatory DCs were compared side-by-side in the CIA-model, but also in the Ovalbumin (OVA)-system, making use of OVA as a model-antigen and OVA-specific T cell-receptor transgenic CD4+ T cells. In this chapter we have showed that TNF modulated DCs as well as IL-10 + LPS and dexamethasone + LPS modulated DCs were able to suppress CIA in a prophylactic setting, but only IL-10 + LPS modulated DCs were able to do so when anti-collagen specific antibodies were already present. Although
the clinical outcome in the prophylactic setting was similar, there were many differences between these DCs, when cytokine production, levels of costimulatory molecules and notch-ligands were measured. As TNF and IL-10 + LPS stimulated DCs induced T cells with a Th2-like phenotype (production of both IL-5 and IL-10) and an Ag-specific decrease in IgG2a antibody titers, Dex + LPS modulated DCs induced IL-10 producing T cells and a non-Ag specific IgG2a antibody decrease. These data show that although several immunomodulatory DCs were all able to suppress or inhibit CIA and Th1-mediated immune responses, their mode of action differs.
In chapter 4, the main focus is on immature DCs. These DCs were prepared via a different protocol, and these immature DCs were also able to suppress CIA. Their mode of action is most likely via the induction or activation of IL-10 producing DX5+CD4+ T cells as this T cell subset was able to transfer protection into naïve DBA/1 mice.
Chapter 5 uses a different approach to inhibit CIA. In this chapter bone marrow transplantation and isolated CD4+CD25+ T cells were used in a therapy setting (after disease induction).
Here, we show that CD4+CD25+ T cells are very strong regulators of the immune system.
In chapter 6 again DCs were used in a vaccination-strategy. However, in this case, we investigated the potential of DCs to prevent atherosclerosis, another systemic, inflammatory disease. Atherosclerosis involves the formation of lesions in the arteries that are characterized by inflammation, lipid accumulation, cell death and fibrosis (68). Fully activated (LPS) DCs, loaded with oxidized low-density lipoproteins (ox-LDL) were used to induce a proper immune response against modified LDL. We show that vaccination using ox-LDL-pulsed DCs represents a successful strategy for the reduction of arterial atherosclerotic lesion formation in LDLr-/- mice.
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