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Studies on the Gm factorsComparison of the agglutinators in serum from patients with rheumatoid arthritis and in serum from healthy donors.

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Arthritis and Rheumatism
~&ia~~rmrnUl
of the gmerican Rheumatismassociation
VOL. V, NO. 4
AUGUST, 1962
Studies on the Gm Factors: Comparison of the
Agglutinators in Serum from Patients with
Rheumatoid Arthritis and in Serum
from Healthy Donors
By ARTHURG. STEIXBERC
With the technical assistance of lanet A. Wilson and Rachel Stauffer
Titration and absorption studies of the
agglutinators used to detect genetically
determined human y-globulin groups
showed that (a) the agglutinators in
rheumatoid arthritis serum and in normal serum are probably the same, (b)
the inhibition of R.A. sera by Cm (-)
serum is due to a non-specific reaction,
and (c) R.A. sera have at least two
kinds of &M molecules, those with
rheumatoid factor activity and those
with both rheumatoid and gamma group
activity.
Studios de titration e absorption del agglutinatores usate pro deteger in human0 s gruppos de geneticamente determinate globulina gamma monstrava que
(a) le agglutinatores in sero ab patientes con arthritis rheumatoide e in
sero normal es probabilemente identic;
(b) le inhibition de seros ab patientes
con arthritis rheumatoide per le sero
Cm-negative es attribuibile a un reao
tion non-specific; e (c) seros ab patientes
con arthritis rheumatoide ha a1 minus
duo classes de moleculas B2M, i.e., illos
con activitate attribuibile a factor rheumatic e illos con activitate tanto de factor rheumatoide como etiam del gruppo
de globulina gamma.
I
T HAS BEEN DEMONSTRATED that human red blood cells (RBC)
coated by selected incomplete anti-D sera can be caused to agglutinate by
sera from some patients suffering from rheumatoid arthritis ( RA).6,27 Grubb
and Laurell’ showed that the agglutinating action of the RA serum could be
inhibited by pooled gamma globuin or by sera from certain individuals, and
that the ability of these sera to inhibit the agglutination was genetically determined. Grubb and Laurel1 called inhibiting sera Gm( a+ ), the others
Gm( a-). Different combinations of RA sera and incomplete anti-D sera
have been used to identify a series of other genetically determined y-globulin
factors [Gm(b),l0 Gm(x),” Gm-like,23and Gm(r)1.6].
From the Biobgical Lizboratoty, Western Reserve Unioersity, C h e l u n d , Ohio.
This investigationwas suppotted in. part by PHS research grant RG-7214from the Dioision
of General Medical Sciences, Public Health S h e .
331
ARTHRITIS& RHEUMATISM,VOL. 5, No. 4 (AUGUST),1962
332
ARTHUR G. STEINBERG
Table
1.-Comparison of Ragg
~__ and SNagg Agglutinators
Agglutinator
Ragg
SNagg
Titer' against
coated cells
~
_
_
~
_
Inhibition titer of
G m ( f ) sera vs.
agglutinator
Inhibition titer of
Gm ( - ) sera vs.
agglutinator
Detect more
than one Grn.
factor?
c64
> O , z8
Yes
no
_
_
1024
c04
5
_
5
.
128
0
'All titers are given as reciprocals.
Although certain sera from patients with other diseases or from healthy individuals were found to cause sensitized RBC to agglutinate, these sera were
not found to be inhibited by pooled gamma g l ~ b u l i n . ~ J ~Grubbb
- ' ~ - ~ men~
tioned, as an addendum to a paper published in 1957, that he had found a
serum from a healthy person which is inhibited by gamma globulin; however,
he appears not to have tested it further.
Ropartz and Lenoir'? confirmed Grubbs finding and demonstrated that
sera from some blood donors, who were not demonstrably ill, could be used
to detect Gm factors. Ropartz, Rousseau, and Rivat'" call such a serum "Serum
Normal agglutinant" and abbreviate it SNagg. The term appeals to me and I
suggest its retention as a generic term for Gm reagents from nonrheumatoid
donors.
Rheumatoid sera used as agglutinators in testing for y-globulin factors
have been referred to as RA sera, anti-Gm reagin, or simply anti-Gm. I suggest that they be referred to as Rheumatoid agglutinators and abbreviated
Ragg. Ragg and SNagg sera differ in their agglutinating titer, in the ease with
which they are inhibited by Gm( ) and Gm( - ) sera and in the number of
Data such as
Gm factors which a given reagent can detect (table
those summarized in table 1 have led Ropartz and his colleaguesZoto suggest
that anti-Gm factors in Ragg and SNagg sera are different. They state that the
action of SNagg sera is purely qualitative, while that of Ragg sera is both
qualitative and quantitative.
It should be noted that the agglutinators in Ragg and SNagg sera are associated with the BzM
This is the same molecule which carries
the Rheumatoid Agglutinating Factor ( R A F ) in RA sera.4a
This paper is a report of comparisons of the agglutinators in Ragg and
SNagg by means of titration, heating, and absorption experiments.
+
l).12J7-209z3
MATERIALS
AND METHODS
Detection of Crn Factor. The reagents used for Gm testing were: Group 0, R l R l red
blood cells, an incomplete anti-D serum (Kim.) from a G m ( a + ) donor, a Ragg serum
(Bowers) and two SNagg sera (Wils. and Scol.). Each of the agglutinating sera detects
G m ( a ) with anti-D Kim.
The Gm tests were performed as follows: One drop of washed, packed RBC was incubated with one drop of anti-D serum and eight drops of saline at 37" C. for 2 hours.
Before use for Gm testing, the cells were washed four times in normal saline and resuspended
in saline at a 0.3 per cent concentration.
One drop of the diluted agglutinator was mixed on a slide with one drop of the diluted
serum which was to be tested. This mixture was shaken for 5 minutes at room temperature.
A drop of the cell suspension was then added, the mixture again shaken for about 5 minutes
and then allowed to incubate for 45 minutes at room temperature. After the incubation
STUMEG ON THE
Gm
333
FACTORS
Table B.-Agglutinatwn Titers of a Ragg Serum (Bowers) and a S N a g g Serum
(Wh.)
and Znhibitwn Titer8 of a Gm(a+) and a Gm(a-) Serum’
-
Ragg titer against SRBC = 1/40962
Ragg 1/64 G m ( a + ) 1/16
no agglutination
no agglutination
Ragg 1/64 Gm( a-) 1/4
SNagg titer against SRBC = 1/32
no agglutination
SNagg 1/8 G m ( a + ) 1/2-56
agglutination
SNagg 1/8 Gm(a-) neat
+
+
+
+
Unita in
undiluted serum
4096 Agg.3
1024 Inhib.4
256 Inhib.
32 Agg.
1024 Inhib.
0 Inhib.
]See text for further explanation.
2SRBC = sensitized red blood cells.
3Agg. = agglutination units.
4Inhib. = inhibition units.
the slide was again shaken and the results read under a dissecting microscope at 60X.
Controls consisted of (1) known G m ( a + ) and Gm(a-) sera in the place of the serum
to be tested; ( 2 ) the coated cells, plus saline, plus agglutinator; and (3) the coated cells,
plus saline, plus the tested serum. Control ( 2 ) was used to check the activity of the
agglutinator, control ( 3 ) was used to see if the tested serum was an agglutinator.
If the cells failed to agglutinate, the serum being tested had inhibited the agglutinator
and was said to be Gm( a+ 1. If the cells agglutinated, inhibition had not occurred and
the serum was said to be Gm( a- ).
Rheumatoid agglutinating factor (RAF) activity was detected by the FII latex test.21,22
Coated and uncoated latex particles were generously supplied by Hyland Laboratories.
Gamma globulin was extracted from Gm( a- ) sera by Dr. Livia Blum. We are grateful
to her for her assistance.
THEDATA
Agglutination and lnhibitiun Titers
Table 2 shows the agglutination titers of Ragg Bowers and SNagg Wils.,
and the inhibition titers of a G m ( a + ) and a Gm(a-) serum against these
agglutinators. The reciprocal of the maximum agglutination titer of the agglutinating serum was designated the number of agglutinating units in the
undiluted serum. Thus Ragg Bowers undiluted is said to have 4096 agglutinating units. Ragg Bowers diluted 1/64 has 64 agglutinating units (i.e., 4096/64
= 64). At this dilution Ragg Bowers was inhibited by a G m ( a + ) serum
diluted 1/16 but not by this serum diluted 1/32. The Cm( a+ ) serum diluted
1/16 is said to have 64 inhibition units and the undiluted serum 16 X 64 or
1024 inhibition units. The same reasoning is used for assigning units when
the SNagg serum is used. Note that in this experiment the G m ( a + ) serum
had the same number of inhibiting units (1024) against the Ragg serum
as against the SNagg serum, and that while the Gm(a-) serum had 256 inhibiting units against the Ragg serum, it had no demonstrable activity against
the SNagg serum (table 2).
The above experiment was repeated with 19 Gm(a+) sera and nine
Gm(a-) sera. The results are shown in table 3. The mean number of inhibiting units of the Gm( a + ) sera against Ragg and SNagg were 820.3 and 964.7,
respectively, that is, less than one “tube” difference, since at this level the titer
of the lower tube would be 512 and of the higher, 1024. Hence, the number of
334
ARTHUR G. STEINBERG
inhibiting units in Gm( a+ ) sera against Ragg sera may be considered to be
the same as those against SNagg sera.
The mean number of inhibiting units of the Gm(a-) sera against Ragg
was 241.8; but it was zero for these sera against the SNagg serum, because
none of the sera used neat inhibited it.
It will be shown in a later section that the inhibition of Ragg sera by
Gm( - ) sera is probably due to non-Gm-specific 7-globulin (see page 335).
Meutralization Experiments
A 1:l mixture of a Gm( a+ ) serum diluted 1/64 and of Ragg Bowers diluted
1/64 when added to SRBC caused the cells to agglutinate. Hence, the inhibiting activity in the Gm( a+ ) serum had been neutralized by the agglutinator and the latter had retained sdicient activity to cause the SRBC to
agglutinate.
If the agglutinators in Ragg and SNagg sera are the same, one would not
expect the above mixture of Gm( a+ ) and Ragg Bowers to inhibit the activity
in a SNagg serum. If they are different, inhibition might occur.
Seven G m ( a + ) sera were titrated against SNagg Wils. and SNagg Scol.;
each SNagg being diluted '/8 for the test. When the inhibiting titers of the
G m ( a + ) sera had been determined, each was diluted 1/64 and mixed with
an equal volume of Ragg Bowers also diluted 1/64, hence, in the mixture, the
concentration of each was 1/128. In each case the addition of the mixture PO
SRBC led to agglutination. The mixture was submitted to a series of two-fold
dilutions in saline. The concentration of each reagent in the final dilution was
1/8192. Each dilution was tested for its ability to inhibit each of the SNagg
sera indicated above. Table 4 presents the protocols for the tests of two
Gm(a+) sera against SNagg Wils. Apparently the addition of Ragg Bowers
to these G m ( a + ) sera did not cause a reduction in the inhibition titer of
either against SNagg Wils. A summary of the scores found for the seven sera
tested against SNagg Wils. and SNagg Scol. is shown in table 5. There is no
evidence of an effect of the Ragg on the titer of Gm( a+ ) sera against these
two SNagg agglutinators. The data seem to indicate, in contradiction to the
previous experiments, that the agglutinator in SNagg is not the same as that
in Ragg.
Titration Experiments with Heated Sera
Steinberg and S t a ~ f f e have
r ~ ~ reported the heating Gm(a-) sera at 63" C.
rendered them Gm ( a + ). These tests were done against a Ragg agglutinator.
The experiments have been repeated using one Ragg and two SNagg agglutinators. Twelve Gm(a-) and 13 G m ( a + ) sera were tested [six of the
Gm(a+) were from Negroes]. The results are shown in table 6. Heated
Gm( a- ) sera remained completely inactive against SNagg, while the titer
of heated G m ( a + ) sera increased to about the same extent against SNagg
as it did against Ragg, i.e., three to four tubes.
Absorption Experiments
The macroglobulin in serum from patients with rheumatoid arthritis will
form precipitates with 7s gamma globulin preparation~.~-**~8
More important
STUDIES ON THE Gm FACTORS
335
for our purposes is Fudenberg and Kunkel's 5b demonstration that the isolated
19s macroglobulin of RA sera will form 22s complexes with the 7-globulin
in untreated normal sera regradless of the Gm type of the latter.
It is assumed that the inhibition of Ragg sera by all undiluted or slightly
diluted sera regardless of their Gm type is due to steric hindrance resulting
from the combination of the 7-globulin in these sera with the RAF of the
&M molecules in the Ragg serum. Support for this assumption is derived
from experiments in which 7-globulin extracted from a Gm(a-) donor was
titrated against Ragg Bowers. It was found that concentrations equal to or
greater than about 300 mg. per cent inhibited the agglutinating activity of the
Ragg Bowers serum diluted 1/32 (128 agglutinating units), while a concentration as great as 1600 mg. per cent failed to inhibit SNagg Wils. diluted
l/s ( 4 units).
If the assumption of steric hindrance is correct at least some of the P2M
molecules in Ragg sera should have both Gm and RAF activity, while none of
those in SNagg sera should show the combined activity. Absorption experiments with SRBC and with latex particles coated with Gm(a-) yglobulin were done to test this hypothesis.
Two Ragg sera (Bowers and Bomb.) were absorbed repeatedly with packed
RBC coated with a series of different anti-D's until all detectable activity
against such cells was removed. (These experiments and others will be reported in detail elsewhere.) The absorbed sera were then titrated against
latex particles coated with pooled gamma globulin. The titer of Ragg Bomb.
against the latex particles was not changed by the absorption with the anti-D
coated RBC, while Ragg Bowers showed a slight reduction in titer. These
experiments indicate that not all the B2M molecules have both Gm and RAF
activity.
In another experiment Ragg and SNagg sera were absorbed with packed
latex particles coated with pooled 7-globulin until the Ragg serum no longer
agglutinated the particles (two absorptions). Both the Ragg and SNagg sera
failed to agglutinate SRBC! The interpretation of these data is unclear because
we have found (as suggested by Dr. Henry Kunkel) that saline or albumin
used to wash latex particles coated with pooled 7-globulin becomes Gm( a+ ) .
Apparently the 7-globulin is easily eluted from the latex particles. It is likely,
therefore, that the inactivation of the Ragg and SNagg sera in the above
experiments is not the result of absorption from them of macromolecules active in the Gm system, but rather the result of inhibition of the Gm agglutinqtors in them by the eluted G m ( a + ) 7-globulin which was present in the
pooled 7-globulin used to coat the latex particles.
The experiments were repeated using gamma globulin extracted from
Gm( a- ) donors to coat the latex particles. Such particles, if the hvpothesis is
correct, should absorb the rheumatoid factor and not inhibit the Gm activitv
in a Ragg serum capable of detecting Gm(a), and, being coated with
Gm( a- ) 7-globulin should have no effect on the SNagg serum. Ragg Bowers
absorbed twice with latex particles coated with gamma globulin from a
Gm( a- ) donor was inactive against particles coated with pooled 7-globulin
and failed to cause SRBC to agglutinate, i.e., had no detectable anti-Gm ac-
336
ARTHUR G. S"BI%RG
Table 3.-Mean Number of Znhibition Units in 19 Gm(a+) Sera and 9 Gm(a-)
Sera vs. a Ragg and a SNagg Agglutinating Serum'
Agglutinator
SNacrcr
Ram
(Bowers)
(Wils.)
820.3
24 1.8
964.7
0
19 Gm(a+)
9 Gm(a-)
'See text for further explanation.
Table 4.-Titratwn of Gm(a+) Serum vs. SNagg Wils. Diluted 1 / 8
( R I R 1 red blood cells were coated with 10 volumes of anti-D Kim. diluted 1/10.)
~Reciprocal of the dilution of the Gm(a+) serum
Gm(a+)
Donor
R.
KI.
Good.
'1
I
Test reagent
Gm(a+)
G m ( a + ) 1/64
Rasg Bowera 1/64'
+
Gm(a+)
Grn(a+) 1/64
Ragg Bowers 1/64'
+
128
266
-
-
-
-
- - -
612
1024
2048
4096
++ +++ ++++ ++++
++ +++ ++++ ++++
+ +++ ++++ ++++
+++ ++++ ++++
8192
Score'
++++
17
++++
++++
++++
17
16
15
++
'The mixture of G m ( a + ) 1/64: R a g Bowers 1/64: saline. l : l : l , gives a
agglutination of the
coated cells. In each of the tests indicated in the above table S N a g g Wils. 1/8 replaced the saline.
?The score equals the sun) of the plus signs which. as usual. indicate agglutination.
Table 5.-Scores for 7 Gm(a+) Sera Tested in Two-fold Dilutions from 1/128
to 1 /8192 for lnhibition of SNaggI
Wils.
Scol.
a
b
87
12.4
82
11.7
___---~_____
Total
I
X
a
117
16.7
b
117
16.7
a. Untreated Gm( a + ) serum.
b. An initial 1 : l mixture of Gm(a+) 1/64 plus Bowers 1/64 was titrated.
'See text for further explanation.
tivity. A similarly treated SNagg serum (Wils.) retuined its ability to cause
SRBC to agglutinate, i.e., retained its anti-Gm activity.
DISCUSSION
The indication, derived from the titration experiments summarized in tables
2 and 3, that the agglutinators in Ragg and SNagg sera are alike is apparently
contradicted by the data of tables 4 and 5 which indicate that Gm( a+ )
serum inactivated by a Ragg serum remains active against a SNagg serum.
The contradiction may be resolved with the aid of two observations:
1. A mixture of Ragg and G m ( a + ) sera which does not cause sensitized
RBC to agglutinate will do so after dilution with ~ a l i n e . ~These
J ~ observations
suggest, as Grubb indicated, that dilution of the mixture leads to a separation
of the agglutinator in the Ragg and the inhibitor in the Gm(a+ ) serum.
The reaction may be summarized as follows:
STUDIES ON THE
Gm
337
FACTORS
Table &--Mean Titers' (Expressed as Last 'Tube' of Serial Two-fold Dilutions
Showing Inhibition) of Unheated (U)and of Heated (H)e Normal
Sera e a i n s t Ragg and SNagg Agglutinators
~~
~
~
~
SNazg (1/8)
Rspz (1/64)
( Bowers )
Gm.
U.
No.
-
H .1
~
12
13
+
2.3
5.1
WilS.
u.
Scol.
H.'
U.
H.'
0
0
10.7
13.7
~~~
6.4
9.7
0
9.8
13.4
0
'Each serum was made up in serial two-fold dilutions, the first tube being a 1/2 dilution.
'Heated at 63 C. until visible aggregates formed. The aggregates were not used for the
agglutination inhibition tests.
+
( a ) R(agg)
I(nhibitor)
RI
dilution
( b ) RI---+
R + I
2. It was observed that, although Ragg 1/64
G m ( a + ) 1/64
saline
(mixed 1:l:l) caused the sensitized cells to agglutinate [i.e., the Gm( a + ) was
too dilute to inhibit the Ragg], Ragg 1/64
G m ( a + ) 1/64
SNugg %
(mixed 1 : l : l ) did not cause the cells to agglutinate (table 4,first two columns
of rows two and four). Paradoxically, the addition of more agglutinating reagent (the SNagg serum) led to an inhibition of agglutination.
Recall that Gm( a- ) sera have approximateIy 250 inhibiting units against
Hagg (tables 2 and 3 and text) and that this is assumed to be non-Gm-specific.
If it is assumed ( a ) that dilution of the Ragg-Gm(a+) mixture frees the
Gm inhibitor in the G m ( a + ) serum, and that the freed inhibitor inactivates
the SNagg serum, and ( b ) that the postulated non-Gm-specific inhibitor in
the SNagg serum and possibly in the Gm( a+ ) serum inhibit the Ragg serum,
the data are explained.
The reaction may be diagrammed as follows:
+
+
+
+
a)
,/-9-
"Diluted RI" t
s-----3
w-
n
where R&
and
3-I.
-I
indicate non-Gm-specific inhibition.
If this reasoning is correct, the addition of SNagg at high concentrations
(i.e., 7-globulin concentration greater than 300 mg. per cent), but not at low
concentrations should inhibit the agglutination caused by the Ragg-Gm ( a+ )
mixture. The addition of Gm( a- ) sera in high concentrations should lead to
the same result. The absorption of all detectable agglutinating activity from
SNagg sera before their addition to the Ragg-Gm(a+) mixture should not influence the result, because the non-Gm-specific inhibitor is postulated to be
7s gamma globulin and the agglutinator is &M globulin. Finally, the mixture
Ragg plus SNagg-unabsorbed should lead to agglutination (since both are
agglutinators and SNagg is not inhibited by Gm(a-) sera, such as Ragg
Bowers), but the mixture of Ragg plus SNagg-absorbed should not lead to
agglutination, because the non-specific inhibitor in SNagg will inhibit Ragg.
Table 7 shows the protocols of some of the experiments done to test this in-
338
ARTHUR C. STEINBERG
Table 7.-Titratwn of SNagg W h . and Gm(a-) Sera
(RIRI cells were coated with 10 volumes of anti-D Kim. dffuted 1/10.)
Titer of serum
Serum titrated
1/2
1/8
1/4
( A . ) Against a mixture of Ragg Bowers 1/64
SNagg unabsorbed
0
0
SSagg absorbed1
0
1
Gm(a-) ( 2 samples)
0
0
Gm(a-) (1 sample)
0
0
+ Gm( a + )
+
++
( B . ) Against Ragg Bowers 1/04
SNagg unabsorbed
SNagg absorbed1
Gm( a - ) ( 3 samples)
++++
0
++++
+++
0
0
0
f
++++
++++
+++
1/16
1/64
+++
+++
+++
+++
++++
++++
++++
'Absorbed with cells coated with anti-D Kim. until no detectable agglutinating activity
remained in the serum.
terpretation. The experiments are clearly in agreement with the explanation
offered above.
The increased titer of heated Gm( a + ) sera against Ragg and SNagg agglutinators may be due to steric hindrance. It is assumed that the aggregates
formed in heated Gm( a + ) sera are composed of 7-globulin with specific Gm
activity and of other proteins. These larger molecules cover more sites, on
the &M molecule, per active G m ( a i ) molecule than do the unaggregated
r-globulin molecules, hence the higher titer. Evidence for this is derived from
the demonstration, by electrophoresis, that Gm( a ) activity in heated serum
extends from the region of the fast albumins to the y-glob~lins,'~~
while such
activity is limited to the 7-globulins in unheated sera.
The increased inhibitory activity of heated Gm(a-) sera against Ragg
may be explained in essentially the same way. The aggregates react with
RAF in Ragg and by steric hindrance inhibit the Gm activity of Ragg. The
heated Gm(a-) sera do not react with the SNagg sera because SNagg sera
have no RAF activity, and the Gm( a- ) sera have no Gm activity.
The absorption experiments with latex particles coated with 7-globulin
from Gm( a- ) donors indicate that in Ragg sera essentially all &M molecules
with Gm activity also have RAF activity (since absorption removed both
activities). The fact that the titer of the Ragg sera against the coated latex
particles was either not reduced, or only slightly reduced, when all Gm
agglutinating activity was absorbed from them indicates that only some of
the &M molecules with R A F activity have Gm activity. In brief, we have
demonstrated in Ragg sera two kinds of &M molecules with activity against
human 7-globulin: ( a ) those with both RAF and Gm activity and ( b ) those
with RAF activity but no Gm activity.
The absence of RAF activity in the presence of the Gm activity in SNagg
sera indicates a third type of B2M molecules, namely, those with Gm activity
but no RAF activity.
It will be recalled that the tests for R A F activity in sera from patients with
rheumatoid arthritis are negative for SNagg sera. 'It is possible, however, that
the RAF is present in SNagg sera but in too low concentration to be detected
smm ON
339
THE cm FACTORS
by the standard technics. SNagg Wils. concentrated five-fold by dialysis
against 20 per cent PVP (polyvinylpyrrolidine) in saline, was still negative in
the latex test. R a g Bowers similarly treated remained positive. Sera tested
this way are 100 times as concentrated as they are in the usual latex test
( Hyland Laboratories ) .
In the abstract submitted for the May, 1961, meeting of The American
Society of Human Genetics, I indicated that I believe that the agglutinators
in Ragg and SNagg were qualitatively different. The basis for this statement
is the data in table 3, which are now interpreted differently, and I believe,
correctly.
SUMMARY
The agglutinators in serum from patients with rheumatoid arthritis and in
serum from healthy donors were compared by serologic methods. Titration
and absorption experiments indicate that the agglutinators are probably the
same and that sera from patients with rheumatoid arthritis, which can be
used for Gm testing, have at least two kinds of &M macromolecules which
react with human 7-globulin: ( a ) those with rheumatoid factor activity only
and ( b ) those with both rheumatoid and Gm activity. The &M molecules in
SNagg sera have Gm activity but no RAF activity and therefore represent a
third type of molecule.
REFERENCES
1. Brandtzaeg, Brita, Fudenberg, H., and
Mohr, J.: The Gm(r) serum group.
Acta genet. 11:170-177, 1961.
2. Christian, C. L.: Characterization of
the “reactant” (gamma globulin fictor) in the F I1 precipitin reaction
and the F I1 tanned sheep cell agglutination test. J. Exper. Med. 108:
139-157, 1958.
3. Epstein, W., Johnson, A., and Ragen,
C.: Observations of a precipitin reaction between serum of patients with
rheumatoid arthritis and a preparation (Cohn fraction 11) of human
gamma globulin. Roc. Soc. Exper.
Biol. & Med. 91:235-238, 1956.
4. Franklin, E. C., Holman, H. R., Miiller-Eberhard, H. J.. and Kunkel, H.
G.: An unusual protein component
of high molecular weight in the
serum of certain patients with rheumatoid arthritis. J. Exper. Med. 105:
424438, 1957.
4a. -, Kunkel, H. G., Miiller-Eberhard,
H. J., and Holman, H. R.: Relation
of high molecular weight proteins to
the serological reactions in rheumatoid arthritis. Ann, Rheumat. Dis. 18:
315321, 1951.
5. Fudenberg, H.: The hereditary human
gamma globulin groups Gm(r). In
press.
5a. -: Personal communication.
5b. -, and Kunkel, H.: Specificity of the
reaction between rheumatoid factors
and gamma globulin. J. Exper. Med.
114:257-278, 1961.
6. Grubb, R.: Agglutination of erythrocytes coated with “incomplete” antiRh by certain rheumatoid arthritic
sera and some other sera. Acta path.
et microbiol. scandinav. 39: 195-197,
1958.
7. -, and Laurell, A. B.: Hereditary serological human serum groups. Acta
path. et microbiol. scandinav. 39:
390-398, 1956.
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I
Arthur G . Steinberg, Ph.D., Professor of Biology, Biological
Laboratory, Western Reserve University, Cleveland, Ohio.
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