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Defective mitogenic responses in myasthenia gravis and multiple sclerosis.

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Defective Ahtogenic Responses
in Myasthenia Gravis and Multiple Sclerosis
Edward J. Dropcho, MD," David P. Richman, MD, Jack P. Antel, MD, and Barry G . W. Arnason, M D
Using in vitro lymphocyte proliferation induced by the phytomitogen concanavalin A (ConA), we investigated
immune function and regulation in patients with myasthenia gravis (MG) and multiple sclerosis (MS). Unfractionated peripheral blood mononuclear cells of normal individuals responded to a wide range of ConA concentrations;
the T cell fraction responded to a lesser degree and only to high concentrations. These findings suggest the presence
of two receptors for ConA, one of high affinity present on a non-T cell accessory cell and the other of low affinity
present on T cells. Contrasting defects in the level of response of unfractionated lymphocytes and T cells were
found in patients with MG and MS. The peak response of T cells in the MG patients was 22.6 t 9.6 x lo3 cpm (mean
t SEM) compared with 54.6 6.5 x lo3for controls ( p < 0.05),while the response of unfractionated lymphocytes
did not differ from that in controls. For MS patients, the unfractionated lymphocyte response was diminished: 56.3
? 2.8 x l o 3cpm versus 70.5 t 4.5 x lo3for controls ( p < 0.05),while the T cell response was normal. These results
indicate a defect in the direct T cell response in MG; in contrast, in MS the response requiring T cell-accessory cell
interaction is abnormal.
*
Dropcho EJ, Richman DP, Antel JP, Arnason BGW: Defective mitogenic responses in myasthenia gravis and
multiple sclerosis. Ann Neurol 11:456-462, 1982
Myasthenia gravis (MG) and multiple sclerosis (MS)
are diseases in which aberrant immune function is
thought to play an important role. In MG, an autoimmune response is directed against the nicotinic
acetylcholine receptor located at the myoneural
junction [14,321. The pathogenesis of this response
remains poorly understood, but considerable evidence supports the view that the autoimmune state in
this disease is accompanied by a defect in immune
regulation [ 5 , 15, 25, 371. In MS, no immune response directed against a specific antigen has yet been
demonstrated, but various abnormalities of immune
function and immune regulation have been observed.
Regulation of the immune response requires normal function of distinct lymphocyte subsets and normal interactions between them. Abnormalities in
both numbers and functional activity of lymphocyte
subsets have been observed in MS and MG. Total
circulating T cells are reported to be reduced in
number in the peripheral blood of patients in some
studies [21,27, 281 but not in others [lo, 1 2 , 17,221.
A more consistent observation in MS has been a reduction in the number of active or avid T cells [231.
Investigation of restricted T cell subsets responsible
for defined functional activities has produced several
promising results. The proportion of peripheral
blood lymphocytes that bind immunoglobulin Gcontaining immune complexes (T, cells) is reduced in
active MS [9]but increased in MG [ 16,261; suppressor cells are found within the TGpopulation. A suppressor cell subset of T cells defined by a specific
monoclonal antibody is reduced in the circulation
during acute MS attacks [29]. Changes in the suppressor cell subset determined by these enumeration
techniques are in keeping with the previously reported lack of functional suppressor activity during
flareups of MS [ 11. Functional studies in patients with
MG have also shown diminished suppressor cell activity in some instances [4, 19, 36, 391. In MG,
decreased suppressor activity may result from an autoimmune attack directed against a nicotinic acetylcholine receptor present on some but not all lymphocytes [SO, 31, 361.
In order to investigate further the abnormalities of
immune function in MG and MS, and in particular to
investigate cell-to-cell interactions, we have used
lectin stimulation of cultured lymphocytes as a model
of T cell activation. There has been some controversy
whether monocytes are required for T cell activation
by these agents. Some workers have found complete
From the Department of Neurology, The Division of the BiologiThe Pritzker School of Medicine, The University
of Chicago, 950 E 59th St, Chicago, IL 60637.
Received Apr 2, 1981, and in revised form Aug 13. Accepted for
publication Aug 19, 1981.
Address reprint requests to Dr Richman.
cal Sciences and
*Present address: Department of Neurology, The Johns Hopkins
University School of Medicine, Baltimore, M D 2 1205.
456 0364-5 134/82/050456-07$01.25@ 1981 by the American Neurological Association
abrogation of response t o lectins in t h e absence of
monocytes [20, 331, while others 16, 8, 34, 381 have
noted a diminished b u t significant lymphocyte response. By examining doselresponse curves, we have
confirmed the contention of Lohtmann et a1 [ 181 that
response to low concentrations of mitogen requires
the presence of monocytes while response to high
concentrations d o e s not. Study of patients with MG
or MS has revealed abnormalities in t h e monocyte-independent system in MG and abnormalities
in the monocyte-dependent system in MS.
Materials and Methods
Six MG patients aged 26 to 71 years (median, 38 years)
were studied. Each patient had a typical clinical picture of
MG, responded to edrophonium, and benefited from anticholinesterase medication. Two patients (aged 29 and 7 1
years) were taking steroids at the time of study, and two
others had undergone thymectomy.
All patients with MS satisfied the usual criteria [35] for
clinically definite disease. Ten patients aged 20 to 45 years
(median, 30 years) were studied. Four had clinically inactive disease or stable disease with varying degrees of disability. Six patients (aged 20 to 45 years) were studied while
hospitalized for exacerbations commencing within the previous three weeks and were considered to have “active”
disease. Three of the patients with active MS were taking
oral corticosteroids at the time of study. No patient showed
evidence of infection.
Controls were twelve healthy volunteers aged 19 to 33
years (median, 23 years). Data from the normal donors
were compared with data from patients only if the patients
and controls were studied simultaneously; of the twelve
normal donors, four served as controls for the MS patients,
four for the M G patients, and four acted as controls for
both patient groups.
Isolation of Cells
Mononuclear cells (MNCs) were separated from peripheral
venous blood by sedimentation over a discontinuous gradient of Ficoll-Hypaque (Pharmacia, Piscataway, NJ;
specific gravity, 1.078 to 1.080) and then washed three
times with calcium-free Hanks balanced salt solution with
5% fetal calf serum.
Sheep red blood cells (SRBC) (MA Bioproducts, Walkersville, MD) were prepared from blood less than one
week old. The blood was washed four times with cold 0.9%
saline, and 1 part of the packed cell button was added to 4
parts of heat-inactivated, SRBC-adsorbed fetal calf serum
and 15 parts of Eagle’s minimal essential medium (MA
Bioproducts) containing glutamine ( 4 mmol/dl) and gentamicin (10 mg/dl). An equal volume of this 5% SRBC suspension was then added to a preparation of mononuclear
cells suspended in minimal essential medium and fetal calf
serum to a concentration of 12 to 20 X lo6 cellslml. The
mixture was centrifuged at 180 g for 5 minutes and incubated at room temperature without resuspending the cell
button. After 1 hour, the cells were gently resuspended
and sedimented at 600 g for 15 minutes over B FicollHypaque gradient as described for MNCs. The supernatant
and the E-negative (E-) cells at the interface of the gradient
were drawn off, and the cell button containing the E rosettes was washed three times in Hanks balanced salt solution
and 5% fetal calf serum. The SRBCs were then lysed by
suspension in a prewarmed solution of ammonium chloride
(0.75% NH&I and 0.2% Tris buffer, p H adjusted to 7.2)
and incubation at 37°C for 10 minutes, after which they
were washed twice in Hanks balanced salt solution with 59%
fetal calf serum.
Enumeration of E-positive Cells
For enumeration of the E-positive (E+) cells in the cell
preparations, 0.5% SRBC in minimal essential medium
and 20% SRBC-adsorbed fetal calf serum were used. Equal
volumes of SRBC and lymphocytes (MNC or E + cells in a
concentration of 1 to 2 x 106/ml) were combined and
sedimented at 180 g for 5 minutes. After 1 hour at room
temperature, the cell button was gently resuspended,
stained with methylene blue, and evaluated in a
hemocytometer. A lymphocyte with at least 3 attached
SRBCs was considered an 5 rosette. At least 200 cells were
counted, without knowledge of the nature of the cell preparation from which they were taken.
Mitogen Stimulation Studies
Lymphocytes (MNCs or E + cells) were suspended in
minimal essential medium supplemented with 20% fetal calf
serum, gentamicin (10 mgfdl), and glutamine (4 mmol/dl).
In each well of a Microtest I1 plate (Falcon, Oxnard, CA)
200 pl of the cell suspension (2 x lo5 cells) were placed,
and concanavalin A (ConA, Sigma Chemical Co., St.
Louis, MO) was added over a dose range of 0.3 to 150
p d m l (final concentration). Quadruplicate cultures were
maintained for 7 2 hours at 37°C in a 5% carbon dioxide
humidified incubator, pulsed for 5 hours with tritiated
thymidine (New England Nuclear, Boston, MA; specific
activity 6.7 Ci/mmol, 1 pCi per well), and harvested on
fiberglass filters with an automated cell harvester (MASH
11, MA Bioproducts). Filters were dried and counted in
vials of Omnifluor (New England Nuclear) in a Packard
liquid scintillation counter. Data are expressed as mean
counts per minute (cpm) with the standard error of the
mean (SEM) and analyzed by a two-tailed Student t test.
Results
Characterization of Cell Fractions
The percentage of E+ cells in the MNC preparations
from t h e normal donors, MS patients, and M G patients was, respectively, 69.0 2.3%, 66.9 4.096,
and 6 2 . 3 +: 7.0%. N e i t h e r of the differences between patients and controls was statistically significant. No correlarion was found in either normal controls or patients between t h e percentage of
E+ cells in t h e MNC preparation and the peak response of the MNC to C o n A stimulation, n o r was
there any clear relation between state of disease activity in the MS patients and their percentage of E +
cells. T h e E+ cell preparations, as assessed by a second rosetting with SRBC, contained 85 to 97% E+
*
*
Dropcho et al: Lymphocyte Responses in MG and MS
457
8or
cells (mean k SEM, 91.1 k 0.9%). Fewer than 1.0%
surface immunoglobulin-positive cells were determined by immunofluorescence using fluoresceinlabeled antihuman immunoglobulin, and fewer than
0.5% monocytes were determined by staining for the
presence of nonspecific esterases.
ConA Stimulation of M N C and T Cells
from Normal Controls
Mononuclear cells from the twelve healthy donors
showed a background tritiated thymidine uptake
(cells cultured in the absence of ConA) of 532 t 80
cpm (mean
SEM), while unstimulated E+ cells (T
cells) had an average background count of 160 l?r. 30
cpm. The MNCs (Fig 1) exhibited stimulation over
the entire range of ConA concentrations (0.3 to 150
pg/ml) with a broad peak of a maximum response of
74.9 k 3.8 X lo3 cpm at 15 pg of ConA/ml. The T
cells responded over a much narrower range of ConA
concentrations (6 to 60 pg/ml) with a sharp peak of
38.1 k 4.4 x 10%cpm at 30 p g of ConA/ml. The
differences between the M N C and E + cell responses
were highly significant (p < 0.001) at each of the
eight concentrations of ConA used, and were most
striking at suboptimal ConA concentrations (0.3 to 6
pg/ml). Addition of E- cells to the T cell fractions
(data not shown) produced an increment in the response to 3 pg of ConA/ml that was directly proportional to the percentage of E- cells added.
T
*
ConA Stimulation of M N C and T Cells
from MG Patients
Uptake of tritiated thymidine by cells from the MG
patients occurred over the same range of ConA concentrations as cells from matched controls, and the
shapes of the dose/response curves for M N C and T
cells were similar to those of the controls. The background uptake of thymidine by unstimulated M N C
from the M G patients (790 k 170 cpm) or by T cells
(230 t 50 cprn) did not differ significantly from the
background counts of the control M N C and E + cells
(560 k 100 and 180 ? 50 cpm, respectively).
The M N C response of the six M G patients was
generally less than the response of the matched controls (Fig 2A), but a great deal of overlap occurred
between M G and control responses, and the difference was significant only at 3 pg of ConA/ml. The
maximum M N C response from the M G patients was
72.5 + 10.4 x lo3cpm, compared with 80.4 t 3.8 x
lo3 cpm for the control group. However, a striking
decrease occurred in the T cell response of the M G
patients (Fig 2B): at optimal doses of ConA (15 and
30 pg/ml) the control responses were 38.7 t 6.4 and
54.6 k 6.5 x lo3 cpm, while the responses of T cells
from M G patients at these doses were 13.1 k 3.9 and
22.6 k 9.6 x 103cpm. The difference between the
M G and control T cell responses were statistically
458 Annals of Neurology
Vol 11 No 5
May 1082
Con A CONCENTRATION (pg/ml)
F i g I . Mean (k SEM) thymidine uptake at three days o f
mononuclear cells (circles) and T cells (squares) cultured in
the presence of various concentrations of ConA in twelve control
individuals.
significant at the four greatest ConA concentrations
< 0.05 at 30 and 60 pg/ml,g < 0.01 at 15 and 150
pg/ml). N o clear relation was found between the T
cell response of the individual M G patients and previous thymectomy or the use of oral corticostesroids;
the two patients with the lowest T cell peak response
were, in fact, young patients who were neither
thymectomized nor taking steroids at the time of
study.
(p
ConA Stimulation of M N C and T Cells
from MS Patients
Neither the unstimulated background counts of the
M N C (580 k 110 cpm) nor those of the T cells (140
+- 30 cprn) from MS patients differed significantly
from the background counts of the cells from eight
matched controls studied simultaneously (520 k 110
and 160 k 50 cpm for M N C and E+ cells, respectively). Tritiated thymidine uptake in response to
ConA occurred over the same range of ConA concentrations as with normal controls, and the shapes of
8
I00
80
6
6C
?
7
0
2
x
X
i0f
I
0
4
4c
i
2c
C
Con A CONCENTRATION ( F g / m l l
Con A CONCENTRATION (pg /ml)
A
B
F i g 2. Mean (k S E M ) thymidine uptake in response t o ConA
of three-day cultures of mononuclear cells (A) and T cells (B)
from patzents with M G (triangles) and from controls (circles).
(" = p < 0.05; = p < 0.01.)
ity (Fig 4). The M N C response of the three patients
with active disease who were not taking steroids was
nearly identical to that of controls at all but the optimal ConA concentrations, 15 and 30 pg/ml. At suboptimal doses of ConA, the response curves of the
MS patients 00 steroids and of those with stable disease closely paralleled each other; both were well
below the curves for the controls and the patients
with active MS who were not taking steroids, with
the difference reaching statistical significance (p <
0.05) at 3 pg of ConA/ml. At all concentrations of
ConA, the T cell responses of the patient subgroups
were virtually identical to each other as well as to the
control values.
It should be noted that the diminished response of
the M N C from the MS patients cannot be attributed
to the use of oral corticosteroids by three of the patients; reexamination of the data with these three patients omitted yielded a dose/response curve for the
remaining seven patients nearly indistinguishable
from that seen with all ten MS patients.
the dose/response curves for the M N C and T cells
were similar to those of controls. The response of the
M N C from MS patients was diminished compared to
the matched controls at each of the eight ConA concentrations employed, with peak responses of 56.3 t
2.8 x lo3 cpm and 70.5 & 4.5 x lo3 cpm, respectively, for the two groups (Fig 3A). The difference
between MS patients and normal subjects was statistically significant (J< 0.05) at 3, 1 5 , 30, and 150 pg
of ConA/ml.
In contrast to the results obtained with MNCs, E+
cells from the MS patients showed a dose/response
curve to ConA stimulation that closely paralleled the
curve seen with control E+ cells (Fig 3B). The peak
E + response was 34.9 t 6.3 x lo3 cprn for normal
controls and 30.9 t 3.9 x lo3cpm for MS patients at
30 pg of ConAIml.
The diminished MNC response of the MS patients
appeared to be related to their level of disease activ-
Discussion
The present data indicate that T cell response to
ConA is mediated by at least two mechanisms and
demonstrate contrasting abnormalities in the re-
Dropcho et al: Lymphocyte Responses in MG and MS
459
50r
T
I
O‘
l
l
I
l
l
013
1.5 3
6
15 30 60
Con A CONCENTRATION ( p Q / m l )
I
150
Con A CONCENTRATION ( p Q / m l )
A
B
sponse to ConA of MNCs and purified T cells from
patients with M G and MS. Only T cells proliferate in
vitro in response to ConA, yet evidence has accumulated that “accessory” cells play a role in this T cell
response. Some investigators have found no T cell
response to mitogens in the absence of monocytes;
others have observed a low-level but significant response only to high concentrations of mitogen. In
our normal individuals, T cells responded modestly
only to high concentrations of ConA. MNCs responded to both low and high concentrations of
ConA, and this response exceeded the T cell responses at all ConA concentrations with the differences most striking at the lowest concentrations.
Addition of E- cells to the T cells (E+ cells) restored
their response to ConA to that of unfractionated
MNCs. Addition of purified monocytes was somewhat less effective [2], suggesting some contribution
to the ConA response by a third cell type (non-T
cell, nonmonocyte).
The present findings, and those of other workers
[18, 34, 381, suggest that two discrete mechanisms
are involved in the response of T cells to ConA: one
system responds to low concentrations of ConA but
requires the presence of accessory cells; another
Fig 3. Mean (& SEM) thymidine uptake i n response to ConA
of three-day cultures of mononuclear cells (A) and T cells (B)
from patients with MS (squares) and from controls (circles).
460 Annals of Neurology
Vol 11 No 5
May 1982
(” = p
< 0.05.)
system is relatively independent of these cells but responds only to high concentrations of ConA. Possibly the two systems involve different ConA receptors,
one of low affinity and one of high affinity. The presence on human MNCs of multiple ConA receptors
with various affinities has been demonstrated by
binding studies [ 113. Whether the receptors involved
in the two systems reside on different T cell subpopulations or on a single cell type cannot be determined from the present data.
Accessory cell enhancement of ConA stimulation
is poorly understood. Accessory cells may present
ConA to T cells in a modified form, or may concentrate it on their surface so as to present a high local
concentration to the T cells. Soluble lymphocyte activating factors elaborated by monocytes [7, 331 may
also play a role in potentiation of response to low
doses of mitogen.
The data for M G patients suggest an abnormality
"
I
1
1.5
1
1
3
6
I
15
I
I
30 60
Con A CONCENTRATION (pg/ml)
0.3
2
150
F i g 4. Mean thymidine uptake i n response to ConA ofthreeday cultures of mononuclear cells. Closed squares represent controls (N = 8); open squares represent patients with stable MS
(N= 4); open circles represent patients with active MS receiving corticosteroids (N = 3);closed circles represent patients
with active MS not receiving corticosteroids (N = 3). * = p <
0.05 for patients with stable MS, or for patients with active
MS who were not taking corticosteroids,when comparpd to
controls. (Valuesfor ConA concentrations of 60 and 150
pglml were not available for the MS patients receiving cort icosteroids.)
of the accessory cell independent system, since the
response of MNCs to ConA was essentially normal
while the response of purified T cells was less than
half that of controls. The defective accessory cellindependent response does not relate to either
steroid therapy or thymectomy.
In contrast t o the findings in MG, the response of
unfractionated MNCs from MS patients was decreased compared to MNCs from controls across the
entire range of ConA concentrations employed.
However, no abnormality in the response of purified
T cells from MS patients was found. The decreased
M N C response in MS can be accounted for by an
abnormality in the accessory cell-dependent system.
The defect is likely one of accessory cell-T cell interaction, but a more generalized abnormality of
function of one of the accessory cell types (e.g.,
monocytes) remains possible. Defective cell-to-cell
interaction may contribute to the aberrant immunoregulation found in MS.
Our findings in MS are consistent with previously
reported decreased mitogen reactivity of peripheral
blood MNCs from MS patients [13, 241. The apparent correlation of the ConA response to level of disease activity in the MS patients must be viewed with
caution, since the number of patients in the various
subgroups was small and the variation between individual responses considerable. The M N C responses
of the MS patients did seem, however, to segregate
into two groups. At suboptimal ConA concentrations, the response of MNCs from patients with
active MS who were not taking steroids was nearly
normal. This response was greater than that of stable
MS patients or of patients with active MS taking
steroids. This finding confirms and extends the previous observation of a decreased M N C response to
low ConA concentrations in patients with stable MS
compared to those with active disease [3].Suppressor
cell activity of patients with active MS is decreased
relative to that of persons with stable MS [I]; the
greater ConA response of patients with active disease
could reflect this fall in suppressor cell activity.
In MG, then, the defect appears to be in the interaction of T cells with high concentrations of
ConA. In MS, the defect is either in the function of
an accessory cell or in accessory cell-T cell interaction. In neither MS nor M G in young adults is an
intrinsic defect in the capacity of T cells to proliferate
apparent; just such an intrinsic defect accounts for
the reduced response of both accessory celldependent and accessory cell-independent systems
observed in elderly individuals [ 2 ] . Investigation of
the mitogen response in other abnormal immune
states may further delineate the mechanisms of lymphocyte activation in the normal situation.
Supported in part by Grants NS 15462 and A G O 1798 from the
National Institutes of Health and by the Muscular Dystrophy Association of America and the Multiple Sclerosis Society (RG
1130).
Presented in part at the 62nd Annual Meeting of the Federation of
American Societies for Experimental Biology, Dallas, TX, May 1,
1978, and the 103rd Annual Meeting of the American Neurological Association, Washington, DC, Sept 23, 1978.
The authors thank Barbara Smith for secretarial assistance.
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