cd89: the human myeloid iga fc receptor

A�

rchivum Immunologiae et Therapiae Experimentalis, 2001, 4�

9,� 217–229P�

L ISSN 0004-069X

Review

CD89: the Human Myeloid IgA Fc Receptor

H. CRAIG MORTON* and PER BRANDTZAEG

H�

. C. Morton and P. Brandtzaeg: CD89 Receptor

Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, The National Hospital,R�

ikshospitalet, 0027 Oslo, Norway

Abstract. CD89 (FcαRI) is the human myeloid IgA Fc receptor expressed on cells, such as neutrophils, eosino-p� hils and monocytes/macrophages. Cross-linking of CD89 on these cells, by IgA-opsonised particl

�es (e.g. bac-

t�eria, viruses) or anti-CD89 monoclonal antibodies, can trigger various immunological effec tor functions which

a re generally protective but may also cause harm to the body. CD89 is a transmembrane glycopro� tein that bindsb

�oth subclasses of IgA in all its molecular forms (i.e. monomeric, dimeric and secretory IgA) via a region of its

membrane-distal EC1 domain. DNA studies have shown that the CD89 gene is located within the newly describedleukocyte receptor cluster (LRC) on chromosome 19. CD89 is more closely related to the KIR a nd MIR proteins,w hose genes are also found in the LRC, than to other human Fc receptors (FcRs). On myeloid cells, C

�D89 is

a ble to associate with the immunoreceptor tyrosine-based activation motif (ITAM)-containing the FcR γ� chain,w hich is responsible for intracellular signaling via CD89. Recently, it has been suggested

� that some cells express

C�

D89 in a form that does not associate with the FcR γ� chain. Although the biological relevance of this observationis not yet clear, it may explain certain anti-inflammatory/inhibitory effects attributed to IgA. Here we reviewc urrent knowledge concerning the genetics, structure and biological function of CD89.

Key words: CD89; FcαR; FcαRI; IgA; Fc receptor; myeloid.

Introduction

R�

eceptors specific for the Fc regions of all immu-noglobulin (Ig) isotypes (Fc receptors – FcRs) are ex-p� ressed by most cells of the innate and adaptive im-m� une systems. These isotype-specific FcRs enablea ntigen (Ag)-bound Igs and Ig-containing immunec omplexes (ICs) to trigger a diverse array of cellulare� ffector functions, such as endocytosis, phagocytosis,a ugmentation of antigen presentation, superoxide pro-d

�uction, antibody-dependent cellular cytotoxicity

(ADCC), degranulation, and the release of various cy-t

�okines and other mediators of immunity3

�8, 83. Termi-

nally differentiated human B cells (plasma cells) pro-d

�uce five Ig classes: IgA, IgD, IgE, IgG, and IgM, with

t�he vast majority (>80%) committed to IgA produc-

t�ion10. Thus, more IgA is produced per day (66

m� g/kg/day) than all other isotypes combined10, 57. Inh

�umans two subclasses of IgA (IgA1 and IgA2) exist,

w hich are differentially distributed between the sys-t

�emic and mucosal compartments. Serum IgA, pre-

d�ominantly monomeric IgA1, produced mainly by plas-

ma cells located in lymph nodes, bone marrow andspleen, constitutes 15–20% of the total serum Ig pool20, 45.In external secretions, IgA produced by local plasmac ells is the predominant isotype. The increased pre-

* Correspondence to: H. C. Morton, Ph.D., Laboratory for Immunohistochemistry and Immunopathology, Institute of Pathology,U�

niversity of Oslo, The National Hospital, Rikshospitalet, 0027 Oslo, Norway, tel.: +47 22 86 86 31, fax: +47 22 11 22 61,e� -mail:[email protected]

v� alence of IgA2-producing plasma cells at exocrine ef-fector sites results in more similar levels of IgA1 andIgA2 in secretions, particularly in the distal gut20, 41, 45.

L�

ocal plasma cells secrete predominantly dimersa nd larger polymers of IgA (collectively calledp� olymeric IgA – pIgA) that also contain a small pep-t

�ide called the joining or J chain, responsible for con-t

�rolling assembly of the secreted polymers42. The

J� chain, furthermore, allows binding of pIgA and pen-

t�americ IgM to the polymeric Ig receptor (pIgR), also

c alled the transmembrane secretory component (SC)11.The pIgR transports pIgA and pentameric IgM throught

�he mucosal epithelial cell to the apical membrane,

w here the ligand-binding portion of pIgR is cleaved andt

�he complex is released into the lumen7

�2. The portion

o� f the pIgR remaining complexed to pIgA or pen-t

�americ IgM is called bound SC, and the released com-

p� lexes are referred to as secretory IgA (SIgA) or se-c retory IgM (SIgM), respectively6

�8, 72. Secretory IgA is

t�he primary mediator of humoral immunity at mucosal

surfaces, where the simple ability of SIgA to bind anti-g� ens leads to immune exclusion, preventing infectionsa nd influx of foreign Ags16, 57, 102.

In addition to simply binding to Ags, the ability ofv� arious Ig isotypes to trigger secondary effector functionsis the key to their effectiveness as antibodies. Activationo� f the complement system is considered one such import-a nt function. However, compared with IgM and IgG, IgAis a poor activator of complement and this is not con-sidered important for the in vivo function of IgA40, 95.T

�herefore, IgA-mediated effector functions are believed

t�o depend upon the interaction of IgA with specific IgAF

�c receptors (FcαR

�s). Such receptors have been described

o� n both myeloid and lymphoid cells and are presumed tofunction in the clearance of IgA-containing ICs and thec ontrol of IgA-mediated immune reactions.

I n humans, the myeloid FcαR

�, CD89 (also termed

FcαRI), represents the first extensively characterized IgAF

�c receptor in terms of genetics, structure, biological

function and cell expression pattern6�6, 90. Although ex-

p� erimental evidence suggests the existence of IgA recep-t

�ors on human lymphoid cells, no such receptors have sof

!ar been characterized at the molecular level. Similarly,

FcαRs from other species have not been identified, either.T

�herefore, this review will focus on current and emerging

knowledge of CD89 and its role in immunity.

G"

enetics

I n 1990, a 1.6 kb cDNA clone encoding CD89 was

isolated from phorbol myristate acetate-stimulated

U#

937 cells5$

4. This cDNA clone included a 39 bp 5’ -un-t

�ranslated region (UTR), an 861 bp open reading frame,

a nd a 711 bp 3’ -UTR ending in a poly-A stretch. The3’ UTR is AT-rich, includes an Alu sequence, but lacksa polyadenylation signal5

$4. Recent analysis of a cosmid

c lone containing the CD89 gene (FCAR) revealeda polyadenylation signal ~1.8kb downstream of thestop codon (Fig. 1)106. Sequence comparisons showedC

�D89 to be a member of the Ig gene superfamily, re-

l�ated to human Fcγ� R

� and Fcε% R

� 5$4. Uniquely amongst

FcR genes, however, the CD89 gene is located on chro-mosome 19, at position 19q13.4 (Fig. 1). Most human,m� ouse and rat Fcγ� R

� and Fcε% R

�I α chain genes mapped

so far are located on chromosome143, 83. The CD89g� ene consists of 5 exons spanning ~12 kb23. The firste� xon (S1) includes the 5’ -UTR, an ATG translationinitiation codon, and a large part of the leader peptide.Exon 2 (S2) is 36 bp long and encodes the remainingp� art of the leader peptide, including the predicted signalp� eptidase cleavage site. A similar mini-exon is foundi

&n all other Fcγ� R

� genes and Fcε% R

�Iα chain genes. In

t�hese genes, however, the S2 mini-exon is only 21bp in

size4'

3, 83. Exons EC1 and EC2 each encodes a singlee� xtracellular Ig-like domain, while the TM/C exon en-c odes a short extracellular segment, the transmembraned

�omain, and a short cytoplasmic tail. DNA sequence

a nalysis, and the existence of a 36bp S2 mini-exon,identified the CD89 gene as a more distantly relatedmember of the Ig receptor gene family2

(3, 43, 54.

Interestingly, CD89 is more closely related to theb

�ovine Fcγ� 2

)R than to other FcRs. In fact, CD89 and

Fcγ� 2R appear to constitute a separate group of FcRs,suggesting that these two genes diverged from eacho� ther before the divergence of humans and cattle120.Recently, it has been shown that CD89 and bFcγ� 2R aremembers of a new gene family that apparently evolvedf

!rom a common ancestral gene. Other human genes be-

longing to this family include the natural killer celli

&nhibitory/activatory receptors (KIRs, KARs), the

Ig-like transcripts (ILTs), the leukocyte and mono-c yte/macrophage Ig-like receptors (LIRs, MIRs),LAIR-1, and HM183

�, 8, 18, 19, 48, 59, 73, 87, 109. The genes

t�hat encode these proteins are located close to the CD89

g� ene within the so-called leukocyte receptor cluster onc hromosome 19q13.4109, 112, 114. Several murine mem-b

�ers of the same gene family have also been de-

scribed44, 110.In addition to the normal full length CD89 mRNA,

n* umerous alternatively spliced CD89 transcripts haveb

�een isolated by reverse transcriptase polymerase chain

r+ eaction (RT-PCR) from human cells (Fig. 1)6�

4, 76, 78, 101.Recently it was claimed that the CD89 gene includes

218 H. C. Morton and P. Brandtzaeg: CD89 Receptor

F,

ig. 1. A. Location of the leukocyte receptor complex on chromosome 19q13.4. EC1 and EC2 – extracell-ular domains 1 and 2; TM –

t.ransmembrane region; Cyt – cytoplasmic tail. B. Location of the CD89 gene (FCAR) within the leukocyte receptor complex which alsoc/ ontains the KIR and MIR genes. C. Intron-exon organization of the CD89 gene. D. Structure of CD89 cDNA and isolated splice variants.The putative S3 exon has been shown to be a pseudo-exon, therefore variants encoding this exon have been omitted19, 39. Please also notet.hat several of the transcripts shown have been isolated by different investigators and have� been given alternative names. Thus the ∆66EC2

v0 ariant has also been named Fcα1 R a. 232

7,� and the ∆EC2 variant Fcα1 RIa2 or Fcα1 R a. 3327, 38

H. C. Morton and P. Brandtzaeg: CD89 Receptor 219

a n additional exon, S3, and that its transcription isc orrelated with the occurrence of IgA nephropathy(IgAN), a disease characterized by a high level of cir-c ulating IgA and IgA-containing ICs (see below)101.However, it has since been shown that the S3 exon isa non-functional pseudo-exon possessing stop codonsi

&n all reading frames106. A novel CD89 isoform

(FcαRb), which appears to result from skipping the 3’splice site at the end of the EC2 exon, has also beeni

&solated. Exon EC2 is thus extended by 23 new amino

a cids before reaching a new stop codon104. The proteinp� roduct of FcαRb has been expressed in transfectantsa nd shown to be unable to associate with the FcRγ� chain (see below) and it may, in fact, code for a pre-d

�ominantly soluble form of CD89104. Whether this iso-

f!orm is related to a newly described soluble form of

C�

D89 is unknown108. While alternatively spliced mRNAt

�ranscripts of other human FcR (Fcγ� R and Fcε% RIα)

3

g� enes that generate biologically relevant isoforms haveb

�een reported, the biological role of the described

C�

D89 splice variants remains obscure3�

8.

Protein Structure, Ligand-Binding and Signaling

The 1.6kb CD89 cDNA encodes a 287-amino-acidp� rotein5

$4. A 21-amino-acid hydrophobic leader se-

q4 uence is removed during processing to form the ma-t

�ure 266-amino-acid transmembrane glycoprotein.

C�

D89 consists of two extracellular Ig-like domains fol-l

�owed by a stretch of hydrophobic amino acids repre-senting the predicted transmembrane domain anda short cytoplasmic tail devoid of recognized signalingmotifs (Fig. 2A). The protein core of CD89 has a pre-d

�icted molecular mass of 30 kDa with differential gly-

c osylation at the six potential N-linked sites, and thep� robability of additional O-glycosylation contributingt

�o the variable size observed for the mature receptor

(55–110 kDa).U

#niquely amongst two-domain FcRs, CD89 binds

its ligand via the membrane-distal EC1 domain6�

7, 115.Furthermore, point mutation of residues within the F-Gl

�oop of EC1 abolished or greatly reduced IgA-bind-

ing115. Conversely, Fcγ� RII, Fcγ� RIII and Fcε% RI all bindt

�heir respective Ig ligands via their membrane-proximal

EC2 domains3�8. Interestingly, the closely related

b�Fcγ� 2R and p58 KIR proteins also bind their ligands

(bIgG2 and HLA molecules, respectively) via their EC1d

�omains6

�7, 116. The high degree of similarity between

C�

D89 and p58 KIR proteins has allowed a three-di-m� ensional model of CD89 to be proposed based on thesolved structure of the KIR (Fig. 2B)2

(6, 115. This model

p� redicts that the F-G loop is located at the bottom oft

�he EC1 domain, apparently in a position close to thec ell membrane. Because the ligand-binding regions ofF

�cRs and KIRs are located at accessible sites on top of

t�he molecule (albeit in EC2), it seems likely that CD89

may have a more upright structure than the KIR to en-sure that the F-G loop is accessible for IgA-binding2

(6,

3�

0, 55, 97.The affinity of CD89 for IgA1, IgA2 and SIgA is

e� stimated to be ~5×5 107� M–1, which in view of the nor-

mal serum concentration of IgA suggests that the recep-t

�or is saturated in vivo5

$6, 99. Domain-swap and muta-

t�ional studies of IgA have mapped its CD89-binding

site at or close to the Cα2-Cα3 boundary (Fig. 2C)14, 79.T

�he fact that SIgA and monomeric IgA bind CD89 with

similar affinity suggests that the binding site is not ob-structed by a bound SC or J chain4

'0. A new model for

IgA1 has also suggested that this isotype has more ofa T shape than the traditional Y shape of IgG (Fig.2C)6

�. Thus, even with this confirmation it seems the

F�

ab arms do not hinder the CD89-binding site in IgA.L

�ike many activatory receptors (including other

FcRs, ILTs, and LIRs), CD89 can associate with theFcR γ� chain, a sp� ecialized immunoreceptor tyrosine-ba-sed activation motif (ITAM)-containing signalingmolecule18, 65, 77, 86. Association between CD89 and theF

�cR γ� chain depends on charged residues located with-

in their transmembrane domains (Fig. 2A)5$1, 65. Evi-

d�ence from transfectant model systems suggests that

C�

D89-mediated signaling, including recruitment ofp� rotein tyrosine kinases (PTKs) and subsequent activa-t

�ion of the intracellular signaling cascade, is accom-

p� lished by association with the FcR γ� chain (seeb

�elow). Interestingly, however, not all CD89 molecules

a ppear to associate with the FcR γ� chain5$

1, 86. Neutro-p� hils, monocytes and the monocytic cell line U937 ap-p� arently express two forms of the receptor: CD89 alonea nd CD89/FcR γ� chain (CD89/γ� 2

( )3. Although both forms

o� f CD89 bind IgA with similar affinity, and IgA com-p� lexes are endocytosed with similar kinetics, the intra-c ellular fate of the internalized complexes differed5

$1, 85.

Experimental data suggest that IgA complexes endocy-t

�osed via CD89 alone may be recycled, while those

internalized via CD89/γ� 2( are degraded and sorted for

a ntigen presentation5$1. Thus, because endocytosis can

o� ccur in the absence of the FcR γ� chain, the ITAMmotifs contained therein are not essential for this func-t

�ion. Presumably, as yet uncharacterized motifs within

t�he cytoplasmic tail of CD89 are sufficient to trigger

t�he internalization process.

T�

he signaling cascade triggered via the FcR γ� chainhas to some extent been unraveled in molecular terms.


Fig. 2. A. Structure of the CD89/FcR γ6 chain signaling complex. B. Model for CD89 generated by the Swiss-Model automated protein--modeling server (GlaxoWellcome Experimental Research, Geneva) with the p58 KIR (PDB ID code: 1NKR) coordinates as a template.The FG loop, which contains residues critical for interaction with IgA, is indicated. Domain-specific mAbs are listed beside their respectived7omains. C. Model for human IgA1 (PDB ID code: 1IGA) showing the CD89-binding site


The ITAM signaling motifs, consisting of two YxxLb

�oxes and present in the cytoplasmic tail of the FcR

γ� chain, were shown to be crucial for triggering cellulara ctivation13. Phosphorylation of tyrosine residues with-i

&n these motifs by PTKs is necessary for the potentia-

t�ion of the signaling cascade. FcR cross-linking results

in phosphorylation of the ITAM motifs by a Src familyP

8TK. The next step is the association of a Syk family

PTK with the (phosphorylated) ITAM, resulting in therecruitment and phosphorylation/activation of a num-b

�er of downstream proteins, including protein kinase

C�

(PKC) and the mitogen-activated protein (MAP) ki-nases88. In the case of CD89/γ� 2

( , cross-linking by IgA

c omplexes or anti-CD89 monoclonal antibodies(mAbs) triggers phosphorylation of the FcR γ� chainITAMs by the Src PTK Lyn3

�5. Syk is then able to bind

t�o the phosphorylated ITAM and subsequently becomes

a ctivated by phosphorylation (probably by Lyn). Insome studies, phosphorylation of the tec family PTKBtk has also been observed47, 50. The signal transductionc ascade continues via numerous adaptor proteins(Grb2, Shc, SHIP, CrkL, Cbl, SLP-76), resulting in therecruitment of the GTPase Sos to the complex. Sosc onverts GDP-RAS to GTP-RAS, which subsequentlya ctivates the Raf-1/MEK/MAP kinase and PI-3 kinasesignaling pathways (Fig. 3)7

�4.

Fig. 3. Signaling pathways and cellular responses following CD89/γ6 2( and CD89 aggregation. For CD89/γ6 2

( ,� cross-linking triggers phos-p9 horylation (P) of the tyrosine (Y) residues within the FcR γ6 chain ITAMs by the Src PTK Lyn. Syk then binds to the phosphorylatedITAM and becomes activated. The signal cascade continues with the recruitment of numerous ada: ptor proteins (Grb2, Shc, Crkl, Cbl,S;

LP-76), the lipid metabolizing enzyme SHIP, and the GTPase Sos to the complex. Sos converts GDP�

-Ras to GTP-Ras, which subsequentlya: ctivates the Raf-1/MEK/MAP and PI-3 kinase signaling pathways. In the case of CD89 alone, nothing is as yet known about thei<ntracellular signals triggered upon cross-linking


E=

xpression and Modulation

Expression of CD89 is restricted to cells of them� yeloid lineage: neutrophils, monocytes/macrophages,e� osinophils, and cell lines corresponding to these cellt

�ypes. Lymphoid cells do not express any detectable

C�

D89 protein or mRNA5$4, 60, 62, 63. CD89 expressed on

neutrophils, monocytes and U937 cells has a molecularmass of 55–75 kDa, whereas eosinophil FcαR is larger(70–100 kDa) due to more extensive glycosylaton2, 62, 63.A number of CD89-specific monoclonal antibodies(mAbs) exist and their binding sites within CD89 haveb

�een localised (see Fig. 2B)6

�0, 67, 93. In general, mAbs

t�hat bind in the EC1 domain of CD89, are able to block

I gA-binding, while those that bind to EC2 do not6

�7.

V>

arious cytokines and other factors can modulatesurface expression of CD89 (Table 1)6

�6. CD89 is up-

regulated on neutrophils in response to formyl-methio-n* yl-leucyl-phenylalanine (FMLP), interleukin 8 (IL-8),a nd tumor necrosis factor α (TNF-α)

3 3�

6, 37, 71. Interes-t

�ingly, this upregulation is unaffected by inhibitors of

p� rotein synthesis, suggesting the existence of an intra-c ellular pool of CD893

�6. The CD89 levels can be modu-

lated by Ca2+-dependent signaling processes in bothn* eutrophils and eosinophils3

�6, 62. The expression of CD89

o� n monocytes and monocyte-like cell lines can be up-r+ egulated by Calcitriol, lipopolysaccharide (LPS), TNF-α,g� ranulocyte-macrophage colony stimulating factor(GM-CSF) and IL-1β, and downregulated by suramina nd transforming growth factor-β (TGF-β)

3 7�

, 31, 84, 92.

B?

iological Function

Triggering of cellular effector functions is a criticalstep in many immune reactions, and Ig-FcR interactionsa re often vitally important for the outcome of this pro-c ess81, 82. Thus, stimulation of neutrophils with aggre-

g� ated serum IgA or SIgA triggers a respiratory burstt

�hat can be primed by prior treatment with FMLP.

Monomeric IgA and pIgA, as well as the anti-CD89m� Ab My43, can induce a similar response if a cross--linking secondary mAb is used3

�2, 53, 89, 93, 98, 99. Al-

t�hough monocytes express lower levels of CD89

r+ elative to other Fcγ� R�

s, stimulation with serum IgA orSIgA triggers production of superoxide at levels com-p� arable to those generated via IgG9

@1. Similarly, IgA2-

-containing ICs trigger neutrophil activation more ef-fectively than ICs with IgG122. IgA-coated particles alsot

�rigger efficient eosinophil degranulation and release of

e� osinophil-derived neurotoxin1. However, reports thatSIgA is a powerful stimulator of eosinophil degranula-t

�ion is complicated by the observation that eosinophils

a lso possess a receptor specific for SC (in addition toC

�D89)4

'6, 69.

NA

eutrophils efficiently bind and phagocytose IgA--opsonized bacteria and yeast particles, but priming withG

BM-CSF or IL-8 (resulting in increased IgA binding)

w as necessary for phagocytosis of IgA-coated latexb

�eads12, 32, 71, 111, 119. Similarly, treatment of monocytes

w ith IL-1, TNF-α, GM-CSF or LPS increased CD89e� xpression levels and promoted IgA-mediated phago-c ytosis9

@2. Likewise, eosinophils bind serum IgA-coated

b�eads poorly unless primed with GM-CSF, IL-4 or IL-5,

w hich presumably upregulate CD89 expression9@.

Somewhat puzzlingly, however, an earlier report sawno effect of these cytokines on the expression level ofC

�D89 on eosinophils6

�2.

C�

D89 has also proven to be an efficient triggermolecule for ADCC in a number of in vitro test sys-t

�ems. Effector cells have been stimulated to lyse target

c ells such as bacteria, SC

chistosoma mansoni schisto-somula, and erythrocytes in an IgA-dependent man-ner17, 25, 52. Recently, the therapeutic potential of CD89h

�as been demonstrated by the use of bispecific anti-

b�odies comprising anti-CD89 mAb A77 F(ab’ ) and

Table 1. Modulation of CD89 expression levels

CD

ell type Increase of CD89 expression Decrease of CD89 expression No effect on CD89 expression

NE

eutrophils

Monocytes/macrophages

Eosinophils

IL-8, TNF-α1 , FMLP, ZAS,ionomysinIL-1β

F, TNF-α1 ,� LPS, GM-CSF,

calcitriolIonomycin, IL-4/5,� GM-CSF

TGF-βF, suramin

GM-CSF, IFN-γ6

IL-3/4/6, IFN-γ6

IL-1α1 /GβF

, TGF-βF, IL-2/3/4/

G5/

G6,

G-CSF, GM-CSF, IFN-α1 /Gβ

F/

Gγ6 ,

Con A, PMA

For definition of the abbreviations used see text (except: ZAS – zymosan activated serum; G-CSF – granulocyte-colony stimulating factor,IFN-α1 /

Gβ

F/

Gγ6 – interferon α1 /

GβF/

Gγ6 ,� Con A – concanavalin A). Bold letters signifies that the data are contradictory.


a nti-tumor antigen mAb F(ab’ ), which were shown tot

�rigger ADCC and phagocytosis of tumor cells by

C�

D89-positive effector cells21, 103.A

H further function of IgA is to trigger the release of

v� arious cytokines and inflammatory mediators throughinteraction with CD89. It has been shown that unprimedm� onocytes secrete IL-1β, TNF-α, IL-6, IL-8, leuko-t

�rienes C4

' and B4' , and prostaglandin E2

( following trig-g� ering of CD89 with IgA-containing ICs or anti-CD89m� Ab22, 27, 28, 75, 80. However, some reports also detailt

�he down-regulation of monocyte TNF-α and IL-6 se-

c retion by IgA117, 118. This disparity probably reflectst

�he activation level of the isolated effector cells. IIA1.6

B cells transfected with CD89/FcR γ� chain secrete IL-2f

!ollowing stimulation with IgA or anti-CD89 mAb6

�5.

I gA is also reported to induce secretion of activated

c ollagenase and lactoferrin from neutrophils5$

, 121.It has also recently become clear that under certain

c ircumstances CD89 may work together with comple-ment receptors to ensure efficient triggering of manyc ellular effector functions. IgA-containing ICs mediatea slow release of lactoferrin from neutrophils, whichb

�ecomes much faster if the ICs also contain comple-

ment factors such as C3b and iC3b121. Similarly, pha-g� ocytes were found to require both specific IgA andc omplement to trigger efficient binding, uptake andk

Iilling of S

Ctreptococcus pneumoniae3

�9. In both these

studies the complement receptors involved were ident-ified as CR1 and CR3. Furthermore, when transgenicmice expressing CD89 were crossed with CR3 deficienta nimals, phagocytosis was unaffected, but lysis of tar-g� et cells was abolished105.

Role in Disease

Endocytosis via CD89 has been proposed to be im-p� ortant for the removal of potentially harmful IgA-con-t

�aining ICs from the bloodstream6

�1, 94. Recently, a de-

fect in CD89-mediated endocytosis has been proposedt

�o contribute to the pathogenesis of diseases such as

I gAN, Sjögren’s syndrome (SS), alcoholic liver cir-

rhosis and HIV infection, which are all characterizedb

�y a high serum concentration of pIgA and increased

levels of circulating IgA-containing ICs3�

3, 34, 61, 94. Ina ddition, it appears that the O-linked glycans of IgA1a re different in IgAN patients and that the IgA fromt

�hese patients shows a reduced affinity for CD89,w hich may contribute to the increased serum IgA le-v� els5

$8, 107. Similarly, in SS, over-sialylation of IgA may

e� xplain its reduced binding to CD89, its inefficient

c learance and its high serum levels4'. Defective clear-

a nce of IgA-containing ICs could lead to their deposi-t

�ion in the mesangium, where they may trigger chronic

kIidney damage29. Such deposition of IgA-containing

ICs in the kidneys might be mediated by CD89 ex-p� ressed on the mesangial cells6

�6. However, this theory

r+ emains controversial because some investigators havefailed to detect expression of CD89 mRNA or proteinin these cells, while others have reported easily detect-a ble levels of both CD89 and FcR γ� chain24, 100, 113.

It was mentioned above that eosinophils expressa highly glycosylated form of CD89. The same reportshowed that eosinophils from some allergic patients ex-p� ressed higher levels of CD89 than those from normali

&ndividuals6

�2. More recently, atopic asthmatics were

shown to have elevated levels of specific IgA in sputuma gainst both allergens and bacterial antigens7

�0. Taken

t�ogether, these data point to a role for IgA and CD89i

&n the pathogenesis of atopic allergy and extrinsic as-

t�hma. Further research is clearly needed to define the

r+ oles of IgA, CD89, and the putative SC receptor one� osinophils for the degranulation of these cells asa component of the allergic reaction.

Future Perspectives

I n terms of signaling via CD89, it would be interes-

t�ing to know whether CD89 can associate with mole-

c ules other than the FcR γ� chain, such as the family ofm� olecules related to the FcR γ� chain and recentlyshown to associate (via charged transmembraner+ esidues) with the KIR/KAR proteins15, 49. It is temptingt

�o speculate that, while activation signals generated by

C�

D89 are transmitted via the FcR γ� chain, anti-inflam-matory/inhibitory actions of CD89 may be attributede� ither to non-association with the FcR γ� chain or, in-d

�eed, association with an as yet uncharacterized immu-

n* oreceptor tyrosine-based inhibitory motif-containinga ccessory molecule. It would also be advantageous touJ nderstand how the IgA-CD89 interaction takes placea t the cell surface. Uniquely (for human FcRs), CD89b

�inds to the Cα2

)/Cα3 region of IgA via its EC1 do-

main. Current structural models for both molecules don* ot easily suggest how this interaction proceeds (Fig.2); perhaps CD89 adopts a more upright conformationt

�han the related KIR proteins. Crystallographic data

w ill probably be needed to truly answer this question.A

H more detailed three-dimensional structure of CD89

should also reveal the stoichiometry of IgA-CD89 com-p� lexing, i.e. do two (or more) CD89 molecules associ-a te at the cell surface prior to or during the interaction


w ith IgA? Interestingly, several investigators have re-p� orted that Fcγ� RII forms dimers to bind one IgG mole-c ule, and it is suggested that KIR p� roteins may also bea ssociated on the cell surface5

$5, 96, 97.

Conclusions

In this review we have described current knowledgeo� n the structure and function of the only well-definedhuman IgA Fc receptor, CD89. This receptor appearst

�o play an important role in immune defense by linking

t�he humoral IgA response to powerful cellular effector

mechanisms. Further studies will no doubt seek to ex-p� loit the CD89-IgA interaction for the design of anti-b

�ody-based therapeutics, including recombinant vari-

a nts of IgA and bispecific anitbodies.

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Received in January 2000Accepted in March 2000


cd89: the human myeloid iga fc receptor

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