Cellular and Molecular Mechanisms of Inflammation. Receptors of Inflammatory Cells: Structure–Function Relationships

254 Pages·1990·3.862 MB·English

by  Charles G. Cochrane and Michael A. Gimbrone (Eds.)

-VOLUME 1
Cellular
and Molecular
Mechanisms
of Inflammation
Receptors of Inflammatory Cells:
Structure-Function Relationships
Edited by
Charles G. Cochrane
Department of Immunology
Research Institute of Scripps Clinic
La Jolla, California
Michael A. Gimbrone, Jr.
Department of Pathology
Brigham and Women's Hospital
Harvard Medical School
Boston, Massachusetts
Academic Press, Inc.
Harcourt Brace Jovanovich, Publishers
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Preface
This volume is the first in a new serial on Cellular and Molecular Mecha-
nisms of Inflammation. The purpose of this serial is to bring together the
latest knowledge in various areas of research in this actively developing
field around a topical focus. These volumes are not intended to present
comprehensive reviews. Rather, each contribution is meant to be a sta-
tus report from laboratories actively working in an area. The editors ac-
cept the responsibility for bringing together a spectrum of contributions
to provide the reader with knowledge in a given topic area of sufficient
breadth to serve as a basis for further research initiatives. By avoiding
any requirement for comprehensive review, by encouraging contribu-
tors to provide their expert viewpoint, and by reducing publication time
to a minimum through the use of computer typesetting, each volume of
this serial will prove to be a timely and useful contribution to the re-
search community's efforts in this area.
In the current issue, an analysis of the structure-function relation-
ships of receptors is presented. It is clear that the structure of receptors
provides the initial guidance for numerous functions of each cell in the
organism. Through an analysis of the submolecular features of the re-
ceptors that are responsible for the initiation of activity of diverse bio-
chemical pathways within the cells, a molecular understanding of the
all important initial, guiding events of cell functions will emerge. In the
broad sense of cells involved in inflammation, this includes mitogenesis,
gene transcription, generation of lipid metabolites and oxidants, clear-
ance of molecules from the surrounding medium, and release of granu-
lar constituents from cytoplasmic vesicles into the external medium,
among others.
Needless to say, the contents of this first volume will serve as a foun-
dation for the subject of the second volume, which is signal transduc-
ix
χ Preface
tion. Four additional volumes are in preparation, including Endothelial
Leukocyte-Adhesion Molecules, Leukocyte Adhesive Mechanisms in In-
flammation and Immunity, a second volume on Signal Transduction,
and Stimulation of Inflammatory Cells.
The editors are particularly grateful to the contributors for the
promptness of their efforts. This is reflected in the fresh quality of each
contribution. We also wish to thank Monica Bartlett for her precise cleri-
cal attention to each facet of the project.
Charles G. Cochrane
Michael A. Gimbrone, Jr.
C Η Α Ρ Τ Ε R 1
Fc Receptors:
7
A Diverse and
Multifunctional
Gene Family
Joseph A. Odin, Catherine J. Painter, and Jay C. Unkeless
Department of Biochemistry
Mount Sinai School of Medicine
New York, New York 10029
Introduction
At a FASEB-sponsored conference in June of 1987, Fc receptors for IgG
(Fc^Rs) were defined as a family of receptors that specifically bind IgG
via the Fc domain and that mediate physiologic functions. Today, it is
clear that these receptors and soluble Ig-binding factors play important
roles in immunity. These roles can be grouped into three areas: cellular
immune defense and lymphocyte regulation, immunoglobulin trans-
cytosis, and autoimmune pathology. In cellular immune defense, upon
cross-linking by IgG aggregates, ¥c Rs activate a variety of leukocyte
y
responses, such as phagocytosis, antibody-dependent cell cytotoxicity
(ADCC), and release of lysosomal hydrolases, reactive oxygen metabo-
lites, arachidonate metabolites, and other mediators of inflammation.
Soluble immunoglobulin-binding factors (IBFs) and cross-linking of cell
Cellular and Molecular Mechanisms of Inflammation, Volume 1
Copyright © 1990 by Academic Press, Inc. All rights of reproduction in any form reserved. 1
2 Joseph A. Odin et al.
surface antibodies to membrane-bound Fc^Rs inhibit Β cell differentia-
tion (Teillaud et al. 1987; Phillips and Parker, 1985). Though not yet
f
tested, it seems likely that Fc^Rs on neonatal rat gut epithelium (Simister
and Mostov, 1989) and syncytiotrophoblasts (Stuart et al., 1989) are in-
volved in transcytosis of immunoglobulin. Dysfunction of macrophage
Fc Rs (Hoffman et al., 1989; Clarkson et al., 1986b) as well as the pres-
7
ence of high titers of anti-Fc R immunoglobulin (Sipos et al., 1988; Boros
7
et al., 1990a) have been reported in both human and mouse autoimmune
disease.
All FcRs, except CD23 (Fc RII), are members of the Ig supergene fam-
e
ily and are homologous to each other. Most Fc Rs are type I membrane
7
glycoproteins with one transmembrane domain and a cytoplasmic do-
main. However, huFc RIII-l is anchored in the neutrophil plasma mem-
7
brane by a glycan phosphatidylinositol (GPI) moiety (Selvaraj et al.,
1988; Huizinga et al, 1988; Ravetch and Perussia, 1989; Scallon et al,
1989; Ueda et al, 1989). Low-avidity forms of membrane-bound Fc^Rs
contain two extracellular Ig-like regions, whereas high-avidity forms
contain three Ig-like regions. Assigning functions to individual Fc Rs
7
has been a challenging task because many share immunologically indis-
tinguishable extracellular domains, within a subclass, and their cellular
distributions overlap considerably. This review summarizes the current
state of knowledge of the structure, function, and signaling mechanisms
of mouse and human Fc receptors. Prior reviews cover older literature
7
in greater depth (Unkeless et al, 1988; Anderson, 1989).
Nomenclature
A nomenclature for the family of Fc receptors was agreed upon in June,
1987. However, since then, numerous new Fc^R genes have been iso-
lated. The nomenclature we have adopted for this review is consistent
with that originally agreed upon and also incorporates additional infor-
mation. To save space, prior designations (pre-1987) (Unkeless et al,
1988) have not been included. The species of origin is designated by two
lower case letters (e.g., mo for mouse and hu for human). The subscript
Greek letter refers to the major class of immunoglobulin bound by the
receptor. The Roman numeral refers to the distinct subclass of the desig-
nated receptor class. The subclasses are based on structural similarity
and reactivity with specific monoclonal antibodies (mAbs). Any symbol
following the Roman numeral refers to a distinct gene within that sub-
class. Subscript Arabic numerals designate a specific splice form of that
CHAPTER 1 Fc Receptors 3
7
gene. Because no consistent nomenclature exists for the newly discov-
ered huFCyRII genes, we selected appropriate designations.
huFc RI
Y
Fc Rs on human monocytes and macrophages were demonstrated by
7
their ability to rosette IgG-sensitized erythrocytes in the absence of se-
rum (Jandl and Tomlinson, 1958; Archer, 1965; LoBuglio et al, 1967).
The rosettes were specifically inhibited by IgG or its Fc fragment. Mono-
cytes phagocytosed erythrocytes coated with either anti-Rh IgG or non-
0
immune IgG, but did not phagocytose those coated with IgM or Fab
fragments of IgG (Huber and Fudenberg, 1968). IgG subclass inhibition
studies indicated that IgGl and IgG3 were 1000-fold more effective in-
hibitors of phagocytosis than IgG2 or IgG4, and direct binding assays
using radiolabeled IgG demonstrated the higher avidity of IgGl and
IgG3 (Alexander et al, 1978; Hay et al, 1972; Huber et al, 1971; Fries et
al, 1982).
The histiocytic cell line U937 has about 18,000 high-affinity (K ~108
a
_1
M ), trypsin-insensitive IgGl-binding sites per cell (Anderson and
Abraham, 1980) and is a good model for human monocytes, which have
20,200 sites with a K of -8.6 x 10 8 M 1 for human IgGl (Kurlander
a
and Batker, 1982). High-affinity binding (10 8-109 M"1) of murine IgG
subclasses IgG2a and IgG3 to both monocytes and U937 cells has been
shown as well (Lubeck et al, 1985). The receptor, now termed huFc^RI
(CD64), was purified by Sepharose-IgG affinity chromatography from
the U937 cell line as well as from monocytes (Anderson, 1982; Cohen et
al, 1983). It has an M as determined by sodium dodecyl sulfate and
r
polyacrylamide gel electrophoresis (SDS-PAGE) of ~72K. The broad
band seen after SDS-PAGE was not affected by neuraminidase treat-
ment, although the charge heterogeneity demonstrated by isoelectric fo-
cusing (IEF) and SDS-PAGE was significantly reduced (Anderson,
1982). Treatment of the receptor with endo-p-N-acetylglucosaminidase
F or N-glycanase yielded a core protein of 40 or 50 kDa, respectively
(Frey and Engelhardt, 1987; Peltz et al, 1988).
Several anti-huFc^RI mAbs have been characterized. mAbs 32 (An-
derson et al, 1986) and 62 bind to an epitope distinct from that to which
mAbs 22 and 44 bind (Guyre et al 1989). None of these antibodies,
f
however, is capable of blocking ligand binding. mAb 197, an IgG2a anti-
FCyRI, blocks ligand binding, perhaps through binding of its Fc region
to huFc^RI (Guyre et al, 1989). mAb 10.1 may bind near the ligand-
4 Joseph A. Odin et al.
binding site, as it can inhibit binding of immune complexes but not mo-
nomeric IgG (Dougherty et al, 1987). mAb FR51 or its F(ab') inhibits
2
the binding of both monomeric and aggregated IgG to U937 cells and
the myeloblast cell line HL-60 (Frey and Engelhardt, 1987).
FcRI is univalent for human IgGl (O'Grady et al, 1986). Recent clon-
7
ing of cDNAs for the huFc^RI showed that the extracellular domain con-
tains six potential N-linked glycosylation sites and six cysteine residues,
presumably disulfide linked to form three C2-set (Williams and Barclay,
1988) Ig-like regions. In contrast, huFc RII and huFc^RIII encode only
7
two Ig-like regions. The transmembrane domain is 21 residues and the
cytoplasmic domain is short and highly charged (Allen and Seed, 1989).
The mouse Fc^RI is similar in structure (Sears et al, 1990). Homology
also exists between the first two N-terminal external Ig-like regions of
each Fc^RI and the analogous domains of mouse and human Fc RII and
7
huFcRIII (Allen and Seed, 1989; Sears et al, 1990). The uniqueness of
7
the third domain and its conservation between human and mouse, as
well as preliminary mutational analysis (Allen and Seed, 1989), suggest
that this third membrane-proximal domain of Fc RI endows high-affin-
7
ity ligand-binding capacity.
The IgG site that interacts with Fc RI has been examined by a combi-
7
nation of techniques: aglycosylated ligand binding, mAb inhibition of
ligand binding, and site-directed mutagenesis (Leatherbarrow et al,
1985; Burton et al, 1988; Duncan et al, 1988). IgG glycosylation is impor-
tant for Fc R function. Aglycosylated murine IgG2b immune complexes
7
bound poorly to the murine Ml macrophage cell line, were cleared
slowly, and inefficiently mediated ADCC (Kurlander and Gartrell,
1983). Aglycosylated murine IgG2a did not bind to human monocytes,
though complement fixation and activation were only slightly decreased
(Leatherbarrow et al, 1985). Inhibition of monomeric human IgG bind-
ing to huFc^RI cells by mAbs directed against various IgG epitopes sug-
gested that the binding site is low in the IgG hinge region (Burton et al,
1988). In support of this conclusion, site-directed mutagenesis of a sin-
gle residue in the hinge region (IgG2b Glu 235 —> Leu235) converted a low-
affinity IgG2b ligand to one with high avidity (K = 3.1 x 108 Λ/Γ1) for
a
huFcRI (Duncan et al, 1988).
7
The huFc^RI binding site may contain a readily oxidizable residue.
Porphyrin photosensitization in vitro of monocytes and U937 cells selec-
tively reduced murine IgG2a binding to huFc RI (Krutmann et al, 1989).
7
This was not due to loss of the receptor from the cell surface, as mAb
surface staining was still possible with some anti-huFc^RI mAbs, which
do not affect binding of ligand. Scavenger experiments suggest that gen-
eration of Ο2 is responsible for the reduced binding.
CHAPTER 1 ¥c Receptors 5
y
It is not clear why there are multiple Fc^Rs, as many of the functions
are subtended by more than one receptor. Indeed, several members of
a Belgian family have a complete absence of huFc^RI expression on their
peripheral blood monocytes (Ceuppens et al, 1985a,b, 1988). Two expla-
nations of their apparent good health are as follows: (1) these individu-
als may possess a developmental defect such that huFc RI is not ex-
7
pressed on monocytes but is expressed on tissue macrophages, where
it functions normally; (2) an absence of huF^RI may be of little con-
sequence due to the redundancy of functions among leukocyte Fc^Rs
(Unkeless, 1989a; Anderson, 1989).
Several investigators have shown that the expression of huFc^RI on
monocytes and various related cell lines in increased from 2- to 10-fold
upon incubation with interferon-7 (IFN-7) (10-1000 U/ml) (Guyre et al,
1983; Perussia et al, 1983; Akiyama et al, 1984), and this effect is blocked
by cycloheximide or actinomycin D (Perussia et «/.,1983). Furthermore,
IFN-7 treatment (at 50 ng/ml) of neutrophils, which normally do not
express huFc RI, resulted in the expression of —13,600 monomeric IgG-
7
binding sites (Perussia et al, 1983). In a clinical study (Maluish et al,
1988), IFN-7 doses of 0.1 mg/m 2 were effective in elevating Fc^,R expres-
sion, as analyzed by binding of fluoroscein isothiocyanate (FITC)-la-
beled IgG (Guyre et al, 1983). In this study, however, objective toxicity
included leukopenia and granulocytopenia. At a higher dose (0.25 mg/
2
m ), the percentage of monocytes bearing Fc^Rs dropped from 48 to 11%
during the 2-week course of daily treatment and dropped further to 2%
by the second day posttreatment.
The IFN-7-induced increased expression of high-affinity huFc^RI sites
on monocytes and macrophages can be further augmented with dexa-
methasone (200 nM) (Crabtree et al, 1979; Girard et al, 1987), whereas
this IFN-7 effect is abrogated by dexamethasone for HL-60 (Crabtree et
al, 1979) and U937 (Shen et al, 1984) cell lines, as well as for neutrophils
(Petroni et al, 1988). The positive effect of dexamethasone on IFN-7-
treated monocytes may be explainable by a dexamethasone-mediated
increase in IFN-7 receptors (Strickland et al, 1986). Glucocorticoid treat-
ment alone has been reported to decrease huFc R expression in HL-60
7
and U937 cell lines (Crabtree et al, 1979; Shen et al, 1984), as well as on
monocytes obtained following glucocorticoid therapy (Fries et al, 1983).
Monocytes treated in vitro with glucocorticoid have an unaltered level
of huFc^RI expression (Girard et al, 1987).
The effects of IFN-7 and dexamethasone on neutrophils shed light
on the functional role of huFc^RI. Dexamethasone inhibited both the
increased expression of Fc^RI as well as the increased capacity for ADCC
and phagocytosis demonstrated by IFN-7-treated neutrophils. Dexa-
6 Joseph A. Odin et al
methasone reduction of IFN-7-induced phagocytosis was more marked,
however, than was the decrease in huFc RI expression (Petroni et al.,
7
1988).
Cross-linking of huFc RI (by either ligand complexes or anti-huFc RI
7 7
mAbs) results in a number of functional responses; monomeric interac-
tions have not been conclusively shown to generate any of these re-
sponses. In contrast to immune complexes, which are endocytosed rap-
idly (Kurlander and Gartrell, 1983; Segal et al, 1983; Jones et al, 1985b),
monomeric ligand is not internalized or degraded through huFc RI
7
(Jones et al, 1985b). These results imply that huFc RI, when occupied by
7
monomeric ligand, does not recycle (Jones et al, 1985b). Cross-linking of
huFc RI using mAb 32 with a secondary anti-IgG reagent results in
7
0 ~ production (Anderson et al, 1986). Continuous 0 ~ production via
2 2
huFc RI is dependent on continuous de novo formation of cross-linked
7
huFc RI (Pfefferkorn and Fanger, 1989). HuFc RI on monocytes, macro-
7 7
phages, and IFN-7-treated neutrophils mediates phagocytosis of eryth-
rocytes coated with heteroantibodies composed of Fab fragments of
anti-huFcRI mAb and Fab fragments of antierythrocyte antibody (An-
7
derson and Shen, 1985).
Recent work has shown that huFc RI is capable of ADCC toward tar-
7
get cells. The ADCC response is dependent on the effector cell type and
maturity, as well as on the target cell type (Shen et al, 1989; Fanger et
al, 1989; Graziano et al, 1989b). Inflammatory mediators may also be
important, because exogenous Clq reconstitutes Fc R-mediated ADCC
7
and phagocytosis in mouse peritoneal macrophages (Leu et al, 1989).
HuFc RI on monocytes and macrophages effects ADCC of both hybrid-
7
oma and erythrocyte targets. IFN-7 treatment augments huFc RI-medi-
7
ated ADCC of monocytes and induces that of neutrophils (Shen et al,
1987, 1989; Fanger et al, 1989; Akiyama et al, 1984). Studies of ADCC
with putative effector cell lines are largely unsatisfactory. Myeloid cell
lines HL-60, U937, and THP-1 are unable to kill either erythroid or hy-
bridoma targets, though IFN-7 treatment of these lines resulted in cyto-
toxicity against erythroid targets. When further differentiated (by 2-day
culture), THP-1 cells exhibited slight huFc RI-mediated cytotoxicity
7
(Fanger et al, 1989).
huFc RII
T
A second subclass of human Fc Rs, huFc RII (CD32), was initially identi-
7 7
fied by affinity chromatography of U937 lysates on IgG-Sepharose (An-