Citation
Boross, P. (2009, June 4). Immune regulation by receptors for IgG.
Gildeprint, Enschede. Retrieved from https://hdl.handle.net/1887/13824
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Introduction and scope of the thesis
1. Receptors for IgG
An important step in an immune response is the generation of antibodies (Abs) that are able to recognize antigens with high specificity and therefore play a major role in eliminating invading pathogens. Antibodies together with their antigens form immune complexes (ICs).
ICs are capable to set on various effector mechanisms by activating the complement system or by binding to Fc receptors.
Fcγ receptors (FcγRs) are cell surface receptors that bind IgGs – mostly in the form of ICs – by their Fc part. Binding of ICs to FcγRs on effector cells can initiate a range of cellular events, such as uptake of ICs, degranulation, secretion of cytokines, antibody-dependent cell- mediated cytotoxicity (ADCC) or antigen presentation (1). In this interaction, the antibody provides antigen specificity to a variety of cells, most of which are devoid of specific antigen recognition structures (2). Fc receptors are therefore at the interface of the innate and adaptive arm of the immune system.
The human and the mouse FcγR systems are highly homologous. Humans have eight FcγRs:
FcγRIa, Ib, Ic, (b and c are pseudogenes) FcγRIIa, IIb, IIc, FcγRIIIa and IIIb. Mice have only four types of FcγR: FcγRI (CD64), FcγRIIB (CD32), FcγRIII (CD16) and FcγRIV (1) (Figure 1). There are many similarities between the murine and human FcγR families. Both mice and humans have one high affinity receptor (FcγRI), in both systems a set of activating receptors are counter-balanced by one inhibiting receptor. The extended human FcγR family is a result of gene amplification during evolution.
Figure 1. Comparison of murine and human FcγRs
This thesis focuses on the mouse FcγRs. In mice, the low-affinity FcγR genes and the gene for FcRγ-chain are clustered on chromosome 1 (92-94 cM), whereas FcγRI maps to chromosome 3 (45.2 cM).
The different FcγRs exhibit distinct but overlapping ligand-specificity and expression pattern.
IgG1 binds with low affinity preferentially to FcγRIIB and FcγRIII. IgG2a binds with high affinity to FcγRI, with intermediate affinity to FcγRIV and with low affinity to FcγRIII. IgG2b interacts with intermediate affinity with FcγRIV and with low affinity with FcγRIII (3-7).
Expression patterns, affinities and subtype preferences of mouse FcγRs are summarized in Table 1 of Chapter 2 of this thesis.
Functionally, FcγR can be divided into two classes; activating and inhibitory FcγR. In the mouse FcγRI, FcγRIII and FcγRIV are activating, whereas FcγRIIB is an inhibitory FcγR.
Figure 2. Schematic representation of murine FcγRs
In most cases activating and inhibitory FcγRs are coexpressed on the same cell; therefore binding of ICs results in simultaneous triggering of activating and inhibiting signaling pathways (Figure 2). Whether this coengagement results in activation or inhibition is determined by the relative affinities of the antibody isotype to specific FcγRs, expression levels of FcγRs and the cytokine environment.
1.1 Activating FcγRs
Activating FcγRs (FcγRI, III and IV) are multi-subunit receptors, in which the ligand-binding α-chain associates with the signal transducing FcRγ-chain. Intracellular signaling is initiated by the FcRγ-chain immunoreceptor tyrosine-based activation motif (ITAM). Next to its role in signaling, the FcRγ-chain is also essential for normal surface expression of activating FcγRs.
Cross linking of activating FcγRs by ICs results in clustering of ITAM motifs, which initiates the activation of intracellular Src-family protein tyrosine kinases, which phosphorylate tyrosine residues of the ITAM. The phosphorylated ITAM serves as a docking site for the Src-homology 2 (SH2) domain of the protein kinase Syk. Activation of Syk results in phosphorylation of ERK, followed by activation of NFκB and transcription of various genes that will mediate effector mechanisms. Despite that all activating FcγRs seem to exclusively signal via the same FcRγ-chain, their biological functions differ. This suggest that the specific role the different FcγR classes play in antibody effector pathways is mainly determined by differences in expression pattern and differences in affinity for the IgG subclasses IgG1, IgG2a, IgG2b. Whether qualitative differences in the intracellular signals elicited by individual activating FcγRs through the FcRγ-chain play also a role is not yet clear.
With the help of mice deficient for the FcRγ-chain and therefore lacking expression of all activating FcγRs (FcγRI, FcγRIII and FcγRIV), it was shown that these receptors are indispensable for IgG-IC-mediated effector functions, such as phagocytosis and ADCC (8).
FcRγ-chain knockout (KO) mice are protected from IC-mediated inflammation in several disease models, such as arthritis, anaphylaxis, and heamolitic aneamia (8-11). However, since the FcRγ-chain also associates with several other receptors, in FcRγ-chain KO mice, their function is also impaired. A better definition of the function of FcγRs came from the analysis of mice that are selectively inactivated for one (or more) FcγR ligand-binding α-chain.
FcγRI is a high affinity FcR, the only FcγR that is able to bind monomeric IgG2a. Under physiological conditions it is occupied by monomeric IgG2a, which restricts its availability to newly formed ICs. Analysis of the human FcγRI showed that the affinity of the receptor is regulated via a so-called inside-out mechanisms, which lowers receptor affinity, thereby freeing the receptor from bound IgG2a and making it available to ICs (12). There are no indications for the presence of this regulatory mechanism in mice. Expression of FcγRI is restricted to mononuclear cells and is strongly upregulated in response to cytokine stimulation.
In FcγRI KO mice IgG2a-IC-induced cellular phagocytosis, cytokine release, ADCC and antigen presentation are impaired. Furthermore, these mice have reduced hypersensitivity responses and arthritis severity and they exhibit impaired protection to bacterial infections (4;13). In addition, antibody therapy of metastatis of melanoma in the lung, using antibodies of IgG2a isotype is not effective in FcγRI KO mice (14).
FcγRIII is expressed on monocytes, macrophages, neutrophils, dendritic cells (DCs), mast cells and NK cells. It is a low-affinity receptor that binds both IgG1 and IgG2a isotypes.
FcγRIII KO mice have impaired IgG1-IC-mediated effector functions in vitro. That IgG1-IC predominantly use FcγRIII in vivo is demonstrated by FcγRIII KO mice that have impaired IgG1-mediated passive cutaneous anaphylaxis, ADCC and phagocytosis (6;15;16).
The recently identified FcγRIV binds both IgG2a and IgG2b with intermediate affinity (17).
In models of immunotrombocytopaenia (ITP), ADCC and nephrotoxic nephritis, the activity of IgG2b antibodies was found to be dependent on the presence of FcγRIV in vivo, despite its capacity to bind to both FcγRIII and FcγRIV in vitro (18-22).
Effector mechanisms Effector cell Immune response Immuno-pathology
Phagocytosis Mφ, DC,
neutrophil
Protection against infectious agents e.g. viruses, bacteria, parasites Release of inflammatory
mediators
Mast cell, Mφ, eosinophil, basophil, neutrophil
Immune modulation Hypersensitivity - anaphylaxis (allergy) - hemolytic anemia
Antibody-dependent cell- mediated cytotoxicity
Mφ, neutrophil, eosinophil, NK cells
Anti-tumor response (immunotherapy) Viral infections
Chronic inflammation:
- arthritis
- glomerulonephritis - myastenia gravis - vasculitis Antigen presentation DC (Mφ) Immune modulation
Table 1. Effector mechanisms of FcγR 1.2 The inhibitory FcγRIIB
FcγRIIB is a potent negative regulator of activation of IC-triggered inflammation. Of all FcγRs, FcγRIIB has the broadest expression pattern; it is expressed on B cells, macrophages, monocytes, neutrophils, mast cells, basophils, DCs, enabling regulation of the immune response on multiple levels. The molecular mechanism of inhibition by FcγRIIB is best characterized in B cells. During the late phase of immune response, ICs might bind simultaneously to B cell receptor (BCR) and FcγRIIB, which are coexpressed by the B cells. Co-clustering of the BCR with FcγRIIB suppress B cell signaling, and function, such as activation of the B cell, antigen presentation, proliferation and antibody production.
The single-chain inhibitory FcγRIIB bears an immunoreceptor tyrosine-based inhibition motif (ITIM) on its intracellular domain. The mechanism of inhibition by FcγRIIB involves the phosporylation of ITIM by the Src-family kinase Lyn. This allows the recruitment of SH2-domain-containing phosphatases, such as SH2-domain-containing protein tyrosine
phosphatase 1 (SHP1) and SH2-domain-containing inositol polyphosphate 5’ phosphatase (SHIP) (23;24). Of the two, SHIP is the primary effector molecule of FcγRIIB-mediated inhibition (25).
FcγRIIB is a low-affinity FcR; it binds IgG1 and IgG2b, and to a lesser extend IgG2a. As a consequence, it is able to regulate the biological activity of IgG1- and IgG2b-ICs the most, whereas the activity of IgG2a-ICs is less subjected to regulation by FcγRIIB (20). On effector cells, FcγRIIB sets the balance for activation by ICs when coengaged with activating FcγRs, on B cells, when it is coengaged with BCR.
Loss of FcγRIIB expression results in uncontrolled B cell activation. Accordingly, FcγRIIB KO mice exhibit a hyperactive immune system, such as increased titers after immunization or enhanced Arthus reaction (26). In addition, these mice develop spontaneous autoimmune syndromes when backcrossed on C57Bl/6, but not on Balb/c background (27). An explanation for this difference between inbred strains could be that silencing of autoreactive IgM heavy chains is more efficient in Balb/c compared to C57Bl/6 mice (28). Nevertheless, lack of FcγRIIB contributes to autoimmunity also on Balb/c background, since Balb/c mice, double deficient for programmed death 1 (PD-1) and FcγRIIB develop autoimmune hydronephrosis (29). The fact that Balb/c FcγRIIB KO and PD-1 KO mice are healthy, suggests that FcγRIIB deficiency is not the initiator of autoimmunity but rather augments the effect of other genetic factors. In addition, Balb/c FcγRIIB KO mice show enhanced severity in a pristane-induced lupus model (30).
An important question is, at which stage is FcγRIIB important since autoreactive B cells can be generated throughout all stages of B cell development. Accumulating evidence shows that FcγRIIB represents a distal checkpoint. Using a knock-in mouse with autoreactive BCR, it was shown that FcγRIIB-deficiency did not impact early events in the bone marrow, such as receptor editing, nor did it enhanced the development of IgM-positive autoreactive B cells.
However, after class switching to IgG, FcγRIIB was essential in preventing the generation of antibody secreting cells and differentiation of plasma cells (28). Homologous crosslinking of FcγRIIB induces apoptosis of B cells in vitro (31;32). This mechanisms might also be relevant in vivo in controlling plasma cell survival and homeostasis and thereby preventing accumulation of autoreactive IgG-secreting cells (33). These findings support the idea that FcγRIIB expression represents an important checkpoint that prevents the development of self-reactive B cells.
Recent data questioned the role of FcγRIIB in spontaneous autoimmunity. FcγRIIB KO mice are generated on C57Bl6/129 mixed background. Inactivation of genes located nearby FcγRIIB on Chr1 also lead to an autoimmune phenotype (e.g. SAP, C1q, CR1/2), much of which has subsequently found to be caused by the adjacent 129-derived genomic region rather than the deletion itself (34-37). In addition, wild type C57Bl/6 mice congenic for the 129-derived region around FcγRIIB show spontaneous autoimmunity (38).
Restoration of FcγRIIB expression on only 30% of the B cells, 20% of immature thymocytes
and 10% of macrophages was enough to reduce humoral autoimmunity in FcγRIIB KO and autoimmune prone NZM2410 mice (39). Restoring normal of FcγRIIB expression on B cells has the ability to reduce humoral immunity, whether that prevents development of severe autoimmune diseases is not yet proven. Importantly, since the FcγRIIB KO mice are congenic for the 129-derived Sle1 locus, they carry the same Sle1 haplotype as NZM2410.
FcγRIIB overexpression has the potency to suppress immune response and therefore may downregulate autoimmunity. It is relevant to know which cell type is the most important in mediating this suppression. Early experiments using transfer of FcγRIIB-deficient bone marrow suggested that FcγRIIB expression on B cells is essential (27). In a recent study, using transgenic mice overexpressing FcγRIIB specifically in the B or myeloid cell compartments, it was shown that FcγRIIB on B cells is the most important in suppressing humoral autoimmunity, whereas FcγRIIB on myeloid cells regulates inflammation and infection (40).
Crosslinking of activating FcγRs on DCs results in cell activation and cross-presentation of the internalized antigen (41). FcγRIIB prevent spontaneous maturation of DCs triggered by low levels of ICs both in humans and mice (42-44). Moreover, uptake of antigen by DCs via FcγRIIB are recycled for cell surface for presentation to B cells that therefore induce TI immune response (45).
Next to its regulatory role on B cells and DCs, FcγRIIB is an important modulator of effector cells, such as macrophages, neutrophils, mast cells (46). FcγRIIB KO mice show enhanced IgG1-IC-induced local anaphylaxis (26) enhanced Arthus-reaction (47), IgG- induced systemic anaphylaxis (48), IC-induced alveolitis (46), and anti-GBM antibody- induced glomerulonephritis (49) and become susceptible to Collagen-Induced Arthritis (50) and Goodpasture’s syndrome (51) when back crossed on C57Bl/6 background. Moreover, FcγRIIB inhibits the activity of anti-tumor antibodies (52). In addition, IVIG action has been shown to involve FcγRIIB, although whether it is a direct or indirect involvement is not yet elucidated (53-56).
2. Autoimmune diseases
Autoimmune diseases are characterized by the destruction of self-tissues by the body’s own immune system (57). Arthritis, multiple sclerosis (MS), autoimmune diabetes and systemic lupus erythematosus (SLE) are autoimmune diseases that affect millions of people worldwide.
Linkage and association studies have established that several genetic and non-genetic factors contribute to the development of autoimmunity (58).
A normal immune response is characterized by a delicate balance between activating and inhibitory signals (59). As a result, the ensuing response is strong and long lasting enough to eliminate pathogens or malignant cells but controlled and specific enough to avoid damage to non-infected or healthy tissues (57). To ensure the latter, several control mechanism are present to prevent autoreactive or overwhelming immune responses, and potentially harmful
cells are deleted or inactivated at central or peripheral checkpoints. For example, during development of B cells in the bone marrow, B cells expressing self-reactive receptors are eliminated by mechanism, such as deletion, receptor editing or anergy (60;61). This process is, however, incomplete and self-reactive B cells can escape to the periphery; in addition, autoreactive B cells can be generated de novo in the periphery during the germinal center reaction (62). This implies the existence of additional peripherial checkpoints that prevent the generation and activation of autoreactive B cells. In particular, B cells that secrete class- switched self-reactive antibodies, which can trigger inflammatory effector functions, need to be tightly regulated (18;63). IgGs are not only the most potent antibody isotype in host defense, but also, when directed against self structures, the ones that can cause the most damage to the host.
In the present thesis two autoimmune diseases are studied; arthritis and systemic lupus erythematosus, SLE.
2.1 Rheumatoid Arthritis
Rheumatoid Arthritis (RA) is a chronic, debilitating systemic inflammatory disorder that mainly affects the joints causing pain and loss of function. RA is more common in women than in man and affects 0.5-1% of the adult population worldwide (64;65). Genetic and environmental factors both contribute to disease incidence, but the precise cause and etiology of RA remains unknown.
Several mouse models are available that mimic most, but not all characteristics of the human disease (66). Arthritis cannot be induced in mice lacking CD4+ T cells, indicating indispensable role for this cell type in the initiation phase (67;68). However, once autoreactive B cells have received T cell help, T cells are no longer needed and autoantibodies are sufficient for maintaining arthritis. Autoantibodies accumulate in the joints and cause inflammation via activating FcγRs and the complement system. Complement activation results in the production of C5a, a strong chemotactic factor that attracts neutrophils to the joint. In addition, C5a acting through C5a receptor (C5aR) exacerbates inflammation by altering the ratio of activating to inhibitory receptors on local macrophages, making them more responsive to IC- mediated activation (69). Local and newly recruited effector cells secrete proinflammatory cytokines (e.g. TNFα, IL-1β) upon triggering via FcγRs that further amplifies inflammation.
In the late stage of RA altered behavior of joint resident cells (synovioctes, chondrocytes and osteoclasts) leads to remodeling of the cartilage and bone.
2.2 Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is characterized by a diverse array of clinical symptoms. Current therapies are only aiming at alleviating disease symptoms. It is a highly heterogeneous disease, presenting differently from patient to patient and with no single clinical or immunological feature required to make a formal diagnosis (70;71). Circulating antinuclear antibodies are commonly seen in SLE and their presence forms part of the diagnosis. The deposition of autoantibodies in organs, such as the
kidney or the skin, results in chronic inflammation. Both the innate and adaptive arms of the immune systems contribute to disease pathogenesis. Immunological dysfunction is likely to precede clinical disease with many years (72).
According to the current model, SLE susceptibility is determined by multiple immunological abnormalities arising from genetic variation at multiple loci. In the majority of the cases these are relatively common variants that are found throughout the population, each of which contributes modestly to disease risk (73). Moreover, studies of both patients and animal models suggest that genetic factors arising from a particular linkage region may contribute to specific clinical or immunological features of SLE.
Our understanding of SLE genetics largely increased due to the publication of two high- density genome-wide association (GWA) analysis (74;75). These studies identified some novel, previously unrecognized susceptibility genes for SLE, such as ITGAM, STAT4 or BLK. In particular, the initial components of the complement system, such as C1q, C2, C4 and FcγRIIa and FcγRIIIa emerge from these studies that point to a likely defect in IC clearance.
Based on the genes found from association studies the pathogenesis of SLE most likely involves multiple critical steps, such as antigen recognition and presentation, autoreactive T and B cell activation. Although genetic factors influence the individual’s risk of developing SLE, the trigger for disease onset is likely provided by environmental triggers, which are largely unknown.
A number of inbred mouse strains are known to show spontaneous lupus-like syndromes, such as (NZB X NZW)F1 hybrid (NZB/W), MRL/lpr strain and BXSB strain (76). These strains exhibit high IgG autoantibody titres against a variety of nuclear autoantigens, hypergammaglobulinemia, splenomegaly, and expanded populations of activated CD4 T cells and B cells. Often IC-mediated glomerulonephritis results in increased mortality due to kidney failure. Murine lupus differs in a number of features from SLE (e.g. lack of skin rashes). Nevertheless, these mouse strains have been successfully used for genetic dissection of systemic autoimmunity. The importance of epistasis in the development of severe systemic autoimmunity was already apparent early in the analysis of lupus-prone mice (76).
2.3 Human FcγRs in autoimmune diseases
It is now well established that FcγRs are key players in several processes that without proper regulation yield to autoimmune phenotypes (77). Since activating and inhibiting FcγRs are often coexpressed on the same cell, IC binding will result in the simultaneous triggering of both activating and inhibiting pathways. Balanced signaling will ensure adequate and regulated activation. This signaling can be perturbed in several ways, such as aberrant expression of FcγRs or allelic variants that bind certain IgG isotype with different affinity (63;78).
In humans, low copy number of FcγRIIIB has been associated SLE (79). This finding is subsequently confirmed with other systemic but not organ-specific autoimmune diseases (80).
More recently, functional characterization of this variation has been done, such as protein expression, neutrophil uptake of and adherence to ICs, and with soluble serum FcγRIIIB (81). It is proposed that reduced FcγRIIIB expression results in impaired clearance of ICs, which may induce development of SLE. FcγRIIIB is a GPI-linked membrane receptor that does not have its own signaling motif. It is proposed that FcγRIIIB signals through either FcγRIIA or CD11b (Mac-1), a subunit of CR3, the receptor for iC3b. Of interest, CD11b has also been associated with SLE, further pointing to a possible role of FcγRIIIB. An SNP in 18% of the healthy population changes the pseudogene FcγRIIC to a functional receptor. This variation associates with autoimmune idiopathic thrombocytopenic purpura (ITP) (82).
Several studies show association between FcγRIIB and autoimmune diseases in humans.
Polymorphism in the promoter region of FcγRIIB that results in decreased receptor expression has been linked to SLE (83). However, Su et al. showed that a promoter polymorphism resulting in increased expression of this inhibitory receptor is associated with SLE (84).
Another study showed that memory B cells from SLE patients fail to upregulate FcγRIIB, resulting in reduced threshold for B cell activation (85). Moreover, an allelic variant of FcγRIIB has been associated with SLE and arthritis in several Asian populations (86-89). In this variant, the exchange of an isoleucine residue in the transmembrane domain (position 232) for threonine results in impaired recruitment of FcγRIIB to lipid rafts, thereby reducing its ability to inhibit BCR-mediated signals (90;91).
3. Mouse models
Although a lot is learned from studies in the human system, most of our knowledge about the role of FcγRs in diseases originates from studies using mice deficient for one (or more) FcγRs in disease models. Even though mouse FcRs somewhat differ from their human counterparts, this underlines the usefulness of the mouse as a model organism to study pathogenesis of human diseases. The development of a wide range of genetic tools in the mouse enables us to analyze in great detail the specific functions of the different FcγRs both in immunity and in disease mechanisms and pathology. Recently the genetic toolbox in the mouse is further extended with methods that allow spatial and temporal control of the modification of the FcγR genes.
3.1 Conditional knockout mouse models
Strategies for unraveling of mechanisms of development and function of immune system increasingly rely on the use of transgenic and knockout mouse models. Our ability to modify the mouse genome has advanced enormously in the recent years (92;93). The limitations of conventional knockout technology, such as early lethality, ubiquitous effect of the inactivated gene and compensation mechanisms have highlighted the importance of spatio-temporally controlled somatic mutagenesis (93). These strategies are generally based on the Cre/loxP system, which makes use of the P1 bacteriophage-derived recombinase, Cre, that specifically
recognizes a 34 bp long DNA sequence (loxP site). After recognition Cre forms a DNA loop and excises the fragment between the two loxP sites (Figure 3).
In this approach a mouse is required in which the targeted gene (or only its essential exons) is flanked by loxP sites, a so called floxed allele. This mouse strain is crossbred to another strain that express Cre recombinase under a cell- or tissue-specific promoter. In the offspring carrying both the Cre transgene and the floxed allele, gene inactivation caused by loxP recombination only occurs in cells, where Cre is active, which allows the study of cell-type specific function of specific proteins.
3.2 Inducible somatic mutagenesis
Some experimental systems provide the opportunity to inactivate a specific gene in adult animals at a desired time point. Temporal control is provided by transgenic mice expressing the Cre recombinase in an inducible manner (94-96).
One such system is CreERT2, which is based on a fusion protein between the Cre recombinase and the modified ligand-binding domain of the estrogen receptor (ER) (97;98). In this system, after transcription, the CreERT2 protein is retained in the cytoplasm bound to heat- shock proteins. Induction is triggered by tamoxifen, a synthetic estrogen receptor antagonist that only binds to the mutated and not the endogenous estrogen receptors. When tamoxifen is administered, CreERT2 dissociates from the heat-shock proteins and translocates to the nucleus, and excises the DNA fragments flanked by loxP sites (Figure 4).
Figure 3. The Cre/loxP system
Figure 4. The CreERT2 system
To date, a number of mouse strains with conditional (‘floxed’) alleles have been generated, as well as cell- or tissue-specific constitutive or inducible Cre-expressing strains (92). Regulated somatic mutagenesis permits detailed in vivo analysis of gene function in adult mice.
Scope and structure of the thesis
The aim of this thesis is to investigate the in vivo role of murine FcγRs with special focus on autoimmunity. Chapters 2 to 5 focus on the role of FcγRs in arthritis. In Chapter 2, an overview from literature describes and discusses what we have learned in the recent years about the role of FcγRs in arthritis from studies in a variety of arthritis models established mainly in genetically modified mouse strains. Chapters 3 to 5 present results using mice deficient for one or more FcγR analyzed in various murine arthritis models to reveal the individual role of the FcγRs. In Chapter 6, as well as in Chapter 7, the generation and characterization of novel genetically modified mouse models is presented. Chapter 6 describes the analysis of the role of the inhibiting FcγRIIB in the development of autoimmune diseases. The generation and characterization of a novel B cell-specific inducible Cre-expressing mouse strain is presented in Chapter 7. Finally, a discussion of the results, future research directions and implications of the data is provided.
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