Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications

o

review

Overview: Fc receptors Some of the most important structures in the immune system are the receptors for the Fc domain of antibodies. These provide an essential feedback between the humoral and the cell-mediated immune responses. In the last few years the structure of these proteins and the genes encoding them have been elucidated, resulting in an explosion of information.Three main areas are reviewed here: first, Jan van der Winkel and Peter Capel discuss the heterogeneity of the haman lgG receptor. To date, three main classes have been recognised, generating at least 12 different isoforms. Second, Michael Bevan and Henry Metzger review signal transduction through the FceRI receptor, the best characterised stucture in this area. Third, Matyas Sandor and Richard Lynch concentrate on Fc receptors residing on T cells, which differ from those on other haemopoietically derived ,:ells. Once considered a poor relation of the family of immune receptors, these structures now seem to be a crucial coordinating factor.

Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications Jan G.J. van de Winkel and Peter J.A. Capel Receptors for the Fc domain of IgG (FcyR) provide a critical link between specific humoral responses and the cellular branch of the immune system. When hFcyR interact with immunoglobulin, a variety of biological responses are triggered. These include phagocytosis, endocytosis, antibodydependent cellular cytotoxicity (ADCC), release of inflammatory mediators, and enhancement of antigen presentation. In the last few years our understanding of the Fcy receptor structure has increased dramatically, due to the availability of monoclonal antibodies (mAb) and cDNA probes. FcyR are members of the immunoglobulin superfamily and three main classes, hFcyRI, hFcyRII, and hFcyRIII are recognized in man ~-~generating at least 12 different isoforms. A further level of complexity is introduced by various genetic polymorphisms and, importantl), recent evidence points at the relevance of this FcyR heterogeneity Three distinct but closely related human (h) FcTR classes - hFqRI (CD64), hF~RlI (CD32) and hFcTRIII (CD16) - have been mapped to chromosome 1 and some of their characteristics and the current nomenclature are summarized in "!'ables 1 to 3. hFcTRI is a 72 kDa glycoprotein which can bind monomeric IgG with high affinit-y+ This receptor is constitutively expressed on monocytes and macrophages, and can be induced on neutrophils and eosinophils 1-4. Analysis o~ the predicted amino acid sequences from cDNA clones have shown hFcTRl to possess an extracellular region of 292 amino acids with three C2 set ig-like domains, a 21 amino acid transmembrane region, and a charged cytoplasmic tail of 61 amino acids (Fig. 1). The third extracellular lg-like domain is unique for hFcTRl, and is not found in class II

or III receptors. Three highly homologous genes (>98% nucleotide identity), hFqRIA, IB and IC, have been identifieds.6, and mapped to the long arm of chromosome 1, band q21.l (Fig. 2); this pericentromeric region is syntenic to a region on mouse chromosome three {where the murine homologue is located) ~. The hFcTR1 genes consist of six exons, two encoding the signal peptide, one exon for each of the Ig-like domains, and one exon for the combined transmembrane/cytoplasmic region. The overall structural organization is characteristic for that of all other Fc~'R genes, in both mouse and humans. In both species FqR genes arose via gene duplication, divergence, and recombination (see below} processes, and share some common structural features: (1) the leader peptide of

0 199], ENevier ~ience Publishers l+td, UK, 0167-56091931506,00

o,,,,,,,otogy Todar 2 15

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review all FqR genes is encoded on two separate exons, the second of which (a 21 nucleotide exon, known as $2) encodes the predicted site of peptidase cleavage; (2) separate exons encode individual Ig-like domains, arid (3) the splice junctions of all exons occur between the first and second nucleotide of an amino acid codon s.s's. An important difference between the hFc~RIA, and IB/IC genes is located in exon EC3, where stop codons are found in the latter two genes (albeit at different sites, Fig. 2). Northern analyses of hF~RI-positive cells show a predominant transcript of 1.7 kb, and a minor one of 1.6 kb. PCR analysis showed hFcTRIA to generate a single transcript encoding a molecule, hFcTRla, which contained three lg-like domains. This molecule is capable of binding monomeric hlgG. hF~RIB yielded two transcripts, a full-length transcript (with the translation stop codon in EC3; hF~Rlbl), and one which lacks EC3. This latter form, therefore, may code for a transmembrane molecule with two Ig-like domains, hF~RIb2 (Fig. 1)6. Interestingly, upon transfection into COS cells this molecule expresses low affinity, and binds IgG in complexed form only9. All hFcTRIexpressing cells analysed so far, however, express both the hFc~Rla and Ib2 transcripts. The 40 kDa class II receptor is the most broadly distributed Fc~R, and is frequently expressed as the sole one on cells (Table 2). This receptor binds IgG only in complexed or polymeric form and cDNA analysis has revealed the existence of multiple proteins with similar extracellular regiens of 180 amino acids containing two Ig-like domains, a transmembrane region 127 to 29 amino acids), and cytoplasmic domains of variable

lengths (44 to 76 amino acids)lt~-n. Six isoforms are currently identified, encoded by a totai of three genes hFq,RIIA, liB, and IIC - located on lq23-24 (Ref. 8). in contrast to the hFc]'RI (and III) genes, which possess a combined transmembrane/cytoplasmic tail encoding exon, the hFcq,RII cytoplasmic tails are encoded by three distinct cxons (C1 to C3). The products of genes IIA and liB were found to differ in their signal peptides, and cytoplasmic tails. Analysis of the gene structures showed the hF~RIIB and IIC genes to be highly homologous at their 5' ends, while hF~RIIC and IIA were very similar in the 3' regions. Recent work showed that the hFcq,RIIC gene was probably generated via an unequal crossover event between the hFcRIIA and liB genes. The putative site of crossover was mapped -300 nucleotides downstream from the C1 exon 13 (Fig. 2). Notably, this C1 exon may constitute a cryptic element in genes IIA and IIC, as no known transcript from either gene contains the information encoded in C1. The hF~RII isoforn:s are heterogeneous in their cytoplasmic domains. The hFq'RIIbl and lib2 isoforms, for example, are identical with the exception of a 19 amino acid insert in llbl (encoded in exon C1; indicated in Fig. 1). Notably, hF~Rllb3 is identical to llb2, but lacks the information encoded on the $2 exon I°. When using hFc'/IIa as a probe, northern analysis showed transcript sizes of 2.5 and 1.8 kb resulting from different polyadenylation sites. A single band of -1.8 kb is noted when northern analysis is performed with probes defining hFqRllb and llc. The exact cell-type distribution of the variot:s isoforms is unclear.

Table 1. General characteristics of human IgG Fc receptors Receptor class (CD)

Molecule

Genes (chromosome)

hrq¢.l

72kDa

(lq21.1)

Transcripts

(CD64) hF~q,RIA hFcyRIB hFcyRIC hFq,Rll (CD32)

40 kDa

hF~RIIB hFcyRIIC 50-80 kDa

Affinity for IgG (Ka)

Monoclonals

hFcTRIy

High (108-109 M-l)

32,197,22, 44,62,10.1

Low (<107M-l)

IV.3,2E1, KB61,AT10, KuFc79, CIKM5, 411116

hFcTRIa shFcTRIbl% hFcTRIb2 shFcyRIc

( 1q23-24) hFcTRIIA

hFq,RIII (CD16)

Receptor subunits

hFcTRIIal, shFcTRIIa2 hFcTRIIbl, hFcTRIIb2, hFcTRIIb3 hFcTRIIc

(lq23-24) hFqRIIIA

hFcTRIIia

hFcyRIIIB

hFcTRIIIb

hFcTRIIIaT, hFcyRllIa~, hFcTRIIlal3b ?

Medium (+ 3 x 107 M-I) Low (<107 M-l)

a s: soluble receptor; b: shown in mouse mast cells; c: mAb 1D3 reacts solely with hFc'/RIIIb, not hFqRIIIa.

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3G8,B73.1, VEP13,GRM1 CLB Granl, CLB Gran 11 BW209/2, 1D3c,MG38, Leul la/b/c

review Table 2. Fc3,R distribution and ligand specificity Fc?R class

Expression

Ligand specificity (IgG isotypes) !nduced

Constitutive hFcTRl

Mouse

Human

2a=3>>>l,2b

3>1>4>>>2

2a=2b=l 2a=2b>>>l 2a,2b~l

3>1>>>2,4 3>1=2>>>4 3~I>4>>2

3>2a>2b>>l

1=3>>>2,4

Neutroph:,!s (IFNT, G-CSF)a Eosinophilis (IFN-7)

Monocytes, macrophages hFcTRII

Ila Ha

IIaLr Ilbl Monocytes, neutrophi': macrophages, basophils eosinophils, langerh.ns cells, B cells, platelets, endothelial cells (placenta)

hF~RIII Ilia lllb

Monocytes (TGFI3)

Monocytes (subpop.) Macrophages, LGUNK cells, T cells (subpop.) Neutrophils

Eosinophils (fiN-y)

cytokine-mediating induction between brackets. hF~RIII precipitates as a broad band with a molecu- cated at amino acid position 203. A serine in hFcTRIIIb lar weight between 50 kDa and 80 kDa, due to exten- determines the GPl-anchoring, whereas a phenylalanine sive giycosylation. Two genes have been identified - in hFcyRIIIa specifies preservation of th~ transmemhFcyRIIIA and IIIB-, both localized on lq23-24, within brane and cytoplasmic regions. Interestingly, the two a distance of 200 kb from the hFcTRII gene complex. genes are expressed in a cell type-specific fashion. The The products of both genes encode proteins with extra- GPl-linked hFcTRIllb molecule is selectively expressed cellular regions o f - 1 9 0 amino acids consisting of two in granulocytes (PMN or eosinophils) and has low lg-like domains. "lhe hFcTRII!A gene encodes a trans- affinity for hlgG. The integral membrane glycoptotein membrane receptor with a 25 amino acid tail, while the hFqRIlla is expressed on macrophages, NK cells and hFc't,RIIIB gene product is linked to the outer leaflet of some T cells 14, and interacts with complexed, as well as the plasma membrane via a glycosyl phosphatidyl- monomeric IgG (albeit with lower affinity than hFcTRI). inositol (GP1) anchor. The most critical difference Northern analyses on hF~RllI-expressing cells revealed between the products of the two hFc'/RIII genes is 1o- a transcript size of -2.2 kb for either gene2'8. Table 3. Biological functions triggered by FcTR hFcTRllI Function

hFcTRI

hFc?RlI

hFcTRllIa

hFc?RI!Ib

Phagocytosis Superoxide generation Cytotoxici~ (ADCC) Tumor targets RBC targets Triggering mediator release Lvsosomal enzymes TNF
+ +

+a +

+ +

_/+b -/+~

+ +

+ +

+ +

_/+b +

~ + + + + -

+ + + +~ + +

+ + ~ ? + -

+

-

biological differences observed between isoforms; b controversial; both positive and negative reports of ability to trigger function; ?: no data available.

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review F

~ev RI

!b

al~..

~

RII

]

the risk to contract infections. Higher shFcTRl!lb levels were found to be associated with a significantly lower risk of infection (T.W.J. Huizinga et al., sobmitted). sl Ib= i spllc Ilc lib, llb.. lib 3 Activation of NK cells also results in release of shFcTRllla, and involves metalloprotease activity2°. A distinct mechanism to generate soluble hF~R has been noted for hF~Rlla2. This isoform lacks the information for the hydrophobic transmembrane region, and is presumably generated via alternative RNA splicing n. A third mechanism is illustrated within the hFcTRI class of molecules, in that two transcripts of hFcTRI genes contain translation stop codons in EC3. Translation of the full-length transcripts may specify lllalx lllb sllla slllb truncated, soluble receptors 6. Indeed, evidence for the presence of soluble hFqRI molecules in human serum has been obtained (A. Ahmed and K. Whaley, pers. commun.). Although the biological relevance of ma~-~ tlh~-~, ;t]a~ tih~-y mal5 ~__" ~'__'~ ~'--'~ ~!--'~ ~-~ ~ ~ ' soluble F~R, or soluble IgG-binding factors is unclear, effects on lgG production are well documented 21. Remarkably, it was recently observed that injection of shF~Rlla together with immune complexes caused a profound inhibition of a reverse passive Arthus reaction in rats (M. Hogarth, pers. commun.). These data point at strong in vivo effects of soluble FcTR, Fig. 1. Schematic representation of tbe human IgG FcR family. All receptors which may also be of therapeutic interest.

II

belong to the immunoglobulin super family, with their extracellular regions composed of disulphide-bonded domains, hFc)'RI and Ilia exist as oligomeric complexes, and associated subunits are indicated. All three classes of FcyR bare members which are not anchored in the membrane. These soluble receptors are generated by three distinct mechanisms; via stop codons in their extracellular domain {hFc]tRlbl and Ic), via alternate RNA splicing /bFc~'Rlla2), or due to proteolytic cleavage (hFc)'RIIIa and lllb).

F c ~ subunits hFcTRIIla was recently shown to exist as a hetero-

Fq,R heterogeneity and genetic polymorphisms hFq,Rl is not polymorphic, although a family has been described in Belgium, containing four healthy members lacking monocyte surface expression of the high-affinity receptor. This was demonstrated by nonreactivity with all known CD64 mAbs (Table 1), as well as monomeric hlgG (Ref. 22). Recent work has revealed that all three hF~RI genes are present in these four individuals, without major structural changes. At

~l;o~mor;r

t. .h. . e. . . . . .megg:aoe level_• hnwr-ver_ a digrincr d i f f e r e n c e w a s . o ...... ......... 7 ..........................

roe.~nr~r

ecsmnlose

~airh

warln.~

cti~,llficlP.

linked subunits Is. These can be dimers of y-chain, originally defined as a component of the high affinity FcERI, or C-chain which also forms part of the TCR-CD3 complex. These subunits can associate either as homo (~"T, ~-~), or heterodimers (~tL~),and are mandatory for surface expression. Apart from preventing degradation of the hFq'RIIIa complex in endoplasmic reticulum *~, the associated y-chains were found to be essential for signal transduction 17. Analysis of F~RIIIa on mast ceils revealed a further level of complexity, as the [~-chain of FcERI was found complexed with F~RIIIa (and T--y)~8. Interestingly, the high affinity hFcTRI is also associated with y-chain homodimers in differentiated (but not undifferentiated) U937 cells, as well as in monocytes. Association with T is not absolutely essential for membrane expression, and a role in hFq,RI-signalling appears likely (L. Pfefferkorn, submitted, and Ref, 55).

Soluble receptors Soluble forms have been demonstrated for all three hF~R classes. Remarkably, these molecules are generated via several molecular mechanisms. Human serum contains high levels of soluble hFc,/RIIlb, which is probably released from PMN because of serine protease activity". Interestingly, the amount of shFcTRIIlb in the sera of neutropenic patients is correlated with

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noted in that normal donors express both 1.7 and 1.6 kb hF~RI messages, whereas only a 1.6 kb message was detectable in the Belgian individuals. Subsequent PCR analyses revealed that the hFcyR!a transcript was present at an -10 to 20-fold lower level than in control individuals, and hFcyRlb2 mRNA levels were significantly increased (van de Winkel, unpublished). These data suggest the 1.7 and 1.6 kb message species to correspond to the hFcTRIal, and Ib2 transcripts, respectively. At least three types of heterogeneity have been noted for hFcTRII between individuals. Best studied is a genetically defined polymorphism of hFcyRllA. Two allotypic forms were originally defined in studies on the interaction between monocytes and mouse (m) IgG1 anti-CD3 mAb. Monocytes from _ 70% of Caucasian donors (high-responders: HR) efficiently supported T-cell mitogenesis reduced by mlgG1 anti-CD3 and 30% did not (low-responders: LR). hF~RIla was subsequently identified as the receptor mediating the interactions with mlgG1. This polymorphism has been documented to have functional importance in various assay systems, including T-ceU mitogenesis, binding of mIgG1 aggregates, Erythrocyte-Antibody (EA)-mlgG1 rosetting, cytotoxicity of mlgGl-sensitized targets, induction of TNF-~ and IL-6 release, and adherence of PMN to mlgGl-coated endothelial cells (reviewed in

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1993

review Ref. 3). The igolymorphic receptor is expressed on monocytes, pla~elets, PMN, and alveolar macrophages, but not on B cells. This last observation is supported by immunofluorescence analyses with a unique mAb, 41H16, which selectively detects the hFcTRllaHRform23. The molecular basis of the HR-LR polymorphism has '-.en studied~ and revealed the hFqRlla HR, and lla LR forms to differ by only two amino acids. A glutamine is found in HR versus a tryptophan in LR at amino acid position 27 (first Ig-like domain), and an arginine (HR) or histidine (LR) at position 137 (second lg-domain) n,24-26. The amino acid at position 137 was found to be critical for the polymorphic reactivity with mlgG1 complexes, as well as mAb 41H16 binding 2~. A polymorphism was also noted in hFc'tRIlbl, in which a single nucleotide difference was found to result in one amino acid change in the cytoplasmic tail of hFcl,Rllbl. At amino acid position 11 in the cytoplasmic region a tyrosine in hFc'/Rllbl was substituted by an aspartic acid (hFcq'RIIbl*)27. The biological consequences, if any, of this polymorphism are currently under study. Of note is that tyrosine-containing internalization signals have been found (at exactly the same location) in other molecules (for example LDL receptor, or lysosomal acid phosphatase), and are critical for internalization 2s. On human platelets, a stable variation in numbers of hFc~/Rlla molecules between indi. viduals has been observed. This level of hFqRlla expression correlates well with platelet activation responses upon immune complex stimulation 29. At least three polymorphic differences have been described for hFq,Rlll. Two hFcTRlll genes encode molecules of two topological forms (the transmembrane hFcTRIlla, and the GPl-linked lllb). Furthermore, hF~Rllla can associate with a variety of subunits (Fig. 1). Recent!y~ a stable expressio, po!ymorphism of hFc'tRllla on NK cells was noted between individuals, who expressed either low numbers (~5500/ce11), or much higher numbers (~14,000/ceil) of receptors. High and low expression correlated with functional activity of the cells (for example in ADCC) 3°. The hFc'/RllIb subclass bears an allotypic polymorphism, referred to as neutrophil antigen 1 (NA1)/NA2 which has been known for several years because of its involvement in blood transfusion reactions, and allo- or autoimmune neutropenias. The allelic frequencies in Caucasians are 37%, and 63% for NA1 and NA2, respectively. This polymorphism is reflected in differences in molecular weights between hFc'tRlllbNM and lIlb NA2. The allotypic hFqRlllb forms can be selectively assayed by immunofluorescence analyses using specific mAb. CLB Gran 11 reacts solely with hFq'RIIIbNM, whereas mAb GRM1 demonstrates specificity for hFcl,RIIIbNA2.Several amino acid differences are observed between hFcl,RIllb sAI and IIIbNA-',two of which, at positions 65 and 82 result in two extr~ glycosylation sites in IIlb NA2 (six versus four), causing a different electrophoretic mobility 3~.

Biological functions Multiple biological functions can be triggered via members of all three hFc,/g classes (Table 3). Nearly

ImmunologyToday

p-area

lie

i [ illil Iil I

I

I

hFe3' RI

$2--S1 I! $1 IA

IB

-i

II

I

IC

IIA.

IIC

liB

IliA

IIIB

Sl $2 EC1

ECI 1

EC2 EC2 [ ] P

S2 -Eel

m

TM/C

EC3 r'-

TM/C J EC2 [] TM 1

2kb]

C3

Fig. 2. Cbromosomal localization and genetic complexity of buman lgG FoR. Exon-intron organizations of bFc~ genes are shown with exons represented by rectangles, and introns by solid lines. Open rectangles indicate untranslated regions, and black/stippled ones coding sequences. Exons are marked S (signal sequences), EC (extracellular Ig-like domain), TM (transmembrane domain), ae~d C (cytoplasmic region). The region of tbe putative unequal crossover site in tbe bFcyRii genes is i, dicated by a dotted line.

all require receptor crosslinking; ligand occupation of receptors seems not essential (in contrast to receptors for hormones or growth factors). Data are emerging now that specific functions c~.n be attributed to distinct hFcl,R isoforms. On normal blood cells hF,_q'Rl mediates phagocytosis 3-'. However, there are conflicting reports regarding the ability of hF~RIa to mediate phagocytosis after transfection into COS cells-~3"34. Upon introduction iato 3T6 fibroblasts, hFcl,Rla is active in triggering IL-6 re!ease35, so it seems likely that hFc'tRIa can be expressed and deliver signals without the requirement for myeloid cell-specific accessory molecules, hFc),Rlla was shown by several investigators to be capable of mediating opsonized erythrocyte phagocytosis upon transfection into COS33, 3T636, or P388D1 cells37, while hFc),Rllbl * proved inactive 36. In the murine system, elegant studies pointed out distinct differences between the mFcq,Rllbl (expressed in B cells), and the macrophage mFc'tRllb2 (for review see Ref. 38). In man, the cell-type distribution of the homologous hFqRllb isoforms seems much less restricted, and similar studies are awaited with interest. Studies in which hFc'yRllla and lllb were introduced in heterologous cells (Jurkat, CHO, P815), showed only the hFc'tRllla isoform capable of triggering various

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Vol. 14No. S 1993

review uals was significantly diminished in a group of children suffering from severe recurrent bacterial infections. Their humoral response was normal, and no differences in the NA1-NA2 allotypes were observed. This clinical observation was paralleled by the finding that PMN from those patients (and control individuals) expressing hFcyRIla LR phagocytosed hlgG2-opsonized encapsulated bacteria consistently more effectively than PMN from HR individuals (C. Sanders et al., submitted). In addition, an independent study showed PMN and monocytes from HR and LR individuals to exhibit significant differences in phagocytosis of hlgG2-sensitized erythrocytes. These differences were apparent even in the context of polyclonal human lgGSl; (2) the majority of individuals in Japan have been documented to be of the LR phenotype (85% of the Japanese population, versus 30% in Caucasians) sz, and epidemiological studies showed a virtual complete absence of Haemophilus influenzae infections in Japan 53. hFcyRlllb on PMN has been shown to be active in phagocytosis of EA-IgG. Remarkably, differences were noted in the phagocytic capacities between hFcq'RlllbNM and llIb N~a. PMN from NA2 individuals Clinical aspects of F~R heterogeneity were consistently found to exhibit lower levels of The biological role of hF~RI has been questioned phagocytosis than NAI-PMN s4. Due to redundancy since this receptor has high affinity for lgG and may, within the Fcq,R system, and co-expression of hFcyRIla therefore, be saturated continuously with hlgG present and hFq,Rlllb on PMN, it seems possible that particular in serum. However, the increased expression of hFq,Rl combinations of polymorphisms may influence suscepthat occurs during streptococcal infectionq6, and during tibility to bacterial infections. Most interesting in this successful prophylaxis by IFN-~/ in chronic granulo- context, is a study of 15 individuals with a terminal matous disease (CGD) patients (P. Guyre, pets. com- pathway of complement deficiency (C6 or C8) belonging mun.), are suggestive of an important role for hFcq'Rl to four families. Six of the individuals with previous in resistance to infection. Also of interest are recent meningococcal disease had the combined hFc'/Rlla HR,HR data showing hFc,/Rl to be active in enhancing antigen and hFcq,Rlllb NA:,NA2 phenotype significantly more presentation. This function may not only have physio- often than those without meningococcal disease" (C. logical relevance, but targeting of antigens to this Fijenetal, submitted). I-~..,I.,IJLWl ~ v l ( l I I I Z l . I.7 L / I I I U l i I ~ llJtl,..glN.I U U L 3 1 U C LIIK7 l l ~ i : l l l U I.- concmslon, classes of numan ' -' . . . . . . . .mree . igG F c recepbinding site) may even constitute an efficient strategy tors are recognized which generate multiple isoCorms, for enhancing the effectiveness of vaccines47. hFcq,Rl some of which are organized in oligomeric receptor also proved to be a highly potent effector molecule in complexes. Recent data provide evidence for an importADCC towards human tumor cells, upon in vivo ant association bet Jveen the overall hFcy receptor induction of PMN with G-CSF (Ref. 48). phenotype and phagocyte functioning. Reactivity of hFcq,Rlla with human lgG2 immune complexes was recently shown to be dependent on We thank Drs Paul Guyre, Hans Clevers and Sief Verbeek the high responder-low responder allotype. The for critical evaluation of the manuscript. hFqRIIa LR ailotypic form interacts effertively with hlgG2 complexes, in contrast to hFcq'Rlla~'~. This was Jan G.]. Van de Winkel and Peter J.A. Capel are at tbe observed on fibroblasts transfected to express each Dept of Immunology, University Hospital Utrecht, allotype, as well as on monocytes, PMN, and platelets G.04.614, Box 85500, 3508 GA Utrecht, The of people in whom the hFc'/RIla allotype was deter- Netherlands. mined independently -'6,49. The LR allotypic form of hFcq,RIIa, therefore, represents the sole hFc~, receptor References capable of interacting effectively with hlgG2 (Table 2). 1 Fanger, M.W., Shen, L., Graziano, R.F. and Guyre, P.M. lgG2, furthermore, is known as the main human (1989) lmmunol. Today 10, 92-99 immunoglobulin G isotype induced upon infection with 2 Ravetch,J.V. and Kinet, J-P. (1991) Annu. Rev. Immunol. encapsulated bacteria such as Haemophilus influenzae 9, 457-492 and Streptococcus pneumoniae. In addition, human 3 Van de Winkel, J.G.J. and Anderson, C.L. (1991) lgG2 was clearly pre-eminent in host protection J. Leukocyte BioL 49, 511-524 against bacterial sepsiss°. It therefore seems possible 4 Hartnell, A., Kay, A.B. and Wardlaw, A.J. (1992) that the hFc'/RIIar~R-phenotype may be linked to sus- J. ImmunoL 148, 1471-1478 Van de Winkel, J.G.J., Ernst, L.K., Anderson, C.L. and ceptibility to bacterial infections. This hypothesis is 5Chiu, I-M. (1991)J. BioL Chem. 266, 13449-13455 supported by two observations; (1) a recent study 6 Ernst, L.K., van de Winkel,J.G.J., Chiu, I-M. and showed that the frequency of homozygous LR individ- Anderson, C.L. (1992)J. BioL Chem. 267, 15692-15700 biological functions i7. This observation contrasts with other reports in which hFcyRlllb on PMN could trigger various effects, including ADCC of tumor targets 39, and lysosomal enzyme release, or superoxide generation 3'4°. Notable is that most studies on biological activity of hFcq,RIIlb employed immune complexes as a stimulus. Since simultaneous triggering of responses via hFcq,Rlla (also present on PMN) is hard to exclude, there may be cooperation between hFq,R subclasses resulting in biological responses. Indeed, hF~Rlla interacts with hFcyRlllb in phagocytosis and immunecomplex induced actin assembly4~, calcium flux4z and release of hydrolytic enzymes triggered by IgM autoantibodies 43. Cooperation with other types of surface receptors may also be essential for proper hFq'R functioning. The integrin CDllb/CD18 (complement receptor 3) was recently found to be involved in various hFc~R triggered functions, including binding via hFcq,RIl on eosinophils 4a, phagocytosis by monocytes and PMN ¢fcwreview see Ref. 45), and PMN-ADCC 39. The exact molecular mechanisms underlying these phenomena remain to be resolved.

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