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Discussionmechanisms of immune regulation.

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D I SCU S SI ON: M ech a ni s ms of I m m un e R eg u 1 at i o n
Hahn: Dr. Gershon, would you clarify whether you
meant that Ly-l cells and Ly-23 cells can function in
different situations either as helpers or as suppressors,
or whether it is the Ly-123 precursor that can function
either way in each situation?
Cershon: There is no substantial evidence to indicate
that the Ly-1 cell can do anything other than what it is
tions of Fc receptors distinguish macrophages which
have either suppressor or helper effects when mixed
with appropriate T cells.
Warner: Would the NTA antibody in NZB mice poten-
tially interfere with any of the Ly typing that you
preprogrammed to do, that is, to help B cells or to
induce a DTH response. This Ly-l cell seems to have
differentiated to a state where it has lost all its previous options, and its only decision is whether to turn
on or not; after turning on with Con A, it still functions the same way. The same is true for Ly-2 positive
cells, although, of course the function of the Ly-2 cell
is quite different. However, there is a large population
of cells that are not known to be committed to a single
function, and it is in this population that all kinds of
strange things happen. The Ly-123 cells can act as
amplifier cells, but also seem to be able to act as a cell
population that can differentiate into either helper
or suppressor cells. The work ahead of us is to try to
fractionate the Ly-123 population by some mechanism in order to determine whether the different effects they produce are stable cells, or Ly-123 just on a
maturation path.
Gershon: If the NTA antibody were noncomplement-
Williams: Since suppressor T cells are supposed to have
Fc receptors for IgG and helper T-cell receptors for
the Fc part of IgM, have you had an opportunity to
look at these receptors in the subpopulations defined
with respect to Ly typing?
Hahn: I would like to make the point that one can
Cershon: We haven’t looked at the Fc receptor distribu-
tion among the cells. Bob Stout and the Herzenbergs
in collaboration with Harvey Cantor showed that the
Fc positivity cuts across all lines and a cell with a
single function cannot be isolated by means of Fc
receptors. No one I know has looked at subpopulations of Fc receptors on T cells in mice. There is also
a problem in that the amount of Fc receptors on T
cells will vary with their stage of differentiation. So
this marker does not seem to have the advantage of
the stability that the Ly markers have. But, we are
looking at subpopulations of Fc receptors on macrophages and Erwin Diener’s group is doing the same
thing. There is a definite suggestion that subpopulaArthritis and Rheumatism, Vol. 21, No. 5 Supplement (June 1978)
fixing and did combine with theta antigen, that could
be why we find theta negative cells. If the NTA is not
gamma-1 and it is complement fixing, its presence
would have been evident in the normal serum controls. Moreover, since there is an excess of Ly-l cells
(over theta-positive cells), it is clear the NTA isn’t
blocking in the Ly-l studies.
Pernis: I was under the impression that Bob Stout could
identify suppressor activity in the Fc receptor gammapositive T cells.
Gershon: I agree that he has shown that, but there are
helper cells that are Fc positive as well. So this particular marker seems to cut across functional cell lines
and has not, so far, been helpful in distinguishing cells
with defined functions.
induce antigen-specific suppressor T cells in the NZBI
W hybrid.
Dr. Lewis Parker and I administered singlestranded DNA on poly-D-lysine carrier 3 times a
week to male or female B/W hybrid mice beginning at
birth. I n this study we showed that disease onset can
be significantly delayed, with less severe nephritis and
reduced amounts of circulating antibodies to DNA.
The next question was whether we could transfer this
phenomenon with cells, and the answer was that we
could. This state of tolerization can be transferred by
placing tolerized spleen cells into lethally irradiated
syngeneic B/W recipients. Tolerance to DNA was
assayed by measuring plaque-forming cells to DNA in
the spleens of recipients repopulated with tolerized or
normal spleen, thymus, or bone marrow cells. Recipients of tolerized spleen, thymus (2:l to normal bone
marrow), or bone marrow cells were tolerant to
sDNA. In contrast, the plaque-forming response to
immunization with SRBC was the same in all three
groups. This same approach prolongs life in older
mice, but we have been unable to transfer tolerance
with cells from the adult.
Warner: I have some questions for both Dr.Steinberg
and Dr. Waldmann: I would plead for a more open
view of the suppressor system. Although it may be
essential that a suppressor T cell is involved, this may
not be the cell that is producing the final suppressive
factor. I wonder if we might keep open the possibility
that there is a defect, for example, in the macrophage
lineage. Could one envision the possibility that the
suppressor T cell, when activated, stimulates the secretion of a factor from the macrophage? And, of
course, there are other data that suggest macrophage
defects in these mice. Since the word macrophage is
probably just as all-embracing as the word lymphocyte, we must recognize that there could be many
subpopulations of macrophages. In relation to this,
could prostaglandin be a factor? Have you cultured
your cells in the presence of indomethacin?
Waldmann: Rich and Pierce showed that T cells are
absolutely required for the generation of SIRS. Dr.
Krakauer has confirmed these observations. If you
remove T cells from spleen cells of mice with antitheta antisera or by affinity columns, or if you use
nude mice, SIRS cannot be generated by the B cells
and macrophages that remain. It is true that macrophages are required for SIRS generation as well, according to Pierce and coworkers. In addition, I’m sure
you are aware that the immediate target of SIRS, as
viewed by Dr. Pierce, is the macrophage. We have not
determined whether the macrophages in our system
produce prostaglandins of the E series, as has been
reported for the inhibitory macrophages in Hodgkin’s
disease by Goodwin and coworkers.
Gershon: I want to comment on Dr. Warner’s point. In
the collaborative work of Pierce and in that of Harvey
Cantor, it was shown that the Ly-2 cell makes the
SIRS factor. The evidence that it is a T-cell product is
fairly strong. Whether that is the suppressor factor in
this case is not known.
I would also like to make a comment to Dr.
Waldmann: we haven’t looked for SIRS production
in old NZB mice, but since they are loaded with Ly-2
cells, it is quite likely that they can make SIRS.The
production of SIRS is a very complicated phenomenon because in the presence of Con A the Ly-1 cells
make a helper factor that can inhibit or counteract the
presence of a suppressor factor. The old NZB mice,
by our analysis, have excess of both types of cellshelpers and suppressors-and they’ve lost modulators. You might be able t o alter the culture conditions
or the dose of Con A that you are using and find that
you can produce SIRS from these animals.
Waldmann: I think that it is obvious t o everyone dealing
with Con A that this lectin stimulates the activation of
both helper and suppressor cells and their products.
This makes analysis of the effect of Con A dependent
on the study protocol. For example, if low doses of
Con A are used or if it is added late in the culture
period, stimulation rather than inhibition is observed.
If it is added at the onset, suppressor effects dominate.
Did you try any other regimens of Con A?
Gershon: No, we tried identical ones.
Steinberg: Dr. Gershon’s supposition is correct. If the
supernates are fractionated, one can get both helper
and suppressor factors with regard to certain functions, for example, nonspecific proliferation.
Green: I would like to briefly present some studies done
along with Drs. Sakane and Steinberg on suppressor
cell measurement in patients with SLE. The experimental design was similar to that reported in the
Journal of Experimental Medicine (143: 1 100, 1976) by
Shou, Schwartz, and Good in which a two-stage culture of lymphocytes from the same individual was
employed. Pure T and B cells were prepared and the T
cells were stimulated with Con A for 3 days. The same
individuals were bled again 3 days later, and again
pure T and B cells were prepared. The Con A stimulated cells from the first culture were added t o cells
obtained from the second bleeding. Inhibition of
mitogen or MLR responsiveness in the second culture
was used as the index of suppressor activity.
In the normal individuals we have done thus
far, we observed a very significant depression from
63% to 71% of the mitogen response of the second
culture when purified T cells, but not B cells, from the
first culture were added. This occurred with PHA,
Con A, or pokeweed mitogen as the stimulant. To
determine which subset of T cells was responsible for
this suppressor function, T cells were separated on
BSA gradients according to their buoyant density
prior t o exposure to Con A. The results of these
studies revealed that the T cells of higher density gave
the greatest degree of suppressor activity. Of interest
was the fact that the cells incorporating the most ’H-
thymidine were present in the fraction of cells of
lowest density. These studies were published in detail
in the Journal of Immunology (1 19:1169, 1977).
So far we have measured suppressor cells of 5
patients with systemic lupus. In all of these patients
some degree of defect was noted, at least to some of
the mitogens.
For example. when Con A was used in the
second culture as a stimulator, there was a marked
difference between normal and SLE cells. The SLE
cells from the first culture did not inhibit the Con A
response, whereas the normal suppressor T cells could
inhibit this response. The SLE cells when used as responder cells in the second culture were inhibited by
normal stimulated T cells, but when the normal cells
were used as the responder in secondary culture, the
SLE T cells from primary cultures did not inhibit this
Thus, the SLE cell can respond to a suppressor
T cell from a normal individual but by itself cannot
generate suppressor cell activity. suggesting that these
suppressor T cells are actually missing to some degree
in lupus patients.
Kunkel: Dr. Steinberg, do you have any evidence that
anti-thymocyte serum was effective at body temperatures in the animal? This is primarily a cold-reactive
antibody. Have you investigated whether it is possible
that other things in the serum of these animals might
be producing your effect?
Steinberg: Good questions. With regard to the cold
reactivity, there is no question that the in vitro phenomenon that was used to describe the activity of the
antibody is cold-dependent. That, of course, doesn’t
bear one way or another on its potential in vivo
binding to cells and alteration of those cells, with
reference to either trafficking or functions. Perhaps
not all of the possible controls have been done. We
don’t find any good reason to believe that what we are
looking at is anything other than NTA. We can isolate the IgM fraction of the serum to get this effectof course, the IgM fraction contains other things including immune complexes-but these adsorb with
thymocytes, thereby removing the activity. We have
done a number of other controls, such as adsorption
with liver powder. There is a very good chance that
the active factor is NTA, but I don’t think it has been
rigorously proved.
Kunkel: One other aspect of that: have you absorbed
with B cells?
Steinberg: I’ve adsorbed just lately with nude cells and
some other B cells. These studies are going on now
and I don’t yet have the results.
Barnett: We’ve heard of different responses in nude mice
to so-called T-dependent and T-indpendent antigens.
From the data with SIRS and low-molecular weight
suppressors, what would be the prediction of response
at different ages with so-called T-dependent and independent imm unogens?
Steinberg: Obviously, there are a lot of abnormalities in
New Zealand mice. As they get older, they have poorer
primary responses to T-dependent antigens. They
make reasonably good secondary responses to Tdependent antigens, and they tend to make good responses to T-independent antigens. SIRS has not been
demonstrated to have in vivo effects in contrast to the
low molecular weight suppressor. The latter causes
enhancement rather than suppression of the response
to disease in old NZ mice.
Studies in nude mice indicate that the timing
of the administration of CONS is important-given
with antigen, it suppresses, whereas given several
(74) days before antigen, it enhances.
Waldmann: SIRS would act to inhibit both T-dependent
and T-independent humoral immune responses without affecting cell-mediated immune responses. This
contrasts with Con A activated T cells that suppress
both humoral and T-cell proliferative responses.
Hahn: I n regard to your experiments with NTA accelerating nephritis in B/W mice, can you elute NTA or
antibody to it from the glomeruli?
Steinberg: No, we don’t know anything about that yet.
Williams: With respect to Dr. Waldmann’s model, we
know that there are many components in the supernatant of the Con A stimulated cells. Have you had
occasion to look at delayed-type hypersensitivity, skin
testing, or any other parameter in the treated animals?
Waldmann: We have not looked at even primary circulating antibody responses, much less delayed-type immune responses. Con A activated T cells act on multiple functions, including both cellular and humoral
functions. However, Parker and coworkers had
looked a t cellular versus humoral responses and concluded that the humoral product-SIRS-acts
on antibody or immunoglobulin-type responses, not
cellular ones.
Williams: The hypogammaglobulinemia you produced
was striking. And since SIRS are known to be prone
to low pH, digested by pronase, and have a relatively
well-defined molecular weight, have you looked at
this in adult acquired agammaglobulinemia patients
to see if they produce a lot of these SIRS? Also,
wouldn’t it be possible finally to devise a radioimmunoassay for the material so that one could titrate
patients, if this is what they need?
Waldmann: We haven’t purified SIRS, but we are using
crude supernatants of Con A stimulated cells that
might contain a number of active factors in addition
to the protein described by Rich and Pierce.
Ziff: Dr. Waldmann, might the amount that you give0.5 p1 twice a week or so-be too small an amount to
act on a whole animal? Is there any possibility that it
is recruiting other cells?
Waldmann: We gave 0.05 ml of Con A supernatant 5
times a week to a 20 gram mouse. We have no information as to whether it would recruit other cells.
NZB/W animals given the Con A supernatants do
not have suppressor cells in the spleens before or after
in vitro treatment with Con A. I would not anticipate
that the Con A supernatants would activate other T
cells to become nonspecific suppressors.
Gershon: I would like to comment that it was Pernis’
pioneering work with the delta-antibody that suggested to us how to find this Lyb 3 antigen. We had
been playing around with it for 6 months, and not
until we applied the techniques pioneered by Dr. Pernis were we able to get the augmentation and find the
antibody activity.
Warner: Dr. Paul, would you elaborate a little more on
the mu/delta story? You make the interpretation that
there is more m u rather than less delta.
Paul: The reason w e reached the conclusion that the
abnormal mu/delta ratio on CBA/N B cells probably
results from increased m u rather than diminished
delta is that fluorescence-activated cell sorter analysis
indicates that CBA/N B lymphocytes have, on the
average, more m u than do normal B lymphocytes.
Indeed, we also reached the conclusion from these
studies that i n normal neonates there was an
enormous heterogeneity in the amount of immunoglobulin per cell and that, on the average, there was
probably somewhat more IgM per B cell than was
found on adult B cells.
The questions have been asked: 1 ) what relationship exists between the Lyb 3 marker that Huber
et al. described and the Lyb 5 marker that I discussed;
and 2) if injected into a recipient, does anti-Lyb 5
increase responsiveness to antigens as anti-Lyb 3 has
been reported to do?
The answer to the first question is that we have
not yet established that Lyb 3 and Lyb 5 are determinants on the same molecule. It seems likely that this
may be so, but these experiments have not yet been
performed. With regard to the second question, preliminary experiments have not shown that anti-Lyb 5
increases antibody responses. However, sera with
anti-Lyb 5 activity block in vitro anti-TNP antibody
responses to TNP-Ficoll, suggesting that this differentiation antigen is not only a phenotypic marker but is
also a membrane structure important in regulating B
cell activation.
Gershon: In that regard, there is one other important
distinction between the two antisera: your serum only
reacts with the cells of some mouse strains. The Lyb 3
antigen, as far as we can tell, reacts with all strains of
animals; it is not reacting with an allotypic determinant, whereas the Lyb 5 apparently is. That doesn’t
mean the two sera are not reacting with the same
molecule, but it does mean that they are reacting with
a different antigenic determinant.
Paul: I would certainly agree. Most of you may not be
aware of how anti-Lyb 3 is produced. It is a serum
produced by the immunization of CBA/N X BALB/
C F, male mice with BALB/C cells; thus it is an F,
anti-parent antiserum. The F, recognized the Lyb 3
antigen presumably because it lacks that particular
antigen, but there is no reason why it should make
antibodies to polymorphic antigenic determinants
rather than to antigenic determinants common to
mice of all strains. Thus, it is not at all surprising that
the antibody is not allotypic. On the other hand, Lyb 5
is clearly an alloantigen, and backcross analysis indicates that it is controlled by a single locus.
Friou: I am quite interested in your K-cell data because,
if I recall correctly, the mouse cell that lyses cultured
cell lines is a nonphagocytic cell, as is the human cell
that has that type of activity, Since we found a reduction in that component of the K-cell activity in active
SLE, would you speculate on what kind of presumably secondary activity might be involved in yielding
reduced activity in your animals?
Paul: We really don’t have a good explanation for that
result. It was, I must say, unanticipated. It’s still quite
possible that it does represent a secondary effect. Of
course, in lupus, circulating immune complexes are an
obvious possible cause for reduction in ADCC activity through the saturation of the Fc receptor on the K
cell. We have no evidence that circulating complexes
exist in CBA/Ns, but we have not looked for such
complexes. Another possibility is that there is a central defect in K-cell function; perhaps the K cell is in
the lineage of B cells, although not formally identifiable as such a cell.
Kincade: I want to make a few comments about some
recent functional studies that we’ve done relevant to
the B cell differentiation studies described by Dr.
Paul. The assay is an in vitro cloning technique where
individual B cells are dispersed in a semisolid gel
matrix and stimulated with mitogens such that they
proliferate and form macroscopic colonies.
Neither helper nor suppressor T cells affect the
assay. Macrophages can profoundly influence cloning
proficieny, both enhancing it and suppressing it, but
we can standardize for that to get a linear assay. The
central finding was that CBA/N mice do not have any
clonable B cells a t any stage of development. As expected, the F, male mice that carry the mutant X
chromosome also do not give B-cell colonies. In the
females of this cross, with one mutant and one normal
X chromosome, the number of colonies is about half
what it is in the age-matched wild type mouse.
Thus it appears that the kind of cell that gives
colonies correlates perfectly with the kind of cell that
CBA/N mice lack. One finding that favors the concept that in normal mice this is a distinct lineage
rather than a stage in differentiation is that fetal liver
and spleen early in gestation contain B cells that form
Talal: Dr. Roubinian and I have studied the regulatory
effect of sex hormones and the thymus by investigating the sequential development of IgM and IgG anti-
bodies to two nucleic acid antigens-double-stranded
DNA and synthetic single-stranded RNA (polyadenylic acid). Both of these antibody responses
occur spontaneously in B/W hybrid mice and also
occur in lupus patients. Very early in life, B/W mice
have very low levels of antibodies. Starting at 4
months of age, females develop a progressive glomerulonephritis associated with an increase in these antibodies, particularly in the IgG response. This occurs
later in males, again showing the influence of sex in
the animal model for SLE.
The response to the synthetic single-stranded
RNA polyadenylic acid, is different. In very young B/
W mice there is no IgG antibody at all. The response
is exclusively IgM.
Polyadenylic acid is not present in the immune
complexes found in the kidneys. One wonders what
the immunogen might be for this response. We know
that sequences of polyadenylic acid are associated
with messenger and viral RNAs.
The effect of thymectomy performed at 2-3
days of life is different in the male compared to female
B/W mice. Mortality in the males is augmented by
thymectomy, whereas in the females, mortality is decreased by thymectomy. The enhanced mortality of
males induced by thymectomy is reflected in earlier
appearance of anti-DNA antibodies. However, the
thymectomized males who are dying earlier failed to
develop IgG antibodies to polyadenylic acid. The IgG
anti-poly A response is essentially aborted by the
removal of the thymus. Thus, these experiments suggest modulating influences both for the thymus and
for sex hormones. The effect of the thymus is different
on these two spontaneous antibody responses to
DNA and poly A. Our results are consistent with the
removal of a suppressor influence for the DNA response, causing an earlier appearance of antibodies to
DNA. They also suggest the removal of a helper
influence for the poly A response that would, without
thymectomy, appear later in life to permit the development of IgG antibodies to poly A.
Davis: I want to make one comment about nucleic acids.
We have been interested in free DNA in human sera
and human plasma. One frequently finds free DNA
after surgery, injury, and burns, associated with certain drugs, and after pulmonary embolization-sometimes large amounts of free DNA. We consider this
phenomenon something that is probably quite repetitive and may occur in all of us from time to time.
Here, then, is another example of our tolerance
to a ubiquitous material. I don’t know whether there is
any evidence that free DNA has led to disease in any
of these patient groups, except for those with SLE.
Steinman: A large number of syndromes are associated
with transitory free DNA in the circulation. We also
found that there is at least one fairly common clinical
condition associated with repeated exposure of the
individual to circulating DNA over long periods of
time, and that is chronic hemodialysis.
We found that release of circulating DNA following dialysis occurs uniformly. There has also been
a report of the occurrence of ANA in these same
patients. We wouldn’t know whether these patients
were at risk for glomerulonephritis, but they clearly
don’t get anything else that looks much like lupus. So
we can certainly tolerate DNA alone for long periods
of time.
Kunkel: Before we discuss this point, I think it is extremely important to stress that you have to know
whether it is ssDNA or relatively native DNA. Relatively native DNA doesn’t immunize experimental
animals. These animals have been examined repeatedly, yet nobody has found any expression of disease.
But when the molecule is denatured, the bases are
very antigenic.
So the fact that these animals tolerate DNA
without getting any manifestations of disease is not at
all surprising from the experimental animal point of
view. But if you have denatured DNA around, that is
another story. That needs to be specified.
Steinman: We haven’t looked at that specifically, but it
seems likely from what we know about the DNA
molecule that any piece of double-stranded DNA that
has been subjected t o physical shear, as it would in the
circulation, is likely to have gaps along it and perhaps
single-stranded ends, so that there would be at least
some exposure to the bases.
Ziff: Loss of suppressor T cells has been suggested as a
reason for the development of a spectrum of autoantibodies of which those to DNA are, of course, the best
known. I think it is appropriate at this time at least to
consider any possible connection between depression
of supressor T cells and viruses. This brings up the
question of the thymus and the virus: What is the role
of the virus in affecting T-cell function through the
Talal: It seems to me that the argument becomes circular. On the one hand, we have heard from several
people in the last few days-Paul Black said it earlier-that activated cells, particularly B lymphocytes,
are a very fertile soil for virus production. This argument says that first you get an activated lymphocyte,
and then that activated lymphocyte produces virus.
On the other hand, we have also heard-as
Dick Gershon said-that the immune system behaves
as if it is stimulated by chronic infection. This argument suggests that the first event is expression of the
virus. Dr. Warner suggested that virus may be selectively expressed on certain subpopulations, as for example suppressor T cells. Thus, there is the circular
argument: you keep going around and around and
maybe, as often happens in this kind of situation,
both arguments are correct. The problem is: Is there
any experiment that would allow us to determine
whether lymphocyte activation or virus expression
comes first?
I was disappointed to learn a number of things
at this meeting that would appear to argue against the
idea of a suppressor cell deficiency. Dr. Dixon and
David Katz recently examined a number of suppressor functions in NZB/W mice and found them to be
normal. Ralph Williams has said that he couldn’t find
T-cell binding of DNA and would have expected to
find it, if there were suppressor cells for DNA. I’m
going away from this meeting with a feeling that the
now almost conventional idea of suppressor cell deficiency needs to be reexamined.
Warner: Just two comments on this point which I think
are worth stressing. The question of the existence of
suppressor cells and their absolute number in NZB
mice is something that can now be analyzed. Dick
Gershon gave us some preliminary data on Ly typing
of NZB, which if anything showed an increased number of Ly-23 cells, and he made the point that in the
absence or reduction of Thy- 1, this is compatible with
differentiation toward terminal stage.
However, it is now clear there are at least two
different Ly-23 positive cells, namely the suppressor
cell and the cytotoxic cell. They can be distinguished
on the basis of the I-J gene product that is expressed
on the cell surface of only suppressor cells. Hence,
NZB mice should by typed for the number of I-J
positive cells. There may well turn out to be further
complexities, but a t this stage, this does seem to be a
specific marker for suppressor cells; so it should be
looked at.
I would like Dr. Kunkel to comment on a
problem: The idea of a regulatory defect is attractive,
but we have to differentiate between a generalized
suppressor defect that affects the entire regulatory
network which is antigen-independent, or an antigen
specific defect.
The problem with the idea of a generalized
regulatory defect mediated through a hormone,
through NTA antibody eliminating the suppressor
function or other agent, is that we don’t see the perpetuation of any antibody response that the mice
naturally encounter. There have been demonstrations
in the literature of hyperresponsiveness in NZB, but 1
think it is fairly clear now that it is not a completely
generalized phenomenon.
I wonder how this is reconciled. Must we have
a separate set of suppressors that deal with autoantibody producing cells, or is it going to be an antigenspecific suppressor cell that we are dealing with?
Kunkel: To some degree we are overly conscious of the
autoantibodies because we do not usually measure
other types, so the fact that antibodies are not there,
and then suddenly they are there, may be the most
visible index we have of a lack of suppression. Perhaps
if we could study these patients’ responses to immunization in more detail, we would see the effect on other
antigens. I think the T-cell defect is a very real one
that we have to cope with. There are so many bits of
evidence that came out a t this meeting and that are
coming out in the literature, particularly recently in
the human clinical studies, it is a logical extension
to suppose that it is a “generalized” lack of suppression that is involved.
Lipsky: I would like to mention one piece of work
presented in Miami by Dr. Tom Chused which might
be of some interest. He demonstrated in the NZB
mice that by taking single-cell suspensions of spleen
cells and letting them synthesize immunoglobulin in
vitro during short-term culture for 4 hours, these mice
make increased amounts of immunoglobulin compared to normal strains. And this can be demonstrated on the first day of life. This finding suggests at
least that these animals are born with some sort of
regulatory defect, again raising the question of
whether some of the suppressor abnormalities that
develop later in life might not, in fact, be an interesting but secondary pheonomenon.
In this same context regarding nonspecific Tcell help in patients with lupus, we have studied a
variety of patients with active disease and looked at
their peripheral blood lymphocyte response to pokeweed mitogen as a polycolonal inducer of immunoglobulin secreting cells. We find that in all of the lupus
patients whom we have studied so far, this response is
highly abnormal, and they do not respond to pokeweed mitogen. This defect, at least, can be ascribed to
an absence of an appropriate T-helper cell in the
peripheral blood.
Clearly, we cannot make any comment about
what might be going on with regard to the internal
lymphoid organs of these patients. But, at least with
regard t o their peripheral blood responsiveness, we
have clear-cut evidence here that there is no nonspecific T-cell helper. In fact, we cannot induce a Thelper cell with a nonspecific activator such as pokeweed mitogen.
Ziff: Don’t you think that, in spite of the fact that the
specific suppressor may be important in the control of
specific antibody disease, it is more likely that we are
dealing with broad effects? Because as we mentioned
before, we get a group of autoantibodies emerging at
the same time. Krakauer and coworkers have in fact
demonstrated that SIRS can knock the whole business out.
So broad regulation seems to be a more important aspect of lupus erythematosus than the specific
control that may be involved in individual autoantibody responses. The fact that a patient develops a
lupus-like syndrome during an attack of infectious
mononucleosis is evidence for a broad effect.
Tan: I just want to make a comment that perhaps man
may be a little more complicated than the mouse. I
think that in the mouse, and to a degree in man, we
are pretty sure there is a T-cell defect that may account for the syndrome of systemic lupus. Immunogenetics may play a role. But the mouse is not exposed
to certain drugs as man is, for example, to hydralazine
or to procainamide. And the mouse is certainly not
exposed to many things that we are exposed to in food
preservatives which are highly reactive chemicals that
may be very reactive with cell membranes and intracellular components.
I think we are all convinced that lupus is a
multifactorial disease. Another feature is that certain
environmental influences may also predispose or help
to induce the disease-the studies that we have shown
with ultraviolet light, for example. Ultraviolet light
can induce the thymidine dimers in DNA which are
highly antigenic, but this is not the whole story. UItraviolet light can also induce many changes between
nucleic acids and proteins such as cross-linkings that
may be very antigenic and that may in part be responsible for the induction of some of the autoantibodies to nuclear antigens.
There is also the controversial finding concerning the deficiency of repair enzymes which are
responsible for repair of damaged or altered nuclear
macromoleclues such as thymine dimers.
There are so many factors that can help to
produce the disease that we should not limit our
thinking to just T o r B cells or the genetics but expand
it to cover these other areas.
Talal: There is no question that we have to visualize the
pathogenetic mechanism of lupus as a very dynamic
system, not static at all. I t doesn’t necessarily start
in one place or in a single event. It’s like Yin and
Yang in which several events may be intertwined.
This leads to a degree of circularity in which cause
and effect become blurred. Thus the question for all
of us to ponder is: how can we diminish the tendency to be caught in this circularity and move
toward finding primary mechanisms?
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discussionmechanisms, immune, regulation
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