Identification of the site on IgG Fc for interaction with streptococci of groups A, C and G.
ABSTRACT The interaction between living groups A, C and G streptococci and IgG Fc was studied using human IgG, IgG Fc and IgG Fc-intermediate (Fci) fragments, chemically modified human IgG and fragment D of staphylococcal protein A (SPA). Diethylpyrocarbonate modification of His or N-acetylimidazole modification of Tyr of human IgG resulted in the loss of its capacity to inhibit the binding of radiolabelled human IgG Fc to the group A streptococci types M1 and M55, and to the group C strain SC-1, indicating that the amino acids His and Tyr are involved in the binding. Lys seems not to participate in the binding of IgG to these bacteria, however, since reductive methylation of Lys did not reduce its inhibitory capacity. Fragment D of SPA also inhibited the binding of radiolabelled human IgG Fc to strains M1, M55 and SC-1. We have previously shown that these bacteria do not bind to IgG fragments consisting of only the C gamma 2 or C gamma 3 domains. On the basis of these results, and the known relative positions in space of the His and Tyr residues on IgG Fc, it is speculated whether streptococci with IgG Fc receptors, like SPA and rheumatoid factors, interact with IgG in the interface between the C gamma 2 and C gamma 3 domains and involve His 435 and one or more of Tyr 436, His 433 and His 310. The similarities in binding sites on IgG for RFs and these bacterial Fc binding proteins suggest structural similarities between them that may be relevant to the production of rheumatoid factors in rheumatoid arthritis.
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ABSTRACT: Fc intermediate (Fci) is a papain-generated fragment of human IgG which is intermediate in charge, mol. wt and state of cleavage between the Fc and Fc' fragments of IgG. It is composed of two polypeptide chains of unequal mol. wt held together by non-covalent bonds between the C gamma 3 regions. The larger polypeptide chain has both a C gamma 2 and C gamma 3 domain and its N-terminus is at Leu 235 (60%) and Leu 234 (40%) (IgGl Eu numbering). The smaller polypeptide chain is composed of a C gamma 3 domain with its N-terminus at Gly 341. The carboxy-termini obtained by carboxypeptidase digestion and by a computer program which determined the most probable sequences by fitting the amino acid compositions to the sequence of IgG Eu Fc were heterogeneous involving residues 440-446 for the large polypeptide chain and 429-436 for the small one. The calculated mol. wt of the large polypeptide chain was 26,183, assuming the N-terminus at Leu 234 and C-terminus at 446 and including the carbohydrate moiety. The calculated mol. wt for the small polypeptide chain was 10,682, with the N-terminus at 341 and assuming the C-terminus at 434, for a combined mol. wt of 36,865 for the Fci fragment. Sedimentation equilibrium ultracentrifugation of Fci under non-dissociating conditions showed an Mn of 36,200 +/- 1200, an Mw of 36,400 +/- 600 and an Mz of 37,000 +/- 300 g/mole. The best yields of Fc were obtained with a 6-hr digestion and the best yields of Fcl and Fc' were obtained with digestion for 18 hr in phosphate buffer. Digestion in Tris buffer for 18 hr gave results similar to the 18-hr digestion in phosphate buffer except the yields of Fc' were less. This fragment may be useful for exploring biological functions of human IgG Fc. In addition, some Fc fragments obtained by papain digestion of human IgG either in phosphate or Tris buffer are not covalently bonded and are probably cleaved on the carboxy-terminal side of the interchain disulfide bonds at Leu 234 or Leu 235, the N-termini for the large polypeptide chain of Fci. This indicates that, if disulfide bonded Fc fragments are needed, gel filtration under dissociating conditions will be necessary to remove non-covalently bonded Fc.Molecular Immunology 07/1985; 22(6):705-13. · 2.65 Impact Factor
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ABSTRACT: Induction of Epstein-Barr virus (EBV) in the human lymphoma lines P3HR-1, and Daudi by TPA (phorbol-12-myristate-13-acetate), n-butyrate, and superinfection with P3HR-1 virus is associated with an increase in the number of cells bearing Fc receptor (Fc-R). The number of Fc-R per cell, as measured by flow cytometry, is also increased in both cell lines after effective induction of EBV antigens. The increase in cells bearing Fc-R correlates with increased expression of the membrane antigen complex (MA). A high proportion of induced cells concomitantly express both Fc-R and MA in double fluorescence studies. Fc-R activity was not induced by these treatments in EBV-negative lines. After induction of B-95-8 cells (an EBV-transformed marmoset cell line), there is an increase both in MA and whole virus production; however, no Fc-R activity has been detected, suggesting that the B-95-8 EBV strain is incapable of inducing an Fc-R at the cell surface.Virology 08/1982; 120(2):376-82. · 3.37 Impact Factor
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ABSTRACT: The antigenic determinant on the Fc region of human IgG for two IgG rheumatoid factors (IgG-RF) from patients with rheumatoid arthritis were investigated in detail. The RF did not interact with IgG fragments that contained the C gamma 2 or C gamma 3 region alone, but required the presence of both regions for binding. The RF binding to solid-phase IgG were poorly inhibited by the IgG3 subclass and strongly inhibited by staphylococcal protein A (SPA) (42 kD), and fragment D of SPA (7 kD), indicating that the binding site is most likely the same as the Ga antigenic determinant described for IgM-RF, and is in the same location as the site on IgG that binds SPA. pH titration studies of the RF binding to IgG indicated the involvement of histidine and lysine or tyrosine side chains. Chemical modification studies showed the histidines were involved on the Fc side of the interactions, and tyrosines were involved on both the antigenic and antibody sides of the interactions. Lysines were not involved. The above information, and the knowledge of the number and position in space of the amino acid residues involved in the C gamma 2-C gamma 3 interface region of IgG, the binding site for SPA, and the amino acid substitutions in IgG3 that account for its inability to bind protein A, allowed the identification of the site on IgG that bind IgG-RF. This binding site involves some of the same amino acid side chains, His 435, Tyr 436, and one or both His 433 and 310, and is in the same location as the site that binds SPA. The same site is likely to be a common antigenic determinant for other RF. Furthermore, the described molecular mimicry suggests a biological relationship between bacterial Fc-binding proteins and the production of RF in rheumatoid arthritis.Journal of Experimental Medicine 01/1986; 162(6):1811-24. · 13.21 Impact Factor
Immunology 1987 62 523-527
Identification of the site on IgG Fc for interaction with
streptococci of groups A, C and G
A. K. SCHRODER,* F. A. NARDELLA,t M. MANNIK,4
Departments of *Rheumatology and tMedical Microbiology, University Hospital of Lund, Lund. Sweden andtDepartment of
Medicine, Division of Rheumatology, University of Washington, Seattle, Washington, U.S.A.
P. J. H. JOHANSSONt & P. CHRISTENSENt
Acceptedfor publication 17 July 1987
The interaction between living groups A, C and G streptococci and IgG Fc was studied using human
IgG, IgG Fc and IgG Fc-intermediate(Fci) fragments, chemically modified human IgG and fragment
D of staphylococcal protein A (SPA). Diethylpyrocarbonate modification of His or N-acetylimida-
zole modification of Tyr of human IgG resulted in the loss of its capacity to inhibit the binding of
radiolabelled human IgG Fc to the group A streptococci types MI and M55, and to the group C
strain SC- 1, indicating that the amino acids His and Tyr are involved in the binding. Lys seems not to
participate in the binding of IgG to these bacteria, however, since reductive methylation of Lys did
not reduce its inhibitory capacity. Fragment D of SPA also inhibited the binding of radiolabelled
human IgG Fc to strains MI, M55 and SC- 1. We have previously shown that these bacteria do not
bind to IgG fragments consisting of only the Cy2 or Cy3 domains. On the basis of these results, and
the known relative positions in space of the His and Tyr residues on IgG Fc, it is speculated whether
streptococci with IgG Fc receptors, like SPA and rheumatoid factors, interact with IgG in the
interface between the Cy2 and Cy3 domains and involve His 435 and one or more ofTyr 436, His 433
and His 310. The similarities in binding sites on IgG for RFs and these bacterial Fc binding proteins
suggest structural similarities between them that may be relevant to the production of rheumatoid
factors in rheumatoid arthritis.
The capacity of microorganisms to bind IgG via the Fc region
has emerged in the last two decades to be a widespread
biological phenomenon. Such activity is found among bacteria,
i.e. streptococci of groups A, C, and G (Kronvall, 1973) and
Staphylococcus aureus (Forsgren & Sj6quist, 1966). Further-
more, IgG Fc receptors have been demonstrated on cells
infected with Herpes simplex virus (Watkins, 1964) of both
serotypes I and 2 (Para, Goldstein & Spear, 1982), Varicella-
zoster (Ogata & Shigeta, 1979), Epstein-Barr virus (Yee et al.,
1982) and Cytomegalovirus (Furatawa et al., 1975), as well as on
cells infected with schistosomes (Torpier, Capron & Ouaissi,
1979). Using a system with solid-phase aggregated IgG, we have
shown previously that purified IgG Fc binding protein (FcBP)
from the M 15 strain ofgroup A streptococci binds to the same
site in the interface between the Cy2 and Cy3 domains as IgG
rheumatoid factors and staphylococcal protein A (SPA) (Nar-
della et al., 1985, 1987). His 435 and Tyr 436 on the IgG heavy
chain, and possibly one or both of His 433 and 310, were
demonstrated to be involved in the binding. Such molecular
Correspondence: Dr A. K. Schr6der, Dept. of Rheumatology,
University Hospital of Lund, S-22185 Lund, Sweden.
mimicry may be important for the production of rheumatoid
factors (Nardella et al., 1985, 1987). However, so far it is
unknown whether this specific binding site is involved for FcBP
present on the surface of living bacteria, or may be found
outside type 15 group A streptococci. In a previous report we
showed that living strains of groups A, C, and G streptococci,
like SPA and IgG RFs, do not bind to IgG fragments consisting
of only the Cy2 or Cy3 domains (Schroder et al., 1986). The
present report extends our previous studies by using human
IgG, chemically modified human IgG, Fcj and fragment D of
SPA to localize further the site on IgG molecules for interaction
with living streptococci of different types and groups.
MATERIALS AND METHODS
The following streptococcal strains were used for these studies:
group A, types M1 (9198), M4 (734), M6 (8302), M8 (8324),
M15 (EF1949), M22 (59/50), M30 (Quinn), M55 (100189), T27
(SF 40), T44 (Henson Glossy); group C, strains SC-l, T7 and 81
C; group G, strain 113 G. Among the strains, M1, M8, M15,
M22, M55 and groups C and G strains expressed receptors for
the Fc region of IgG, whereas the remaining strains were
A. K. Schroder et al.
negative for FC binding. The strains were grown overnight at
370 in Todd-Hewitt broth, washed in phosphate-buffered saline
(PBS, 0 05 M phosphate, 0 12 M NaCl, pH 7-4) and suspended in
the same buffer to a concentration of 2 x 1010 bacteria per ml
(Christensen & Oxelius, 1974).
The human IgG and Fc fragments were isolated and prepared as
described previously (Schroder et al., 1986). Fcj fragments were
prepared and isolated from human Cohn Fraction II (Sigma
Chemical Company, St Louis, MO) (Nardella & Teller, 1985).
Chemical modifications of His in IgG with diethylpyrocar-
bonate, Tyr with N-acetylimidazole and Lys by reductive
methylation and reversal ofthe His and Tyr modifications with
hydroxylamine were performed as described in previous work
(Nardella et al., 1985). The degree of His modification in IgG
was 52 3%, which was reduced to 12% after hydroxylamine
reversal. Of the Tyr, 13-3% was modified in IgG, with 5-2%
remaining after hydroxylamine reversal, and 30 3% ofthe Lys in
IgG was modified.
Fragment D ofstaphylococcal protein A (SPA) was a gift from
Dr John Sjoquist, University of Uppsala, Sweden, and was
prepared from the secretory product of the V-1 mutant strain
I (Movitz, Masuda &
IgG and IgG fragments were radiolabelled with '25I using the
lactoperoxidase method (Marchalonis, 1969). In brief, 0 1 mCi
of carrier-free Na'25 I (The Radiochemical Centre, Amersham,
Bucks, U.K.) was added to a mixture of2 p1 lactoperoxidase (2-5
mg/ml) (lot no. L8250, Sigma) and 25
preparation to be labelled. The reaction was started by adding
2 p1 30% (v/v) H202 diluted 1:20,000 in PBS (E. Merck,
Darmstadt, FRG) and stopped by adding 500 pl PBS containing
0-02% (w/v) sodium azide. The free 1251 was removed by dialysis
The binding test was performed as described previously
(Christensen& Oxelius, 1974). In brief, 50 pl (2 ,ug) radiolabelled
IgG, IgG Fc or IgG Fcj fragments were added to a 200 p1
suspension of 2 x 109 bacteria unless otherwise stated. After
incubation for 30 min at 370, 2 ml PBS were added and the tube
centrifuged at 3000 g for 15 min. The supernatant was aspirated
and the radioactivity bound in the pellet counted and expressed
as a percentage of the total radioactivity added. Binding below
10% was considered negative, i.e. to be due to entrainment of
the radiolabelled test material in the pelleted bacteria. Under
the test conditions given, a substantial excess of possible
bacterial binding sites is present in the test system (Christensen
& Oxelius, 1974).
pg) of the
Unlabelled immunoglobulin preparations, i.e. chemicallymodi-
fied IgG, chemically modified and hydroxylamine-reversed IgG,
human IgG, IgG Fc and IgG Fcjor fragment D ofstaphylococ-
cal protein A, were added in amounts from 10 to 50 pg to the
bacterial suspensions and incubated for
temperature followed by the addition of2 pg '25l-labelled human
IgG Fc or '251-labelled human IgG Fc. The capacity of the
hr at ambient
Table 1. The capacity of streptococci groups A, C and G to
bind radiolabelled human IgG and IgG Fc and IgGFcj
Binding (± SEM) of:
Group A streptococci
With IgG Fc receptors
Without IgG Fc receptors
Group C streptococci
Group G streptococci
*Two micrograms of immunoglobulin added to 2 x 109
bacteria to bind the radioactive fragments was then determined
as described above. In order to obtain optimal sensitivity,
however, the number of bacteria was lowered to 2 x 108. The
capacity ofthe fragments to inhibit the binding was expressed as
percentage inhibition, and was calculated from the formula:
where Ba is the binding in the absence and Bp in the presence of
the fragment to be tested for inhibitory capacity.
Binding of radiolabelled human IgG, IgG Fc and IgG Fci
fragments to different streptococci
In repeated experiments, group A streptococci with IgG Fc
receptors bound 49-86% of the '251-labelled human IgG, and
34-79% ofthe '251-labelled human IgG Fc fragments compared
with 0-19% ofthe '251-labelled human IgG Fcj fragments (Table
1). The group A streptococci without IgG Fc receptors did not
take up any of the preparations. The groups C and G
streptococcal strains, all possessing IgG Fc receptors, revealed a
somewhat higher uptake of the IgG preparations, 82-100% of
the intact IgG, 73-87% of 125I-labelled human IgG Fc frag-
ments, and 16-64% of the '251-labelled human IgG Fcj frag-
ments (Table 1).
Interaction ofIgG Fc with streptococci
0 ~ ~~~~ ~~~5
Amount of unlabelled Fc and Fci
fragments added (fig)
Figure 1. The capacity of unlabelled human IgG Fc and IgG Fcj to
inhibit the binding of 25 I-labelled human IgG Fc (a) and '251-labelled
human IgG Fcj (b) to streptococci group A type Ml and group C
Inhibition of the binding of radiolabelled human IgG Fc and IgG
Fc, fragments to streptococci by the corresponding unlabelled
The capacity of unlabelled human IgG Fc and IgG Fcj
fragments to inhibit the binding of 251I-labelled IgG Fc and 1251_
labelled IgG Fc,to streptococci group A type Ml and group C
strain SC-I was tested using 5, 10, 25 and 50Mgof each of the
unlabelled preparations (Fig. 1). Five micrograms ofunlabelled
IgG Fc inhibited the binding of1251-labelled IgG Fc to the strains
Ml and SC-I better than unlabelled Fcq. When the amounts of
unlabelled Fc andFcjwere increased to 50 pg, similar relations
between the capacity of the two preparations to inhibit were
found (Fig. la). In the test system with '25I-labelled IgG Fcj,the
inhibitory capacity for the binding to the streptococcal strain
MI was better for Fc than for Fci. For the SC-I strain, Fc and
Fcjproduced similar degrees ofinhibition but exhibited a more
pronounced inhibitory effect on the binding of'251-IgGFc,to the
SC-l strain than to the Ml strain (Fig. Ib).
Inhibition of the binding of radiolabelled human Fc fragments to
different streptococci by unlabelled chemically modified human
IgG and fragment D of SPA
Virtually no inhibition of the binding of radiolabelled human
IgG Fc to the streptococci group A strains MI and M55 was
obtained with 10-50 pg human IgG on which 52-3% of the His
Amount of unlabelled preparation added(19)
Figure 2. The capacity ofunlabelled diethylpyrocarbonate modified His
on human IgG (1), diethylpyrocarbonate-modified and hydroxylamine-
reversed IgG (2), N-acetylimidazole-modificated Tyr on human IgG (3),
and hydroxylamine-reversed IgG
reductively methylated Lys on human IgG (5), fragment D ofSPA (6),
and unmodified human IgG Fc (7) to inhibit the binding of 'l25-labelled
human IgG Fc to streptococci group A types Ml (a) and M55 (b), and
group C strain SC-I (c).
had been modified with diethylpyrocarbonate, whereas 15-32%
inhibition was found for strain SC-I (Fig. 2a, b and c). When
77% of the His modifications were reversed with hydroxyla-
mine, the capacity to inhibit the binding of '251-labelled human
IgG Fc to the bacteria was partially regained for all three strains.
N-acetylimidazole modification of 13 3% of the Tyr on human
IgG resulted in the loss ofcapacity to inhibit the binding of '25I-
labelled human IgG Fc fragments to strains MI and SC-I (this
part of the experiments was only performed with 40 pg of
modified IgG because ofshortage ofmaterial). With hydroxyla-
mine reversal (61% of modified Tyr reversed), the capacity to
A. K. Schrdder et al.
inhibit increased to 13-28% fortheM I strain and to 10-27% for
the SC-I strain (Fig. 2a and c). Reductive methylation of303%
of the Lys on human IgG had no effect on the inhibitory
capacity for the binding of '251-labelled human IgG Fc to strains
MI, M55 and SC-1. Unmodified human Fc was strongly
inhibitory in these systems (Fig. 2).
The monovalent subunit fragment D of staphylococcal
protein A added in amounts from 10 to 50yginhibited the
binding of radiolabelled human IgG Fc to strains Ml, M55 and
SC-l (Fig. 2a, b and c).
We have shown previously that group A, C and G streptococci
with IgG FcBP do not bind human or rabbit IgG fragments that
contain only the Cy2 or Cy3 domains (Schrdder et al., 1986).
Subsequently, we showed that the isolated Fc binding protein
from the Mi 5 strain of group A streptococci binds to the same
site in IgG as SPA and IgG rheumatoid factors and involves His
435, Tyr 436 and one or both His 310 and 433 on the gamma
chains of IgG (Nardella et al., 1987). The present results extend
previous observations to other group A strains and the group C
streptococci. These results also apply to group G streptococci,
since group C and G streptococcal Fc receptors have the same
terminal 15 amino acid residues and thus may be identical (Reis,
Hansen & Bjorck, 1986).
In this report we show that the monovalent fragment D of
SPA inhibited the binding of radiolabelled human IgG Fc to
strains Ml, M55 and SCl-1, providing further evidence to
suggest that streptococcal FcBP bind to the same site on IgG as
is involved in the binding ofSPA. Furthermore, diethylpyrocar-
bonate and N-acetylimidazole modification of human IgG
resulted in the loss of its ability to inhibit the binding of
radiolabelled human IgG Fc to the group A streptococci types
Ml and M55 and to group C strain SC-1, indicating that the
amino acids His and Tyr were involved in the binding. It has to
be taken into account that only 52% of the His and 13% of the
Tyr residues were modified and the reactive residues not
identified. Hydroxylamine reversal of the Tyr-modified IgG did
not allow even partial return of inhibitory capacity of the
binding ofFc to M55, although it did for bindingstrains Ml and
SC- 1. The reasons for this are not known, but point to the slight
heterogeneity of the specific binding determinants for the
different strains within the same general Cy2-Cy3
Another explanation might be that modification outside the
binding site results in conformational changeat thebinding site,
and this may not be reversed on deblocking. In contrast, Lys
seemed not to participate in the binding of IgG to group A
streptococci types MI and M55 or the group C strain SC-I as
reductive methylation ofLys did not reduce inhibiting capacity;
only 30% of Lys residues were modified, and hence there could
be a Lys in the binding site that was not affected. Coupledwith
previous data, and the known relative positionsinspaceof His
and Tyr residues on IgG Fc, these results indicate that the FcBP
on group A, C and G streptococci involve His 435 and one or
more ofTyr 436, His 433 and His 310. This is the same site that
binds SPA (Deisenhofer, 1981) and rheumatoid factors (Nar-
della et al., 1985). Probably the best evidence for the involve-
ment of His 435 in the binding site for SPA is from 'natures'
experiments with IgG3 allotypes, i.e. the Arg/His interchange
between Caucasian and Mongoloid populations-this is also
reflected in RF binding (Matsumoto et al., 1983).
IgG Fc binding proteins on a number ofdifferent streptococ-
cal strains have different molecular weights (Schroder et al.,
1986). The possible existence of differences in the amino acid
sequences of the Fc receptors and in the number of receptors
may explain differences in avidity for the binding of immuno-
globulin preparations to the streptococci.
The capacity ofthe IgG Fc receptor-positive streptococci to
bind the intermediate Fc fragment (Fci) was generally only 20%
ofthe capacity for IgG Fc and intact IgG, with the exception of
the group C strain SC-1, which bound a three to four times
higher proportion ofFci (Table 1). In inhibition experiments,
the Ml and the SC-I strain also showed higher affinity for Fc
than for Fci. TheFci is composed of two polypeptide chains of
unequal molecular weight, where the larger polypeptide chain
has both Cy2 and Cy3 domains, the smaller is composed on only
a Cy3 domain (Nardella & Teller, 1985). Since the interaction
between the streptococci and human IgG takes place in the
interface between Cy2 and Cy3 domains, Fci is monovalent,
whereas the intact Fc fragments are divalent. One explanation
for the difference in binding capacity might be that the group A
strains and at least strain 81 C and 113 G interacted with both
Cy2-Cy3 interfaces, because these strains showed considerably
lower affinity for Fcias compared to Fc. On the other hand, the
capacity of strain SC-I to bind Fci was practically the same as
for Fc. This strain might therefore only bind to one of the two
Cy2-Cy3 interfaces on an intact IgG, or,in otherwords, IgGFc
reacted monovalently with strain SC-1. Another interpretation
of these data is that both Fc and Fci fragments interacted
monovalently with all the strains of streptococci, but that the
interaction energy was less with Fci. Nardella, Teller & Mannik
(1981) found that the interaction of Fab fragments of IgG
rheumatoid factor with Fciwas oflower interaction energy than
the binding of these fragments to intact IgG. Thus, it is possible
that conformational changes are induced in the Cy2-Cy3
interface region of one gamma chain of Fci fragment when the
Cy2 domain is absent from the other gamma chain, which has a
greater effect on the binding of all the strains except SC-l. In
addition, these differences suggest that although all strains bind
to the same general locale, there is microheterogeneity in the
exact binding determinants.
The Cy2-Cy3 interface region of Fc is the site of interaction
for SPA, the FcBP ofthe groups A, C and G streptococci, and is
likely to be the site ofinteraction ofFc receptors induced on cell
surfaces by HSV-I (Johansson etal., 1986). Whyis thisregionof
Fc the site of interaction for all of these substrates? On purely
biochemical grounds, this region offers groupings of residues
that form exposed hydrophobic patches (Burtonetal., 1980),an
important component of protein-protein interactions. It also
has large probe-accessible convex surface areas, which are
important to antigenic sites (Novotny, Handschumacher &
Bruccoleri, 1987). Furthermore, immunologically,this area was
one of the three major sites on the Fc region of human IgGto
which mouse monoclonal antibodies were directed(Jafaaretal.,
1984). An important question
similarities mean in terms of RF production in rheumatoid
arthritis. The binding site similarities suggeststructural similari-
ties between these microbial FcBP and RF,andsuggestthat RF
antibody-combining sites carry the internal image of these
bacterial Fc-binding structures. We (Nardella et al., 1985, 1987)
is what these binding site
Interaction ofIgG Fc with streptococci
and others (Mouritsen, 1986) have proposed that RFcould arise
as anti-idiotypic antibodies to antibodies to FcBP of microbial
agents. Alternatively, the FcBP could present IgG to the
immune system in such amanner that renders that region ofself-
This work was supported by research grants AM-12849 from the
National Institutes of Health and the Townsend-Henderson Fund, the
Swedish Medical Research Council, the Rheumatism Association in
Sweden, and the Osterlunds Fund.
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