F o l i a Mierobiol. 29, 4 7 6 - - 5 1 6 (1984)
Fc Receptor More Answers, More Questions
L. F o R ~ S ~ X * and V. V]~TVI6KA
Department of Immunology, Institute of Microbiology,
Czechoslovak Academy of Sciences, 142 20 Prafue 4
Received September 16, 1983
A B S T R A C T . F c r e c e p t o r s , b e l o n g i n g to t h e m o s t i m p o r t a n t s u r f a c e s t r u c t u r e s o f a n u m b e r o f
cells p a r t i c i p a t i n g in t h e i m m u n e processes, h a v e b e e n i n t e n s e l y s t u d i e d d u r i n g t h e p a s t d e c a d e .
T h e p r e s e n t r e v i e w s u m m a r i z e s t h e c o n t e m p o r a r y k n o w l e d g e o f t h e specificity a n d h e t e r o -
geneity of Fe receptors and of factors influencing their expression, and includes some views on
t h e i r f u n c t i o n . I n a d d i t i o n , it m e n t i o n s t h e i r r e l a t i o n s h i p to o t h e r cell s u r f a c e s t r u c t u r e s , e x -
p r e s s i o n o f F e r e c e p t o r s d u r i n g o n t o g e n y o f t h e o r g a n i s m a n d in c e r t a i n diseases. F i n a l l y , d a t a
concerning the isolation and biochemical characterization of the Fc receptor molecule are
presented.
Contents
1 T h e i m m u n o g l o b u l i n m o l e c u l e a n d i t s i n t e r a c t i o n w i t h t h e F e r e c e p t o r 477
2 I m m u n o g l o b u l i n - b i n d i n g s t r u c t u r e s 479
3 M e t h o d s of F e r e c e p t o r d e t e c t i o n 479
4 Specificity o f F c r e c e p t o r s 484
5 F c r e c e p t o r - b e a r i n g cells 485
6 N u m b e r of F c r e c e p t o r s o n a cell 487
7 F a c t o r s i n f l u e n c i n g F c r e c e p t o r e x p r e s s i o n 487
8 R e l a t i o n s h i p of F e r e c e p t o r s to o t h e r r e c e p t o r s a n d a n t i g e n s on t h e p l a s m a m e m b r a n e 491
9 F u n c t i o n s o f F c r e c e p t o r s 493
10 F e r e c e p t o r s d u r i n g o n t o g e n y of t h e o r g a n i s m 496
1i F e r e c e p t o r s a n d disease 496
12 I s o l a t i o n a n d c h a r a c t e r i z a t i o n o f t h e F c r e c e p t o r m o l e c u l e 498
References 500
Abbreviations: A D C C -- a n t i b o d y - d e p e n d e n t cellular c y t o t o x i c i t y , C3 r e c e p t o r -- r e c e p t o r for
t h e C3 c o m p o n e n t o f c o m p l e m e n t , E A R F C a s s a y -- a n t i b o d y - c o a t e d e r y t h r o c y t e r o s e t t e -
f o r m i n g cell a s s a y , F o R - - F c r e c e p t o r s (used w i t h t h e i n d e x o f t h e g i v e n i m m u n o g l o b u l i n class,
I B F -- i m m u n o g l o b u l i n - b i n d i n g factor, K cells -- killer ceils, N K cells -- n a t u r a l killer cells,
s F c R -- soluble F e receptors, S p A -- p r o t e i n A, TT-, T~z-, Tee-lymphocyte -- T l y m p h o c y t e - b e a r -
i n g F e r e c e p t o r for t h e g i v e n i m m u n o g l o b u l i n class, TH l y m p h o c y t e -- h e l p e r T l y m p h o c y t e ,
T s l y m p h o c y t e -- s u p p r e s s o r T l y m p h o c y t e , T R F -- T cell-replacing f a c t o r .
Receptors for Immunoglobulins (Fc receptors)
I t was observed in the sixties t h a t , in addition to macrophages (Boyden
and Sorkin 1960; Howard and Benacerraf 1966), certain lymphocytes can
* Present address: I n s t i t u t e o f P a r a s i t o l o g y , C z e c h o s l o v a k A c a d e m y of Sciences, 370 05 ~esk6
B u d ~ j o v i c c , Czechoslovakia.
,1984 Fc R E C E P T O R S 47"1
bind immunoglobulins in a complex with antigens in the absence of opsonins
(LoBuglio et a/ 1967). Soon after this discovery, the receptors involved
were considered to be a k e y element of certain immune reactions because
t h e y were found to mediate interactions between the i m m u n o c o m p e t e n t
cell and immunoglobulins (review b y Dickler 1976). At present, the far more
frequently used term Fc receptors (FeR) is derived from the fact t h a t their
main binding specificity is directed against the Fc portion of the immune-
globulin molecule.
1 The i m m u n o g l o b u l i n m o l e c u l e and its interaction with the
Fc receptor
To begin with, let us briefly review the structure and function of immune-
globulins.
Immunoglobulins possess a basic four-chain structure; t h e y are composed
of two identical h e a v y and two identical light cha:s which are mutually
connected b y interchain disulfide bonds. Each chain is composed of several
homologous domains, each having its specific function. Using papain
(EC 3.4.22.2), the immunoglobulin molecule can be split into a divalent
antigen-binding fragment F(ab~2 and a Fc fragment (---- crystallizable frag-
ment). F u r t h e r splitting of the Fc fragment with pepsin A (EC 3.4.23.1)
results in splitting off the terminal fragment, the so-called p F c ' fragment,
i.e. in a separation of the CH2 and CH3 domains. The Cri2 domain bears
saccharide side chains and the combining site for the Clq complement
component.
There exist five main t y p e s of heavy chains (isotypes) which serve as
a criterion for classification of immunoglobulins into classes. The most
common are immunoglobulins G (IgG), occurring both in the extra- and
intravascular space where t h e y provide defense against microorganisms and
toxins. Some subclasses of IgG can fix complement. IgA occurs either as
a monomer in the plasma or in the form of a dimer in the secretions of
mucous membranes where it represents the principal immunoglobulin, af-
fording protection of the b o d y surfaces. IgM is a pentamcr ; it can be found
mostly in the intravascular space. I t is produced at the early phase of the
immune response. Because of its multiple valency, it is a very important
agglutinJn and opsonin, as well as a mediator of complement-dependent
cytolysis. IgD, together with the monomeric modified form of IgM, is a re-
ceptor for the antigen on the surface of B lymphocytes; however, it can
be found even in plasma. I g E is the most important immunoglobulin of the
reagin nature; it plays an important role both in parasitic infections and
as an opsonin.
The most important isotypic structural variants are localized on the Fc
portion of the immunoglobulin molecule. They arc of basic importance for
the determination of the above-mentioned secondary functions of immune-
globulins. Obviously, t h e y are related even to the combining site for F c R
(see chapter 4).
The controversy, concerning the determination of the domain of the
immunoglobulin Fc portion that bear the combining site for F c R (review b y
Dorrington and Klein 1982), has not yet been resolved. The finding that
binding of complement to its combining site on the Fc portion of immune-
globulin blocks at the same time the binding of this immunoglobulin to F c R
,478 L. FORNI~SEK and V. V ~ T V I ~ K A Vol. 29
(Michl et al. (1979) would suggest.here the C~2 domain. Of a similar opinion
are Diamond et al. (1979) who could: not detect any decrease in the binding
to Fel~ using a defective variant of monoclonal antibody that lacked the
CH3 domain. This view was also supported by Hofstaetter et a l . (1982)
who specified that this combining site is not identical with the combining
site for protein A. On the other band, Endresen and Forre (1982) claim t h a t
the combining site for FcR of thrombocytes is localized on the C~3 domain.
They found, in contrast to Ganczakowski and Leslie (1979) who observed a
certain decrease in macrophages, that IgG is bound as well as its pFc'
fragment. It seems, however, t h a t the truth lies somewhere in between (even
though one cannot exclude 'differences l~etween biological species, individual
immunoglobulin classes or cell types), i.e. both domains would probably
participate on the binding of the immunoglobulin Fc portion to Fcl~. In the
course of studies on the binding of the Fc portion of immunoglobulin molecule,
several authors reached the conclusion that for an effective binding of
immunoglobulin to FcR, an intact structure of.the whole Fc portion is
required (Haeffner-Cavaillon et al. 1979a; Bast et al. 1980a; van der Meulen
et al. 1980; Matre et al. 1981 ; Seller et al. 1981). Kulczycki and Vallina (1981)
showed that the FcR does not bind single heavy chain, even if bound
with the light chain. This is documented by inhibition tests using peptides
derived from the Fc portion of immunoglobulins (Ratcliffe and Stanworth
1982; S~rmay et al. 1982).
A different situation is observed with IgE (Kulczycki 1980) which is
obviously bound through its CR4 extradomain which is probably connected
by an unusually high affinity of this isotype to its FcR, in contrast to affini-
ties of the other isotypes. On the basis of experiments aimed at, a reduction
of the disulfide bonds, ttaeffner-Cavaillon et al. (1979), suggested the possible
participation of the Fab portion of the immunoglobulin molecule in the
binding to FcR. It had already been shown before that not all types of
antigen-immunoglobulin immune complexes can bind equally well to FcR.
Birshtein et al. (1982), employing hybrid monoclonal antibodies bearing
the CH1 domain and the hinge region of the IgG2B and CH2 and CH3 domains
of IgG2n, showed that this immunoglobulin molecule can bind to the Fcl~
for IgG2n only after splitting off the F(~b) fragment.
So far it has not been definitely decided whether the binding of immune-
globulins to Fcl~ involves the saccharide chains borne by the Fc portion.
Kulczycki and Vallina (1981) found that both the glycosylated and non-
glycosylated IgE immunoglobulins bind to Fcl~. On the other hand, Bragado
et al. (1982) observed a substantial decrease of the IgG-binding capacity
following treatment of the glycoside chains of the Fc portion of the immune-
globulin molecule.
As regards the proper binding of immunoglobulins to FcR, or, more pre-
cisely, requirements for the presence of other substances, a number of
authors (Lay and Nussenzweig 1969; Uher st al. 1981b; Andersson et al.
1981) confirmed the interesting fact that binding of IgM to its FcR in macro-
phages depends on the presence of Ca 2+ ions and is independent of Mg 2+
ions whereas in thymocytes, lymph node and spleen lymphocytes, the de-
pendences are reversed. A dependence of macrophage activation by binding
a dimer or aggregated IgE on the presence of Ca 2+ ions was described by
Dessaint et al. (1980).
, 1984 Fc RECEPTORS 479
In addition to immunoglobulins, F c R interacts with certain types o f
T-cell replacing factors (TRF) (Schimpl and Wecker 1972; K61sch et el.
1980). However, it is not quite clear whether t h e binding takes place at the
same binding site: of the receptor or whether F c R bears two different binding
sites so that the inhibition of the latter ligand takes place as a consequence
of steric hindrance o r steric changes of FcR.
2 l m m u n o g l o b u l i n - b i n d i n g structures
In the strict sense, F c R usually denotes receptors with a specificity for
the Fc portion ofimmunoglobulins (chapter 1) as are found on the cell sur-
face of higher vertebrates, i.e. animals with developed immune system.
As a rule, we also consider only FcR, present on cells participating in i m m u n e
processes. In addition, the so-called immunoglobulin-binding factor (IBF),
described b y Fridman and Golstein (1979), also called the FcR-like substance,
Fc-binding component, FcR-s, haemagglutination-potentiating factor, etc.
(review b y Fridman et al. 1981), used to be included with these factors.
Actually. all evidence suggests that we are dealing with the soluble form
(sFcR) of membrane F c R (Kahn-Perles et el. 1980; Fridman et el. 1981).
However, recent data suggest t h a t there exist several types of such m e m b r a n e
FcR-derived soluble factors (Yodoi and Ishizaka 1980b; J a r r e t 1981; Ishi-
zaka et al. 1981; Ueda et al. 1983).
In a broader sense, F o R denotes all structures that can bind immunoglobu-
lins through their Fc portion, regardless of their localization. Perhaps the.
only exception is the structure borne b y staphylococci which, for historical
and other reasons is called protein A (SPA; review Goding 1978). I m m u n e -
globulin-binding strctures of other bacteria, however, are called FcR. Thus,
for example, streptococci bear besides the SpA four other F e R ' s (Nilsson
et al. 1982), the best known being F c R for h u m a n IgA, which is known t o
play an important role in bacterial survival. The binding of h u m a n IgA
to this F c R triggers the production and liberation of proteases, splitting IgA
into the F e b and Fc fragments (Lindahl et al. 1981) which permits t h e
streptococci to overcome the outer mucuous membrane barriers of the in-
fected individual.
Not only bacteria, but even viruses carry FcR. For example, following
an infection of mouse fibroblasts with the herpes simplex virus, F c R is
expressed on the surface of these cells as well as on the virus particles (Costa
and Rabson 1975). Thus it seems t h a t at ]east in this instance F c R is virtually
coded b y the virus and is supposed to protect the host cell from lysis b y
antibody (Baucke and Spear 1979).[
It is not clear whether all types of F c R react with the immunoglobulin
molecule at the same site of its Fc portion. We only know that the combining
site for the best known of these structures, SpA, is different from the binding
site for F c R of cells of the vertebrate immune system, even though it is most
probably localized very near as documented b y the possibility to inhibit
binding of immunoglobulins to F c R b y SpA (Tony and Schimpl 1981).
3 M e t h o d s o f Fc r e c e p t o r detection
Methods for FcR detection are many; on the one hand, this makes it
possible to choose the most suitable method for solving a given problem,
