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Inflammation in autoimmunity: receptors for IgG revisited
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Inflammation in autoimmunity: receptors for IgG revisited Hilde M. Dijstelbloem, Jan G.J. van de Winkel and Cees G.M. Kallenberg During the past decade, our knowledge of Fc receptor interactions in inflammation has increased dramatically owing to the availability of single and multiple Fc-receptor-deficient mice. The deletion of activating Fcγγ receptors protects against inflammation in models of immune-complex-mediated diseases, whereas the deletion of inhibitory Fcγγ receptors triggers increased susceptibility to immune-complex-induced inflammation. These new insights have a profound impact on our understanding of inflammation in autoimmune diseases, such as systemic lupus erythematosus (SLE). Comprehending the complex interactions between activating and inhibitory Fcγγ receptors might lead to new therapeutic approaches for human diseases, including SLE.
Receptors for the Fc domain of IgG (FcγRs) provide a crucial link between the humoral and cellular branches of the immune system. Ligation of these receptors can trigger a variety of immune effector functions1–3. An important role for FcγRs has been demonstrated in the uptake of immune complexes (ICs) by tissue-resident macrophages4,5. Since the late 1970s, it has been known that this FcγRmediated uptake is defective in the prototypic IC-mediated autoimmune disease systemic lupus erythematosus (SLE)6. Indeed, during the past decade, heterogeneity of the FcγRs has been found to affect binding to IgG and influence the clinical manifestations of SLE (Ref. 7). The influence of differential FcγR responses on inflammatory processes, as shown elegantly in panels of Fcreceptor-deficient animal models3, is a challenging new concept in our understanding of this disease. An imbalance in FcγR interactions might underlie the severity of inflammation in systemic autoimmune diseases, such as SLE. Structural diversity of Fcγγ receptors Hilde M. Dijstelbloem Cees G.M. Kallenberg Dept of Clinical Immunology, University Hospital Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. Jan G.J. van de Winkel* Immunotherapy Laboratory, Dept of Immunology and Genmab, Kc 02-085.2, University Medical Center Utrecht, Lundlaan 6, 3584 EU, Utrecht, The Netherlands. *e-mail: J.vandeWinkel@ azu.nl
Several articles have reviewed the structural and functional aspects of Fc receptors for IgG extensively1–3. Currently, three classes of FcγRs are distinguished on cells of the immune system: the high-affinity receptor FcγRI (CD64), capable of binding monomeric IgG; and the low-affinity receptors FcγRII (CD32) and FcγRIII (CD16), which interact preferentially with complexed IgG. Although these receptors show overlapping binding patterns for IgG subclasses, they vary in their cellular effector functions. FcγRI, FcγRIIa and FcγRIIIa are activating receptors, characterized by the presence of an immunoreceptor tyrosine-based activation motif (ITAM), either in the cytoplasmic domain of the receptor (FcγRIIa) or associated with the receptor as an accessory signaling subunit (γ and/or ζ chains http://immunology.trends.com
associated with FcγRI and FcγRIIIa). By contrast, FcγRIIb is an inhibitory receptor, containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. A marked exception to this dichotomy is FcγRIIIb; this receptor is linked to the outer leaflet of the plasma membrane by a glycosyl phosphatidylinositol (GPI) anchor and does not contain or associate with ITAMs or ITIMs. There is presently no homolog described for FcγRIIIb (or FcγRIIa) in mice. Activating FcγRs are found on platelets and most leukocytes – including monocytes, granulocytes, macrophages and natural killer (NK) cells – but only on a few subsets of lymphocytes. Upon interaction with IgG, these receptors initiate phagocytosis, antibody (Ab)-dependent cellular cytotoxicity (ADCC), the transcription of cytokine genes and the release of inflammatory mediators. By contrast, the inhibitory FcγRIIb is expressed on immune cells, such as B cells, dendritic cells and macrophages. Coligation of this receptor to ITAM-containing receptors inhibits ITAMtriggered activation and proliferation. Furthermore, the homo-aggregation of FcγRIIb has been shown to induce apoptosis in B cells8. The characteristics of activating and inhibitory receptors are summarized in Table 1 and Figure 1. The recently described crystal structures of FcγRIIb (Ref. 9), FcγRIIa (Ref. 10) and FcγRIII (Refs 11,12) have revealed that FcγRs exist as dimers on the cell surface. The two Ig domains of FcγRII and FcγRIII are arranged to expose the ligand-binding site at one end of the second domain (Fig. 1). Whether a 1:1 or 2:1 stoichiometry exists between the receptor and the Fc part of IgG remains a matter of debate. Because the FcγR–IgG interaction might represent a suitable target for immunotherapy, as discussed later in this review, a better understanding of this interaction is crucial to the structure-based design of drugs. In addition to their expression on cells of the immune system, receptors for IgG are present on endothelial cells, and epithelial cells of mammary gland, intestine, liver and kidney. Unlike leukocyte FcγRs, these so-called neonatal Fc receptors (FcRns) are related structurally to MHC class I molecules, and were first identified as receptors that transfer maternal IgG across the maternofetal barrier during gestation13. More-recent data have indicated a role for FcγRIIb in this process also; this receptor is expressed in the villus endothelial cells of human placenta14.
1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)02014-2
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Table 1. General characteristics of human leukocyte IgG receptorsa Receptor class (CD)
Molecular weight (kDa)
Genes (chromosome)
Signaling motif
Signaling subunits
Affinity for IgG (K a)
Mouse equivalent
FcγRI (CD64)
72
FcγRIA FcγRIBb FcγRICb (1q21.1)
– – –
γ ND ND
High (108–109 M–1)
FcγRI
FcγRII (CD32)
40
FcγRIIA
ITAM
γ
Low (<107 M–1)
FcγRIII (CD16)
50–80
FcγRIIB
ITIM
–
FcγRIICb (1q23–24)
ITAM
ND
FcγRIIB
FcγRIIIA FcγRIIIB (1q23–24)
– –
γ, ζ –
Medium (±3 × 107 M–1) Low (<107 M–1)
FcγRIII
aAbbreviations:
FcγR, Fcγ receptor; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ND, not determined. bNot discussed in this review.
Whether FcγRIIb functions as a transporter of IgG in these cells, or possibly as an IC scavenger receptor, remains a matter of debate. The activity of FcRns appears to be pH-dependent. IgGs are taken up by endothelial and epithelial cells through nonspecific pinocytosis and subsequently, enter acidic lysosomes. If IgG binds to FcRn, transport back to the cell surface will favor its release at neutral pH; if IgG does not bind to FcRn, transfer to lysosomes will favor its degradation. In this respect, FcRn has been shown to be responsible for the maintenance of serum IgG levels, both systemically and locally in organs, such as liver and kidney13. Remarkably, FcRn appears to be expressed functionally, with a regulated cellular distribution, in monocytes, macrophages and dendritic cells also15. This expression might confer novel IgG-binding functions upon these cell types, involving the I
protection of IgG from catabolism, and as such, might impact on other FcγR-related functions. These and other intriguing aspects of this receptor have been reviewed in detail recently13. Heterogeneity of Fcγγ receptors
Genetically determined variation has been described for FcγRIIa, FcγRIIIa and FcγRIIIb, for example: an Arg to His substitution at amino acid position 131 of FcγRIIa; a Val to Phe substitution at amino acid position 158 of FcγRIIIa; and four amino acid substitutions, termed neutrophil antigen polymorphisms (NA1 and NA2), for FcγRIIIb (Fig. 1). Some of these polymorphisms are relevant functionally, because they have a profound influence on binding to human IgG (Table 2). Moreover, these polymorphisms were found to influence susceptibility to a number of infectious and autoimmune diseases7,16.
IIa
IIb
IIIa
IIIb
EC1 EC2 Val158Phe
Arg131His ζ ζ
ζ γ
γ γ
S–S
S–S
S–S
+
+
EC3
EC1 EC2
EC1 EC2
EC1 EC2
NA1/NA2 64 88 • 47 EC1 18 EC1 EC2 EC2 GPI
+
+
Extracellular
Intracellular
_
+
+
+
+
+
+
Key: +
+
+
+
_
ITAM ITIM TRENDS in Immunology
Fig. 1. Structural diversity and heterogeneity of human Fcγ receptors (FcγRs). All receptors belong to the Ig super family, with their extracellular regions (ECs) composed of disulfide (S–S)-bonded domains. FcγRI, FcγRIIa and FcγRIIIa are activating receptors, characterized by the presence of an immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of the receptor (FcγRIIa) or associated with the receptor as an accessory signaling
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subunit (γ and/or ζ chains associated with FcγRI and FcγRIIIa). FcγRIIb is an inhibitory receptor, containing an immunoreceptor tyrosinebased inhibitory motif (ITIM) in its cytoplasmic domain. FcγRIIIb is linked to the plasma membrane by a glycosyl phosphatidylinositol (GPI) anchor. Functional polymorphisms in FcγRIIa, FcγRIIIa and FcγRIIIb are indicated by red circles. Abbreviation: NA, neutrophil antigen polymorphism.
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Table 2. Heterogeneity and ligand specificity of human IgG receptorsa
FcγRIa
Receptor variant
–
3>1>4>>>2
2a=3>>>1,2b
FcγRIIa
Arg131 His131
3>1>>>2,4 3>1=2>>>4b
2a=2b=1 2a=2b>>>1
FcγRIIb
–
3>1>4>>2
2a=2b>1
FcγRIIIa
Val158 Phe158
1=3>4>>2c 1=3>>>2,4
3>2a>2b>>1 3>2a>2b>>1
NA1 NA2
1=3>>>2,4d
3>2a>2b>>1 3>2a>2b>>1
FcγRIIIb
Arg/Arg131
Ligand specificity for IgG isotypes Human Mouse
1=3>>>2,4
aAbbreviations:
FcγR, Fcγ receptor; NA, neutrophil antigen polymorphism. has higher affinity for human IgG3 than FcγRIIa-Arg131 does. cFcγRIIIa-Val158 has higher affinity for human IgG1 and human IgG3 than FcγRIIIa-Phe158 does. dFcγRIIIb-NA1 internalizes human IgG1- or human IgG3-opsonized particles more efficiently than FcγRIIIb-NA2 does. bFcγRIIa-His131
Evidence in support of a role for the heterogeneity of FcγRs in susceptibility to SLE has been controversial, although genome scans have indicated that the FcγR locus on chromosome 1 is genetically relevant17. Several studies have reported an increased frequency of the FcγRIIa-Arg131 or FcγRIIIa-Phe158 variants in patients with SLE compared with healthy controls, specifically in patients with SLE nephritis7,16,18,19. These variants interact with various IgG subclasses with reduced efficiency, in particular, the interaction of FcγRIIa-Arg131 with IgG2 (Table 2)7,16. Although allelic associations could not be reproduced in all studies7,16,20, the Arg–His polymorphism of FcγRIIa was shown to affect the clearance of ICs in vivo in a small population of patients (Fig. 2)20. Indeed, the effect of heterogeneity of FcγRIIa on the handling of ICs might have important implications for a disease such as SLE. Also, polymorphic variants of FcγRs have been implicated in autoimmune diseases other than SLE, including neurological disorders, such as Guillain–Barré syndrome and myasthenia gravis21,22. In rheumatoid arthritis, the Val–Phe polymorphism of FcγRIIIa appears to be involved in susceptibility to disease, although findings have been contradictory23,24. A skewed distribution of the FcγRIIa-Arg131His polymorphism has been observed in patients with different forms of thrombocytopenia, although not consistently in all studies25–27. Notably, the combined homozygous FcγRIIa-Arg/Arg131 and FcγRIIIa-Phe/Phe158 phenotype was shown to influence the relapse rate of Wegener’s granulomatosis, a systemic vasculitis characterized by autoAbs against neutrophil granular constituents28. Although such allelic combinations could be of relevance in SLE as well, this has not been demonstrated as yet20. Fcγγ receptors and inflammation in autoimmunity The humoral immune response
Both activating and inhibitory FcγRs are involved in the generation and control of an appropriate http://immunology.trends.com
Half-life (min.)
Receptor class
70
Arg/His131
60
His/His131
50 40 30 20 10 0 FcγRIIa phenotype TRENDS in Immunology
Fig. 2. Half-life in minutes (min.) of IgG-coated erythrocytes in the blood of patients with systemic lupus erythematosus expressing different Fcγ receptor IIa (FcγRIIa) phenotypes. Labeled erythrocytes coated with anti-rhesus antiserum were injected intravenously, and blood samples were taken regularly to determine their half-life. Half-life was prolonged in patients expressing the homozygous FcγRIIA-Arg/Arg131 phenotype compared with patients expressing other FcγRIIA genotypes (heterozygous Arg/His131 and homozygous His/His131) (P = 0.027), demonstrating an effect of this phenotype on the clearance of immune complexes in vivo.
humoral immune response (Fig. 3). Activating FcγRs have been shown to enhance Ab responses by the efficient internalization of ICs by antigen (Ag)-presenting cells (APCs) and increased presentation of Ag (Refs 29–31). Indeed, the IgG-mediated enhancement of Ab responses is low in FcR γ-chain-deficient mice, lacking expression of FcγRI and FcγRIII, but increased in FcγRIIb-deficient mice31,32. In addition, the internalization of ICs by activating FcγRs might influence the epitopes that will be presented by APCs, because certain epitopes are presented selectively after FcγRIII- but not FcγRII-mediated internalization29,30. This might have consequences for the ensuing specific T-cell responses, in particular when otherwise cryptic epitopes are presented. The participation of activating FcγRs in revealing cryptic epitopes in vivo and consequently, their possible involvement in autoimmunity remains to be established. By contrast, the inhibitory FcγRIIb acts to set thresholds for B-cell activation upon co-crosslinking with surface Ig, a mechanism whereby ICs can suppress the production of Ab (Fig. 3c). FcγRIIb is both necessary and sufficient for the downregulation of B-cell-receptor-induced calcium mobilization and cellular proliferation33,34. In addition, self-ligation of FcγRIIb induces B-cell apoptosis8. This characteristic of FcγRIIb might contribute to the maintenance of peripheral tolerance during the affinity maturation of B cells, by promoting the deletion of low-affinity, selfreactive lymphocytes. In accordance with these findings, FcγRIIb-deficient mice on a specific genetic
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(a) Antigen presentation
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(c) Humoral immune response __
FDC _ _
__
++
+
–
MHC I
B cell
BCR
TCR
Proliferation Ca2+ mobilization
__
+ APC
MHC II T cell B cell
__
Apoptosis BCR
(b) Clearance of immune complexes
(d)
++
++
+
+
__
__
++
__
+
Balance
Inflammation
No inflammation TRENDS in Immunology
Fig. 3. Receptors for IgG are involved in the development and progression of autoimmune disease at different levels of the immune response. Although both activating and inhibitory receptors influence (a) the presentation of antigen to T cells and (b) the clearance of immune complexes, inhibitory receptors alone control (c) the humoral immune response. Inhibitory receptors either suppress the activation and proliferation of B cells when co-crosslinked to the B-cell receptor (BCR), or induce apoptosis when self-ligated, contributing to the control of antibody production or the maintenance of peripheral tolerance, respectively. Furthermore, inflammation and tissue damage is dependent on (d) a balance between the ligation of activating and inhibitory receptors. Dysregulation at any of these levels might have profound influence on immune-complex-mediated diseases, such as systemic lupus erythematosus. Abbreviations: APC, antigen-presenting cell; FDC, follicular dendritic cell; TCR, T-cell receptor.
background develop autoAbs spontaneously, eventually culminating in lupus-like disease35. The primary site for the interaction of B cells with ICs is in the germinal center, where ICs are retained by follicular dendritic cells (FDCs). FcγRIIb, the sole Fc receptor on FDCs, has been shown to be important in the presentation of ICs to B cells and the generation of a strong recall response36. Consequently, deletion of FcγRIIb from FDCs might compensate, at least in part, for the deletion of FcγRIIb from B cells. Thus, the lupuslike phenotype developed by FcγRIIb-deficient animals might not be attributable to the effect of FcγRIIb on the development of autoAbs alone, as discussed later. Clearance of immune complexes
The clearance of ICs from the circulation is regulated normally by the mononuclear phagocyte system (MPS). In this system, erythrocytes bind to ICs through complement receptor 1 (CR1), providing a mechanism for transport of the complexes to mononuclear phagocytes located in liver and spleen. http://immunology.trends.com
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Subsequently, the complexes are removed from the erythrocytes by the proteolytic cleavage of CR1, and internalized by tissue-resident phagocytes4,5. The importance of FcγRs in this process (Fig. 3b) has been demonstrated by studies of FcγR blockade in primates and mice37, as well as in vitro studies modeling this ‘transfer reaction’5. Defective FcγR-mediated clearance of ICs has been described in patients with SLE (Ref. 6). Recently, we determined the contribution of individual FcγRs to the function of the MPS, using a model IC and panels of FcγR-deficient mice38. Remarkably, FcγRIIb was found to be the crucial receptor for the clearance of ICs. Because this receptor acts as an inhibitory receptor, FcγRIIb might well be the primary receptor for noninflammatory clearance of ICs by the MPS. In accordance with these findings, several studies have shown that the deletion of FcγRIIb results in increased susceptibility to IC-induced diseases, for example, collageninduced arthritis and Goodpasture’s syndrome39–41. Moreover, functional polymorphisms in the regulatory regions of the FcγRIIB gene, which affect the surface expression and function of the receptor, have been associated with autoimmune manifestations in mice42,43. These results, in combination with the spontaneous development of lupus-like disease in FcγRIIb-deficient mice35, indicate that FcγRIIb has a dual influence on autoimmunity, involving both the development of autoAbs and the clearance of ICs. Inflammation
When the handling of ICs by the MPS is impaired, their subsequent deposition in the tissues might result in inflammation and tissue damage. This autoimmune-associated inflammation is generally classified as type-II or -III hypersensitivity. The generation of single and multiple FcγR knockout mice44–47 provided an opportunity to study the role of different FcγRs in these types of inflammation. The classical model of IC-mediated inflammation is the reverse passive Arthus reaction, in which Ab is applied to skin or lung and Ag is administered intravenously. The inflammatory response that develops subsequently, characterized by the infiltration of granulocytes, plasma exudation and hemorrhage, was shown to be severely impaired in FcR γ-chain-deficient mice, which lack expression of FcγRI and FcγRIII, and FcγRIII-deficient mice46,48,49. These results indicate the involvement of activating FcγRs, in particular FcγRIII, in IC-mediated inflammation. By contrast, an enhanced inflammatory response was observed in FcγRIIb-deficient mice, demonstrating the inhibitory effect of this receptor on ITAM-triggered activation45,49. Whether the activation of complement is a crucial factor in this reaction or is involved in the later stages of the inflammatory response remains a matter of debate49–51.
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Similarly, other animal models of human diseases have demonstrated a crucial role for activating FcγRs in autoimmune-mediated inflammation, most strikingly in a murine model of lupus, the New Zealand Black/New Zealand White mouse. The spontaneous generation of anti-DNA Abs and circulating ICs in these animals is followed by the deposition of ICs and the activation of complement in kidney and other tissues. Although these mice have a greatly reduced life expectancy, owing to the development of severe glomerulonephritis, disruption of the FcR γ-chain alone was found to completely abrogate the inflammatory response52. Similar protection from tissue damage upon deletion of the FcR γ-chain was observed in models of antiglomerular basement membrane glomerulonephritis and collagen-induced arthritis40,53–55. As in the Arthus reaction, the inhibitory FcγRIIb was shown to suppress FcγR-mediated activation in these models39,40. Cytotoxic IgGs directed against red blood cells or platelets are characteristic of several autoimmune diseases, including SLE. Once again, a crucial role for FcγRIII was shown in the pathogenic mechanism of these Abs, because FcR γ-chain- or FcγRIII-deficient mice were both protected from the development of hemolytic anemia and thrombocytopenia56,57. Although this autoAbinduced process was heavily dependent on the subclass of IgG, related to the capacity of the Ab to interact with activating FcγRs (Ref. 57), the activation of complement did not appear to be important50,56. Remarkably, ligation of the inhibitory FcγRIIb did not affect autoAb-mediated cell destruction, either directly or by counterregulating FcγRIII (Ref. 58). The reason for this marked difference in the influence of FcγRIIb on cytotoxic IgG-induced responses compared with other types of IC-mediated inflammation is presently unclear. As indicated by these recent studies, inflammation and tissue damage in IC-mediated diseases, such as SLE, are dependent on a balance between the ligation of activating FcγRs, in particular FcγRIII, and inhibitory receptors, such as FcγRIIb (Fig. 3d). An imbalance in the opposing actions of these receptors might well underlie the severity of inflammation in systemic autoimmune disease. Therefore, the lupus-like phenotype developed by FcγRIIb-deficient animals might be attributed to an effect of the absence of FcγRIIb on IC-triggered inflammatory responses, by lowering the thresholds for activating FcγRs. FcγRIIb does not appear to have this kind of influence on all autoimmune phenomena, as shown for autoAb-induced hemolysis. Whether this differential regulation is owing to the expression levels of activating and inhibitory FcγRs on the specific effector cell, selective affinity for a certain ligand, the particular cell type involved in the inflammatory response or additional factors, such as http://immunology.trends.com
the activation of complement, remains to be elucidated. Concluding remarks and perspective
During the past decade, mouse models of inflammatory diseases have established the clear involvement of receptors for IgG in the development and progression of autoimmune disease, at different levels of the immune response: the generation and control of cognate interactions, the clearance of ICs and the inflammatory response. Dysregulation at any of these levels might have a profound influence on IC-mediated diseases, such as SLE. Indeed, mice deficient in FcγRIIb develop lupus-like disease spontaneously35, and many autoimmune-prone mouse strains have reduced surface expression and function of this inhibitory receptor42,43. Conversely, mice deficient in activating FcγRs are resistant to IC-induced inflammatory responses and tissue damage40,46,48,49,52–57. It should be noted that neither functional defects in FcγRIIb nor polymorphic variants of this receptor have been described in patients with SLE thus far. By contrast, several functional polymorphisms of activating FcγRs have been associated with disease and the reduced clearance of ICs (Refs 7,16,18–20). Hence, it remains to be determined whether dysregulation in human SLE is predominantly at the level of activating or inhibitory FcγRs. The mouse models described in this review indicate that FcγRs are potential targets for immunotherapy. Abrogating the inflammatory potential of activating FcγRs through manipulation of IgG–FcR interactions might be an attractive therapeutic approach in SLE. In this respect, interference with the Fc domain of (pathogenic) Abs might prevent the ligation of activating FcγRs and their subsequent downstream effects. Indeed, administration of an Ig-binding peptide prevented disease in lupus-prone mice59. An alternative approach would be to stimulate the catabolism of (pathogenic) IgG. Administering Abs that block the actions of FcRns could achieve this effect. In accordance with this hypothesis, mice deficient in FcRns are protected against the development of experimental SLE in two separate models60,61, most probably because they catabolize IgG as well as pathogenic autoAbs rapidly. Intervention could also be accomplished with Abs that block the ligand-binding domain of activating FcγRs, thus inhibiting the initiation of effector-cell responses. Preliminary results of a Phase II study in humans indicate this novel therapeutic concept to be successful in the treatment of idiopathic thrombocytopenic purpura62. Correspondingly, the immunomodulatory effects of treatment with intravenous Ig (IVIg) have long been recognized in (autoimmune-mediated) inflammation. Although the blockade of FcRs is believed to be the primary action of IVIg in this treatment, other activities might
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Acknowledgement We thank Marjolein van Egmond for kind help with the artwork.
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contribute to its therapeutic potential, including the attenuation of complement-mediated tissue damage, neutralization of autoAbs by anti-idiotype Abs, modulation of cytokine responses and downregulation of B-cell function63. Remarkably, a recent study contradicts this dogma, suggesting that the primary activity of IVIg is in stimulating the antiinflammatory properties of the inhibitory FcγRIIb, rather than blocking activating FcγRs (Ref. 64). These findings implicate the ligation of inhibitory FcγRs as a potent therapeutic strategy for autoAb-mediated diseases. Recent advances in Ab engineering might provide a promising method to influence immune
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recruitment by FcγRs specifically. Altering residues in the IgG Fc portion might abrogate or improve binding to one or more receptor or, in fact, simultaneously improve binding to one type of receptor and reduce binding to another type65. Indeed, such engineered Abs would be capable of ligating inhibitory FcγRs, at the same time as blocking activating FcγRs. In addition, the half-life of therapeutic IgG in the serum might be increased by altering the interaction of the IgG Fc with FcRns (Ref. 66). In the future, these new developments might guide the rational design of engineered Abs with improved therapeutic efficacy for complex autoimmune-mediated diseases, such as SLE.
pedigrees. Proc. Natl. Acad. Sci. U. S. A. 95, 14869–14874 Michel, M. et al. (2000) The R131 low-affinity allele of FcγRIIa receptor is associated with systemic lupus erythematosus but not with other autoimmune diseases in French Caucasians. Am. J. Med. 108, 580–583 Koene, H.R. et al. (1998) The FcγRIIIA-158F allele is a risk factor for systemic lupus erythematosus. Arthritis Rheum. 41, 1813–1818 Dijstelbloem, H.M. et al. (2000) Fcγ receptor polymorphisms in systemic lupus erythematosus: association with disease and in vivo clearance of immune complexes. Arthritis Rheum. 43, 2793–2800 Van der Pol, W.L. et al. (2000) IgG receptor IIA alleles determine susceptibility and severity of Guillain–Barre syndrome. Neurology 54, 1661–1665 Raknes, G. et al. (1998) FcγRIIa and FcγRIIIb polymorphisms in myasthenia gravis. J. Neuroimmunol. 81, 173–176 Nieto, A. et al. (2000) Involvement of Fcγ receptor IIIA genotypes in susceptibility to rheumatoid arthritis. Arthritis Rheum. 43, 735–739 Morgan, A.W. et al. (2000) Fcγ receptor type IIIa is associated with rheumatoid arthritis in two distinct ethnic groups. Arthritis Rheum. 43, 2328–2334 Williams, Y. et al. (1998) Correlation of platelet FcγRIIa polymorphism in refractory idiopathic (immune) thrombocytopenia purpura. Br. J. Haematol. 101, 779–782 Carlsson, L.E. et al. (1998) Heparin-induced thrombocytopenia: new insights into the impact of the FcγRIIa-R/H131 polymorphism. Blood 92, 1526–1531 Burgess, J.K. et al. (1995) Single amino acid mutation of Fcγ receptor is associated with the development of heparin-induced thrombocytopenia. Br. J. Haematol. 91, 761–766 Dijstelbloem, H.M. et al. (1999) Fcγ receptor polymorphisms in Wegener’s granulomatosis: risk factors for disease relapse. Arthritis Rheum. 42, 1823–1827 Amigorena, S. et al. (1998) Type II and III receptors for immunoglobulin G (IgG) control the presentation of different T-cell epitopes from single IgG-complexed antigens. J. Exp. Med. 187, 505–515 Regnault, A. et al. (1999) Fcγ receptor-mediated induction of dendritic-cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune-complex internalization. J. Exp. Med. 189, 371–380
31 Hamano, Y. et al. (2000) Immune complex and Fc receptor-mediated augmentation of antigen presentation for in vivo Th cell responses. J. Immunol. 164, 6113–6119 32 Wernersson, S. et al. (1999) IgG-mediated enhancement of antibody responses is low in Fc receptor γ-chain-deficient mice and increased in FcγRII-deficient mice. J. Immunol. 163, 618–622 33 Amigorena, S. et al. (1992) Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256, 1808–1812 34 Muta, T. et al. (1994) A 13 amino-acid motif in the cytoplasmic domain of FcγRIIb modulates B-cell receptor signaling. Nature 368, 70–73 35 Bolland, S. and Ravetch, J.V. (2000) Spontaneous autoimmune disease in FcγRIIb-deficient mice results from strain-specific epistasis. Immunity 13, 277–285 36 Qin, D. et al. (2000) Fcγ receptor IIb on follicular dendritic cells regulates the B-cell recall response. J. Immunol. 164, 6268–6275 37 Kurlander, R.J. et al. (1984) The blockade of Fc receptor-mediated clearance in vivo by a monoclonal antibody (2.4G2) directed against Fc receptors on murine leukocytes. J. Immunol. 133, 855–862 38 Dijstelbloem, H.M. et al. (2000) Crucial role for FcγRII (CD32) in non-inflammatory IC clearance in the liver. Arthritis Rheum. 43, S275 39 Yuasa, T. et al. (1999) Deletion of Fcγ receptor IIB renders H-2b mice susceptible to collagen-induced arthritis. J. Exp. Med. 189, 187–194 40 Kleinau, S. et al. (2000) Induction and suppression of collagen-induced arthritis is dependent on distinct Fcγ receptors. J. Exp. Med. 191, 1611–1616 41 Nakamura, A. et al. (2000) FcγRIIb-deficient mice develop Goodpasture’s syndrome upon immunization with type IV collagen. J. Exp. Med. 191, 899–906 42 Jiang, Y. et al. (2000) Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility. Immunogenetics 51, 429–435 43 Pritchard, N.R. et al. (2000) Autoimmune-prone mice share a promotor haplotype associated with reduced expression and function of the Fc receptor FcγRII. Curr. Biol. 10, 227–230 44 Takai, T. et al. (1994) FcR γ-chain deletion results in pleiotrophic effector cell defects. Cell 78, 519–529 45 Takai, T. et al. (1996) Augmented humoral and anaphylactic responses in FcγRII-deficient mice. Nature 379, 346–349
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46 Hazenbos, W.L.W. et al. (1996) Impaired IgGdependent anaphylaxis and Arthus reaction in FcγRIII (CD16)-deficient mice. Immunity 5, 181–188 47 Gavin, A.L. et al. (1998) Identification of the mouse IgG3 receptor: implications for antibody effector function at the interface between innate and adaptive immunity. J. Immunol. 160, 20–23 48 Sylvestre, D.L. and Ravetch, J.V. (1994) Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265, 1095–1098 49 Clynes, R. et al. (1999) Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activating and inhibitory Fc receptors. J. Exp. Med. 189, 179–185 50 Sylvestre, D. et al. (1996) Immunoglobulin Gmediated inflammatory responses develop normally in complement-deficient mice. J. Exp. Med. 184, 2385–2392 51 Hopken, U.E. et al. (1997) Impaired inflammatory responses in the reverse Arthus reaction through genetic deletion of the C5a receptor. J. Exp. Med. 186, 749–756 52 Clynes, R. et al. (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052–1054
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53 Park, S.Y. et al. (1998) Resistance of Fc receptordeficient mice to fatal glomerulonephritis. J. Clin. Invest. 102, 1229–1238 54 Wakayama, H. et al. (2000) Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRγ-deficient mice. Eur. J. Immunol. 30, 1182–1190 55 Van Lent, P.L. et al. (2000) Role of Fc receptor γ-chain in inflammation and cartilage damage during experimental antigen-induced arthritis. Arthritis Rheum. 43, 740–752 56 Clynes, R. and Ravetch, J.V. (1995) Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 3, 21–26 57 Fossati-Jimack, L. et al. (2000) Markedly different pathogenicity of four IgG isotype-switch variants of an anti-erythrocyte antibody is based on their respective capacity to interact in vivo with low-affinity FcγRIII. J. Exp. Med. 191, 1293–1302 58 Schiller, C. et al. (2000) Mouse FcγRII is a negative regulator of FcγRIII in IgG immune complex-triggered inflammation but not in autoantibody-induced hemolysis. Eur. J. Immunol. 30, 481–490 59 Marino, M. et al. (2000) Prevention of systemic lupus erythematosus in MRL/lpr mice by
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administration of an immunoglobulin-binding peptide. Nat. Biotechnol. 18, 735–739 Mozes, E. et al. (1993) Resistance of MHC class Ideficient mice to experimental systemic lupus erythematosus. Science 261, 91–93 Christianson, G.J. et al. (1996) MHC class I dependence of the lupus-like autoimmune syndrome of MRL/lpr mice. J. Immunol. 176, 4933–4939 Terjanian, T. et al. (2000) A proof-of-concept Phase II study of monoclonal antibody MDX-33 in adult subjects with chronic stable ITP. Blood 96, 251a Rhoades, C.J. et al. (2000) Monocyte–macrophage system as targets for immunomodulation by intravenous immunoglobulin. Blood Rev. 14, 14–30 Samuelsson, A. et al. (2001) Anti-inflammatory activity of IVIg mediated through the inhibitory Fc receptor. Science 291, 484–486 Shields, R.L. et al. (2001) High-resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn and design of IgG1 variants with improved binding to the FcγR. J. Biol. Chem. 276, 6591–6604 Martin, W.L. et al. (2001) Crystal structure at 2.8 Å of an FcRn–heterodimeric Fc complex: mechanism of pH-dependent binding. Mol. Cell. 7, 867–877
From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens Joachim L. Schultze and Robert H. Vonderheide Clinically successful specific cancer immunotherapy depends on the identification of tumor-rejection antigens (Ags). Historically, tumor Ags have been identified by analyzing either T-cell or antibody responses of cancer patients against the autologous cancer cells. The unveiling of the sequence of the human genome, improved bioinformatics tools and optimized immunological analytical tools have made it possible to screen any given protein for immunogenic epitopes. Overexpressed genes in cancer can be identified by gene-expression profiling; immunogenic epitopes can be predicted based on HLA-binding motifs; candidate peptides can be identified by mass spectrometry of tumor-cell-derived HLA molecules; and peptidespecific T cells can be qualitatively and quantitatively analyzed at the singlecell level using ELISPOT and tetramer technologies. Here, we suggest that, based on these advancements, a new class of tumor Ags can be identified by directly linking cancer genomics to cancer immunology and immunotherapy.
Ten years after the landmark studies by Boon1 and Rosenberg2, the once suspect hypothesis that human cancers express antigens (Ags) that can be targeted specifically by cellular immunity, now forms a scientifically justifiable rationale for the design and http://immunology.trends.com
clinical testing of novel Ag-specific cancer immunotherapies. Moreover, the development of novel adjuvants and delivery modalities has accelerated, given the ability to measure specific immune responses to particular prototypic tumor Ags, particularly in melanoma and lymphoma. First-generation tumor Ags were discovered largely by deciphering the molecular targets of anti-tumor T-lymphocyte responses in patients with disease. However, despite clear demonstrations that immunity to these Ags can be generated in cancer patients by a variety of therapeutic approaches, meaningful clinical responses have been minimal. The results reflect, in part, the fundamental limitations of first-generation tumor Ags, which are too restricted in expression to permit wide clinical applicability and too irrelevant to the oncogenic process to prevent the selection of Ag-loss tumor mutants. Here, we propose the advent of a second generation of tumor Ags poised to overcome these obstacles,
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Inflammation in autoimmunity: receptors for IgG revisited Hilde M. Dijstelbloem, Jan G.J. van de Winkel and Cees G.M. Kallenberg During the past decade, our knowledge of Fc receptor interactions in inflammation has increased dramatically owing to the availability of single and multiple Fc-receptor-deficient mice. The deletion of activating Fcγγ receptors protects against inflammation in models of immune-complex-mediated diseases, whereas the deletion of inhibitory Fcγγ receptors triggers increased susceptibility to immune-complex-induced inflammation. These new insights have a profound impact on our understanding of inflammation in autoimmune diseases, such as systemic lupus erythematosus (SLE). Comprehending the complex interactions between activating and inhibitory Fcγγ receptors might lead to new therapeutic approaches for human diseases, including SLE.
Receptors for the Fc domain of IgG (FcγRs) provide a crucial link between the humoral and cellular branches of the immune system. Ligation of these receptors can trigger a variety of immune effector functions1–3. An important role for FcγRs has been demonstrated in the uptake of immune complexes (ICs) by tissue-resident macrophages4,5. Since the late 1970s, it has been known that this FcγRmediated uptake is defective in the prototypic IC-mediated autoimmune disease systemic lupus erythematosus (SLE)6. Indeed, during the past decade, heterogeneity of the FcγRs has been found to affect binding to IgG and influence the clinical manifestations of SLE (Ref. 7). The influence of differential FcγR responses on inflammatory processes, as shown elegantly in panels of Fcreceptor-deficient animal models3, is a challenging new concept in our understanding of this disease. An imbalance in FcγR interactions might underlie the severity of inflammation in systemic autoimmune diseases, such as SLE. Structural diversity of Fcγγ receptors Hilde M. Dijstelbloem Cees G.M. Kallenberg Dept of Clinical Immunology, University Hospital Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. Jan G.J. van de Winkel* Immunotherapy Laboratory, Dept of Immunology and Genmab, Kc 02-085.2, University Medical Center Utrecht, Lundlaan 6, 3584 EU, Utrecht, The Netherlands. *e-mail: J.vandeWinkel@ azu.nl
Several articles have reviewed the structural and functional aspects of Fc receptors for IgG extensively1–3. Currently, three classes of FcγRs are distinguished on cells of the immune system: the high-affinity receptor FcγRI (CD64), capable of binding monomeric IgG; and the low-affinity receptors FcγRII (CD32) and FcγRIII (CD16), which interact preferentially with complexed IgG. Although these receptors show overlapping binding patterns for IgG subclasses, they vary in their cellular effector functions. FcγRI, FcγRIIa and FcγRIIIa are activating receptors, characterized by the presence of an immunoreceptor tyrosine-based activation motif (ITAM), either in the cytoplasmic domain of the receptor (FcγRIIa) or associated with the receptor as an accessory signaling subunit (γ and/or ζ chains http://immunology.trends.com
associated with FcγRI and FcγRIIIa). By contrast, FcγRIIb is an inhibitory receptor, containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. A marked exception to this dichotomy is FcγRIIIb; this receptor is linked to the outer leaflet of the plasma membrane by a glycosyl phosphatidylinositol (GPI) anchor and does not contain or associate with ITAMs or ITIMs. There is presently no homolog described for FcγRIIIb (or FcγRIIa) in mice. Activating FcγRs are found on platelets and most leukocytes – including monocytes, granulocytes, macrophages and natural killer (NK) cells – but only on a few subsets of lymphocytes. Upon interaction with IgG, these receptors initiate phagocytosis, antibody (Ab)-dependent cellular cytotoxicity (ADCC), the transcription of cytokine genes and the release of inflammatory mediators. By contrast, the inhibitory FcγRIIb is expressed on immune cells, such as B cells, dendritic cells and macrophages. Coligation of this receptor to ITAM-containing receptors inhibits ITAMtriggered activation and proliferation. Furthermore, the homo-aggregation of FcγRIIb has been shown to induce apoptosis in B cells8. The characteristics of activating and inhibitory receptors are summarized in Table 1 and Figure 1. The recently described crystal structures of FcγRIIb (Ref. 9), FcγRIIa (Ref. 10) and FcγRIII (Refs 11,12) have revealed that FcγRs exist as dimers on the cell surface. The two Ig domains of FcγRII and FcγRIII are arranged to expose the ligand-binding site at one end of the second domain (Fig. 1). Whether a 1:1 or 2:1 stoichiometry exists between the receptor and the Fc part of IgG remains a matter of debate. Because the FcγR–IgG interaction might represent a suitable target for immunotherapy, as discussed later in this review, a better understanding of this interaction is crucial to the structure-based design of drugs. In addition to their expression on cells of the immune system, receptors for IgG are present on endothelial cells, and epithelial cells of mammary gland, intestine, liver and kidney. Unlike leukocyte FcγRs, these so-called neonatal Fc receptors (FcRns) are related structurally to MHC class I molecules, and were first identified as receptors that transfer maternal IgG across the maternofetal barrier during gestation13. More-recent data have indicated a role for FcγRIIb in this process also; this receptor is expressed in the villus endothelial cells of human placenta14.
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Table 1. General characteristics of human leukocyte IgG receptorsa Receptor class (CD)
Molecular weight (kDa)
Genes (chromosome)
Signaling motif
Signaling subunits
Affinity for IgG (K a)
Mouse equivalent
FcγRI (CD64)
72
FcγRIA FcγRIBb FcγRICb (1q21.1)
– – –
γ ND ND
High (108–109 M–1)
FcγRI
FcγRII (CD32)
40
FcγRIIA
ITAM
γ
Low (<107 M–1)
FcγRIII (CD16)
50–80
FcγRIIB
ITIM
–
FcγRIICb (1q23–24)
ITAM
ND
FcγRIIB
FcγRIIIA FcγRIIIB (1q23–24)
– –
γ, ζ –
Medium (±3 × 107 M–1) Low (<107 M–1)
FcγRIII
aAbbreviations:
FcγR, Fcγ receptor; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ND, not determined. bNot discussed in this review.
Whether FcγRIIb functions as a transporter of IgG in these cells, or possibly as an IC scavenger receptor, remains a matter of debate. The activity of FcRns appears to be pH-dependent. IgGs are taken up by endothelial and epithelial cells through nonspecific pinocytosis and subsequently, enter acidic lysosomes. If IgG binds to FcRn, transport back to the cell surface will favor its release at neutral pH; if IgG does not bind to FcRn, transfer to lysosomes will favor its degradation. In this respect, FcRn has been shown to be responsible for the maintenance of serum IgG levels, both systemically and locally in organs, such as liver and kidney13. Remarkably, FcRn appears to be expressed functionally, with a regulated cellular distribution, in monocytes, macrophages and dendritic cells also15. This expression might confer novel IgG-binding functions upon these cell types, involving the I
protection of IgG from catabolism, and as such, might impact on other FcγR-related functions. These and other intriguing aspects of this receptor have been reviewed in detail recently13. Heterogeneity of Fcγγ receptors
Genetically determined variation has been described for FcγRIIa, FcγRIIIa and FcγRIIIb, for example: an Arg to His substitution at amino acid position 131 of FcγRIIa; a Val to Phe substitution at amino acid position 158 of FcγRIIIa; and four amino acid substitutions, termed neutrophil antigen polymorphisms (NA1 and NA2), for FcγRIIIb (Fig. 1). Some of these polymorphisms are relevant functionally, because they have a profound influence on binding to human IgG (Table 2). Moreover, these polymorphisms were found to influence susceptibility to a number of infectious and autoimmune diseases7,16.
IIa
IIb
IIIa
IIIb
EC1 EC2 Val158Phe
Arg131His ζ ζ
ζ γ
γ γ
S–S
S–S
S–S
+
+
EC3
EC1 EC2
EC1 EC2
EC1 EC2
NA1/NA2 64 88 • 47 EC1 18 EC1 EC2 EC2 GPI
+
+
Extracellular
Intracellular
_
+
+
+
+
+
+
Key: +
+
+
+
_
ITAM ITIM TRENDS in Immunology
Fig. 1. Structural diversity and heterogeneity of human Fcγ receptors (FcγRs). All receptors belong to the Ig super family, with their extracellular regions (ECs) composed of disulfide (S–S)-bonded domains. FcγRI, FcγRIIa and FcγRIIIa are activating receptors, characterized by the presence of an immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of the receptor (FcγRIIa) or associated with the receptor as an accessory signaling
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subunit (γ and/or ζ chains associated with FcγRI and FcγRIIIa). FcγRIIb is an inhibitory receptor, containing an immunoreceptor tyrosinebased inhibitory motif (ITIM) in its cytoplasmic domain. FcγRIIIb is linked to the plasma membrane by a glycosyl phosphatidylinositol (GPI) anchor. Functional polymorphisms in FcγRIIa, FcγRIIIa and FcγRIIIb are indicated by red circles. Abbreviation: NA, neutrophil antigen polymorphism.
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Table 2. Heterogeneity and ligand specificity of human IgG receptorsa
FcγRIa
Receptor variant
–
3>1>4>>>2
2a=3>>>1,2b
FcγRIIa
Arg131 His131
3>1>>>2,4 3>1=2>>>4b
2a=2b=1 2a=2b>>>1
FcγRIIb
–
3>1>4>>2
2a=2b>1
FcγRIIIa
Val158 Phe158
1=3>4>>2c 1=3>>>2,4
3>2a>2b>>1 3>2a>2b>>1
NA1 NA2
1=3>>>2,4d
3>2a>2b>>1 3>2a>2b>>1
FcγRIIIb
Arg/Arg131
Ligand specificity for IgG isotypes Human Mouse
1=3>>>2,4
aAbbreviations:
FcγR, Fcγ receptor; NA, neutrophil antigen polymorphism. has higher affinity for human IgG3 than FcγRIIa-Arg131 does. cFcγRIIIa-Val158 has higher affinity for human IgG1 and human IgG3 than FcγRIIIa-Phe158 does. dFcγRIIIb-NA1 internalizes human IgG1- or human IgG3-opsonized particles more efficiently than FcγRIIIb-NA2 does. bFcγRIIa-His131
Evidence in support of a role for the heterogeneity of FcγRs in susceptibility to SLE has been controversial, although genome scans have indicated that the FcγR locus on chromosome 1 is genetically relevant17. Several studies have reported an increased frequency of the FcγRIIa-Arg131 or FcγRIIIa-Phe158 variants in patients with SLE compared with healthy controls, specifically in patients with SLE nephritis7,16,18,19. These variants interact with various IgG subclasses with reduced efficiency, in particular, the interaction of FcγRIIa-Arg131 with IgG2 (Table 2)7,16. Although allelic associations could not be reproduced in all studies7,16,20, the Arg–His polymorphism of FcγRIIa was shown to affect the clearance of ICs in vivo in a small population of patients (Fig. 2)20. Indeed, the effect of heterogeneity of FcγRIIa on the handling of ICs might have important implications for a disease such as SLE. Also, polymorphic variants of FcγRs have been implicated in autoimmune diseases other than SLE, including neurological disorders, such as Guillain–Barré syndrome and myasthenia gravis21,22. In rheumatoid arthritis, the Val–Phe polymorphism of FcγRIIIa appears to be involved in susceptibility to disease, although findings have been contradictory23,24. A skewed distribution of the FcγRIIa-Arg131His polymorphism has been observed in patients with different forms of thrombocytopenia, although not consistently in all studies25–27. Notably, the combined homozygous FcγRIIa-Arg/Arg131 and FcγRIIIa-Phe/Phe158 phenotype was shown to influence the relapse rate of Wegener’s granulomatosis, a systemic vasculitis characterized by autoAbs against neutrophil granular constituents28. Although such allelic combinations could be of relevance in SLE as well, this has not been demonstrated as yet20. Fcγγ receptors and inflammation in autoimmunity The humoral immune response
Both activating and inhibitory FcγRs are involved in the generation and control of an appropriate http://immunology.trends.com
Half-life (min.)
Receptor class
70
Arg/His131
60
His/His131
50 40 30 20 10 0 FcγRIIa phenotype TRENDS in Immunology
Fig. 2. Half-life in minutes (min.) of IgG-coated erythrocytes in the blood of patients with systemic lupus erythematosus expressing different Fcγ receptor IIa (FcγRIIa) phenotypes. Labeled erythrocytes coated with anti-rhesus antiserum were injected intravenously, and blood samples were taken regularly to determine their half-life. Half-life was prolonged in patients expressing the homozygous FcγRIIA-Arg/Arg131 phenotype compared with patients expressing other FcγRIIA genotypes (heterozygous Arg/His131 and homozygous His/His131) (P = 0.027), demonstrating an effect of this phenotype on the clearance of immune complexes in vivo.
humoral immune response (Fig. 3). Activating FcγRs have been shown to enhance Ab responses by the efficient internalization of ICs by antigen (Ag)-presenting cells (APCs) and increased presentation of Ag (Refs 29–31). Indeed, the IgG-mediated enhancement of Ab responses is low in FcR γ-chain-deficient mice, lacking expression of FcγRI and FcγRIII, but increased in FcγRIIb-deficient mice31,32. In addition, the internalization of ICs by activating FcγRs might influence the epitopes that will be presented by APCs, because certain epitopes are presented selectively after FcγRIII- but not FcγRII-mediated internalization29,30. This might have consequences for the ensuing specific T-cell responses, in particular when otherwise cryptic epitopes are presented. The participation of activating FcγRs in revealing cryptic epitopes in vivo and consequently, their possible involvement in autoimmunity remains to be established. By contrast, the inhibitory FcγRIIb acts to set thresholds for B-cell activation upon co-crosslinking with surface Ig, a mechanism whereby ICs can suppress the production of Ab (Fig. 3c). FcγRIIb is both necessary and sufficient for the downregulation of B-cell-receptor-induced calcium mobilization and cellular proliferation33,34. In addition, self-ligation of FcγRIIb induces B-cell apoptosis8. This characteristic of FcγRIIb might contribute to the maintenance of peripheral tolerance during the affinity maturation of B cells, by promoting the deletion of low-affinity, selfreactive lymphocytes. In accordance with these findings, FcγRIIb-deficient mice on a specific genetic
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(a) Antigen presentation
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(c) Humoral immune response __
FDC _ _
__
++
+
–
MHC I
B cell
BCR
TCR
Proliferation Ca2+ mobilization
__
+ APC
MHC II T cell B cell
__
Apoptosis BCR
(b) Clearance of immune complexes
(d)
++
++
+
+
__
__
++
__
+
Balance
Inflammation
No inflammation TRENDS in Immunology
Fig. 3. Receptors for IgG are involved in the development and progression of autoimmune disease at different levels of the immune response. Although both activating and inhibitory receptors influence (a) the presentation of antigen to T cells and (b) the clearance of immune complexes, inhibitory receptors alone control (c) the humoral immune response. Inhibitory receptors either suppress the activation and proliferation of B cells when co-crosslinked to the B-cell receptor (BCR), or induce apoptosis when self-ligated, contributing to the control of antibody production or the maintenance of peripheral tolerance, respectively. Furthermore, inflammation and tissue damage is dependent on (d) a balance between the ligation of activating and inhibitory receptors. Dysregulation at any of these levels might have profound influence on immune-complex-mediated diseases, such as systemic lupus erythematosus. Abbreviations: APC, antigen-presenting cell; FDC, follicular dendritic cell; TCR, T-cell receptor.
background develop autoAbs spontaneously, eventually culminating in lupus-like disease35. The primary site for the interaction of B cells with ICs is in the germinal center, where ICs are retained by follicular dendritic cells (FDCs). FcγRIIb, the sole Fc receptor on FDCs, has been shown to be important in the presentation of ICs to B cells and the generation of a strong recall response36. Consequently, deletion of FcγRIIb from FDCs might compensate, at least in part, for the deletion of FcγRIIb from B cells. Thus, the lupuslike phenotype developed by FcγRIIb-deficient animals might not be attributable to the effect of FcγRIIb on the development of autoAbs alone, as discussed later. Clearance of immune complexes
The clearance of ICs from the circulation is regulated normally by the mononuclear phagocyte system (MPS). In this system, erythrocytes bind to ICs through complement receptor 1 (CR1), providing a mechanism for transport of the complexes to mononuclear phagocytes located in liver and spleen. http://immunology.trends.com
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Subsequently, the complexes are removed from the erythrocytes by the proteolytic cleavage of CR1, and internalized by tissue-resident phagocytes4,5. The importance of FcγRs in this process (Fig. 3b) has been demonstrated by studies of FcγR blockade in primates and mice37, as well as in vitro studies modeling this ‘transfer reaction’5. Defective FcγR-mediated clearance of ICs has been described in patients with SLE (Ref. 6). Recently, we determined the contribution of individual FcγRs to the function of the MPS, using a model IC and panels of FcγR-deficient mice38. Remarkably, FcγRIIb was found to be the crucial receptor for the clearance of ICs. Because this receptor acts as an inhibitory receptor, FcγRIIb might well be the primary receptor for noninflammatory clearance of ICs by the MPS. In accordance with these findings, several studies have shown that the deletion of FcγRIIb results in increased susceptibility to IC-induced diseases, for example, collageninduced arthritis and Goodpasture’s syndrome39–41. Moreover, functional polymorphisms in the regulatory regions of the FcγRIIB gene, which affect the surface expression and function of the receptor, have been associated with autoimmune manifestations in mice42,43. These results, in combination with the spontaneous development of lupus-like disease in FcγRIIb-deficient mice35, indicate that FcγRIIb has a dual influence on autoimmunity, involving both the development of autoAbs and the clearance of ICs. Inflammation
When the handling of ICs by the MPS is impaired, their subsequent deposition in the tissues might result in inflammation and tissue damage. This autoimmune-associated inflammation is generally classified as type-II or -III hypersensitivity. The generation of single and multiple FcγR knockout mice44–47 provided an opportunity to study the role of different FcγRs in these types of inflammation. The classical model of IC-mediated inflammation is the reverse passive Arthus reaction, in which Ab is applied to skin or lung and Ag is administered intravenously. The inflammatory response that develops subsequently, characterized by the infiltration of granulocytes, plasma exudation and hemorrhage, was shown to be severely impaired in FcR γ-chain-deficient mice, which lack expression of FcγRI and FcγRIII, and FcγRIII-deficient mice46,48,49. These results indicate the involvement of activating FcγRs, in particular FcγRIII, in IC-mediated inflammation. By contrast, an enhanced inflammatory response was observed in FcγRIIb-deficient mice, demonstrating the inhibitory effect of this receptor on ITAM-triggered activation45,49. Whether the activation of complement is a crucial factor in this reaction or is involved in the later stages of the inflammatory response remains a matter of debate49–51.
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Similarly, other animal models of human diseases have demonstrated a crucial role for activating FcγRs in autoimmune-mediated inflammation, most strikingly in a murine model of lupus, the New Zealand Black/New Zealand White mouse. The spontaneous generation of anti-DNA Abs and circulating ICs in these animals is followed by the deposition of ICs and the activation of complement in kidney and other tissues. Although these mice have a greatly reduced life expectancy, owing to the development of severe glomerulonephritis, disruption of the FcR γ-chain alone was found to completely abrogate the inflammatory response52. Similar protection from tissue damage upon deletion of the FcR γ-chain was observed in models of antiglomerular basement membrane glomerulonephritis and collagen-induced arthritis40,53–55. As in the Arthus reaction, the inhibitory FcγRIIb was shown to suppress FcγR-mediated activation in these models39,40. Cytotoxic IgGs directed against red blood cells or platelets are characteristic of several autoimmune diseases, including SLE. Once again, a crucial role for FcγRIII was shown in the pathogenic mechanism of these Abs, because FcR γ-chain- or FcγRIII-deficient mice were both protected from the development of hemolytic anemia and thrombocytopenia56,57. Although this autoAbinduced process was heavily dependent on the subclass of IgG, related to the capacity of the Ab to interact with activating FcγRs (Ref. 57), the activation of complement did not appear to be important50,56. Remarkably, ligation of the inhibitory FcγRIIb did not affect autoAb-mediated cell destruction, either directly or by counterregulating FcγRIII (Ref. 58). The reason for this marked difference in the influence of FcγRIIb on cytotoxic IgG-induced responses compared with other types of IC-mediated inflammation is presently unclear. As indicated by these recent studies, inflammation and tissue damage in IC-mediated diseases, such as SLE, are dependent on a balance between the ligation of activating FcγRs, in particular FcγRIII, and inhibitory receptors, such as FcγRIIb (Fig. 3d). An imbalance in the opposing actions of these receptors might well underlie the severity of inflammation in systemic autoimmune disease. Therefore, the lupus-like phenotype developed by FcγRIIb-deficient animals might be attributed to an effect of the absence of FcγRIIb on IC-triggered inflammatory responses, by lowering the thresholds for activating FcγRs. FcγRIIb does not appear to have this kind of influence on all autoimmune phenomena, as shown for autoAb-induced hemolysis. Whether this differential regulation is owing to the expression levels of activating and inhibitory FcγRs on the specific effector cell, selective affinity for a certain ligand, the particular cell type involved in the inflammatory response or additional factors, such as http://immunology.trends.com
the activation of complement, remains to be elucidated. Concluding remarks and perspective
During the past decade, mouse models of inflammatory diseases have established the clear involvement of receptors for IgG in the development and progression of autoimmune disease, at different levels of the immune response: the generation and control of cognate interactions, the clearance of ICs and the inflammatory response. Dysregulation at any of these levels might have a profound influence on IC-mediated diseases, such as SLE. Indeed, mice deficient in FcγRIIb develop lupus-like disease spontaneously35, and many autoimmune-prone mouse strains have reduced surface expression and function of this inhibitory receptor42,43. Conversely, mice deficient in activating FcγRs are resistant to IC-induced inflammatory responses and tissue damage40,46,48,49,52–57. It should be noted that neither functional defects in FcγRIIb nor polymorphic variants of this receptor have been described in patients with SLE thus far. By contrast, several functional polymorphisms of activating FcγRs have been associated with disease and the reduced clearance of ICs (Refs 7,16,18–20). Hence, it remains to be determined whether dysregulation in human SLE is predominantly at the level of activating or inhibitory FcγRs. The mouse models described in this review indicate that FcγRs are potential targets for immunotherapy. Abrogating the inflammatory potential of activating FcγRs through manipulation of IgG–FcR interactions might be an attractive therapeutic approach in SLE. In this respect, interference with the Fc domain of (pathogenic) Abs might prevent the ligation of activating FcγRs and their subsequent downstream effects. Indeed, administration of an Ig-binding peptide prevented disease in lupus-prone mice59. An alternative approach would be to stimulate the catabolism of (pathogenic) IgG. Administering Abs that block the actions of FcRns could achieve this effect. In accordance with this hypothesis, mice deficient in FcRns are protected against the development of experimental SLE in two separate models60,61, most probably because they catabolize IgG as well as pathogenic autoAbs rapidly. Intervention could also be accomplished with Abs that block the ligand-binding domain of activating FcγRs, thus inhibiting the initiation of effector-cell responses. Preliminary results of a Phase II study in humans indicate this novel therapeutic concept to be successful in the treatment of idiopathic thrombocytopenic purpura62. Correspondingly, the immunomodulatory effects of treatment with intravenous Ig (IVIg) have long been recognized in (autoimmune-mediated) inflammation. Although the blockade of FcRs is believed to be the primary action of IVIg in this treatment, other activities might
Review
Acknowledgement We thank Marjolein van Egmond for kind help with the artwork.
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contribute to its therapeutic potential, including the attenuation of complement-mediated tissue damage, neutralization of autoAbs by anti-idiotype Abs, modulation of cytokine responses and downregulation of B-cell function63. Remarkably, a recent study contradicts this dogma, suggesting that the primary activity of IVIg is in stimulating the antiinflammatory properties of the inhibitory FcγRIIb, rather than blocking activating FcγRs (Ref. 64). These findings implicate the ligation of inhibitory FcγRs as a potent therapeutic strategy for autoAb-mediated diseases. Recent advances in Ab engineering might provide a promising method to influence immune
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From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens Joachim L. Schultze and Robert H. Vonderheide Clinically successful specific cancer immunotherapy depends on the identification of tumor-rejection antigens (Ags). Historically, tumor Ags have been identified by analyzing either T-cell or antibody responses of cancer patients against the autologous cancer cells. The unveiling of the sequence of the human genome, improved bioinformatics tools and optimized immunological analytical tools have made it possible to screen any given protein for immunogenic epitopes. Overexpressed genes in cancer can be identified by gene-expression profiling; immunogenic epitopes can be predicted based on HLA-binding motifs; candidate peptides can be identified by mass spectrometry of tumor-cell-derived HLA molecules; and peptidespecific T cells can be qualitatively and quantitatively analyzed at the singlecell level using ELISPOT and tetramer technologies. Here, we suggest that, based on these advancements, a new class of tumor Ags can be identified by directly linking cancer genomics to cancer immunology and immunotherapy.
Ten years after the landmark studies by Boon1 and Rosenberg2, the once suspect hypothesis that human cancers express antigens (Ags) that can be targeted specifically by cellular immunity, now forms a scientifically justifiable rationale for the design and http://immunology.trends.com
clinical testing of novel Ag-specific cancer immunotherapies. Moreover, the development of novel adjuvants and delivery modalities has accelerated, given the ability to measure specific immune responses to particular prototypic tumor Ags, particularly in melanoma and lymphoma. First-generation tumor Ags were discovered largely by deciphering the molecular targets of anti-tumor T-lymphocyte responses in patients with disease. However, despite clear demonstrations that immunity to these Ags can be generated in cancer patients by a variety of therapeutic approaches, meaningful clinical responses have been minimal. The results reflect, in part, the fundamental limitations of first-generation tumor Ags, which are too restricted in expression to permit wide clinical applicability and too irrelevant to the oncogenic process to prevent the selection of Ag-loss tumor mutants. Here, we propose the advent of a second generation of tumor Ags poised to overcome these obstacles,
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