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Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10 production were suppressed in AChR-immunized
IL-6-/- mice. EAMG resistance in IL-6-/-
mice was associated with a significant reduction in germinal center
formation and decreased serum complement C3 levels. The data provide
the first direct genetic evidence for a key role of IL-6 in the
autoimmune response to AChR and in EAMG
pathogenesis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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was immunosuppressive in the development of EAMG (5, 6). Also, high-dose, AChR T cell epitope-specific tolerance and
prevention of EAMG were associated with down-regulation of IL-2,
IFN-, and IL-10 production (7). In contrast to IFN-,
IFN-, one of the proinflammatory cytokines, facilitated the
autoimmune response to AChR and EAMG development (8, 9),
as did IL-12, the IFN--driving cytokine (10). However,
IL-4 was found to be less important for inducing Ab-mediated EAMG in
C57BL/6 (B6) mice, since IL-4-deficient mice developed EAMG in the same
manner as did wild-type (WT) B6 mice (11). We hypothesized that IL-6 also plays a key role in EAMG development because it promotes growth of hemopoietic stem cells, modulates differentiation of activated B cells into plasma cells, facilitates T cell-dependent Ab responses, costimulates T cell differentiation, promotes inflammation, and up-regulates MHC class II expression (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). More importantly, cultured MG thymic epithelial cells express high levels of IL-6 mRNA and overproduce IL-6. These cells potentially could be involved in thymic hyperplasia and thymic germinal center (GC) formation in MG patients (22). In addition, AChR-reactive blood mononuclear cells of MG patients express elevated mRNA for IL-6, IL-10, and IL-12 (23). To demonstrate direct genetic evidence for a critical role of IL-6 in EAMG pathogenesis, normally developed IL-6-/- and WT mice were immunized with AchR in CFA. They were then examined for cellular and humoral immune responses to AChR and development of clinical EAMG. The findings reported here provided the first direct genetic evidence for a key role of IL-6 in the autoimmune response to AChR, especially in the production of the anti-AChR IgG2 isotype, GC, and complement C3 and thus contributed to the pathogenesis of Ab-mediated EAMG.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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AChR was purified from the electric organ of Torpedo
californica by -neurotoxin affinity column (24, 25). Torpedo AChR -chain peptide (146–162)
(7) was synthesized in the protein core laboratory at the
University of Texas Medical Branch (Galveston, TX). Seven- to 8-wk-old
B6 and IL-6-/- mice in the B6 background were purchased
from The Jackson Laboratory (Bar Harbor, ME). All animals were housed
in the viral Ab-free barrier facility at the University of Texas
Medical Branch and maintained according to the Animal Care and Use
Committee Guidelines.
Induction and clinical evaluation of EAMG
For in vivo studies, all mice were anesthetized and immunized with 20 µg AChR emulsified in CFA (Difco, Detroit, MI) s.c. at four sites (two hind footpads and shoulders) on day 0. All of the mice were boosted with 20 µg AChR in CFA s.c. at four sites on the back on days 30 and 60. Mice were screened for clinical EAMG on a daily basis. Clinical muscle weakness was graded (clinical scores) as follows: grade 0, mouse with normal muscle strength; grade 1, normal at rest, with muscle weakness characteristically shown by a hunchback posture, and difficulty to raise the head after exercise, consisting of 20–30 paw grips on cage top grid; grade 2, mouse showed grade 1 symptoms without exercise; grade 3, dehydrated and moribund with grade 2 weakness; and grade 4, dead. Clinical EAMG was also confirmed by i.p. administration of 50 µl neostigmine bromide (0.015 mg/ml), along with atropine sulfate (0.006 mg/ml) in PBS, and observing improvement in muscle strength.
Immunopathological evaluation of EAMG
The primary pathology of MG and EAMG in mice is the loss of
muscle AChR due to Ab- and complement-mediated attack
(26, 27, 28). The total concentration of AChR per mouse was
determined according to previously published methods and expressed as
picomoles of 125I-labeled -bungarotoxin binding sites
(25, 27). The serum anti-mouse AChR Ab was measured by
-bungarotoxin (Amersham, Arlington Heights, IL) RIA (24, 25) and the anti-mouse AChR IgM and IgG isotypes were
measured by ELISA (6, 25).
Lymphocyte proliferative and cytokine assays
Inguinal and axillary lymph node cells (LNC) were collected at
termination of the experiments (day 7 or 90) and 4 x
105 cells in 200 µl were exposed in vitro in triplicate
wells of 96-well plates to AChR (250 µg/ml) and 146–162 peptide
(40 µg/ml) and incubated for 5 days, and lymphocyte proliferative
response was measured (7, 25). Culture supernatants were
measured for IFN-, IL-4, IL-6, and IL-10 by ELISA and IL-2 by
cytotoxic T lymphocyte line assay (7, 25).
Flow cytometry
Single-cell suspensions of LNC were incubated for 30 min with one of the following Abs: PE-conjugated B7-1, B7-2, and CD40 (BD PharMingen, San Diego, CA) and FITC-conjugated I-Ab, B220, CD4, and CD3 (Caltag Laboratories, Burlingame, CA) anti-mouse mAbs. PE- or FITC-conjugated isotypes were used for controls. Cells were washed twice and then were fixed with 2% paraformaldehyde and analyzed by FACStation flow cytometry (BD Biosciences, San Jose, CA).
Immunohistochemical staining for GC
Four-micrometer-thick sections of 10% Formalin-fixed and paraffin-embedded spleens were prepared. Sections were deparaffinized and rehydrated. Endogenous peroxidase activity was quenched with 3% H2O2 in methanol. Sections were blocked for nonspecific binding with normal goat serum diluted 1/20 in DAKO Ab diluent for 15 min. Ag retrieval was done with DAKO Target Retrieval Solution in steam for 20 min. Sections were then cooled down on the bench top for 20 min, rinsed two to three times with distilled water, and transferred to TBS. Slides were then incubated for 30 min with peanut agglutinin (PNA)-biotin (Vector Laboratories, Burlingame, CA) diluted 1/250 in DAKO Ab diluents and washed, followed by a second incubation with streptavidin-HRP for the LSAB2 system (KO675). Bound conjugates were visualized with DAKO Liquid diaminobenzidine substrate-chromogen for 5 min when a brown color for PNA-positive cells was obtained. For all staining steps, a DAKO Autostainer was used. Slides were counterstained for 2 min with Mayer’s modified hematoxylin diluted 1/5 in distilled water.
Measurement of serum C3 levels by ELISA
Ninety-six-well microtiter plates (Dynatech Immulon 2; Dynatech Laboratories, Chantilly, VA) were covered with goat Abs to mouse C3 (ICN Biomedicals/Cappel, Aurora, OH) in 0.1 M sodium carbonate buffer (pH 8.2) overnight at 4°C. The plates were then blocked with 2% BSA in PBS at room temperature for 30 min. Diluted (1/3 in PBS-0.05% Tween 20) serum samples (30 µl) were added and incubated at 37°C for 90 min. After four washes, HRP-conjugated goat anti-mouse C3 complement (ICN Biomedicals/Cappel), diluted 1/500 in PBS/0.05% Tween 20, was added and incubated at 37°C for 90 min. Subsequently, ABTS substrate solution in 0.1 M citric buffer (pH 4.3) in the presence of H2O2 was added and color was allowed to develop at room temperature in the dark. Plates were read at a wavelength of 405 nm using a Dynatech ELISA reader and the results were expressed as OD values.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-6-/- and WT mice were immunized with AChR in CFA
on days 0, 30, and 60. In the first experiment, 5 of 12 B6 mice
developed typical clinical EAMG after the first boost with AChR and
another 5 B6 mice developed clinical EAMG after the second boost with
AChR. One of the mice with severe disease died. Overall, 10 (83%) of
12 WT mice developed clinical EAMG in contrast to only 1 of 12
IL-6-/- mice which developed grade 1 and a short course
of clinical EAMG after the first boost with AChR. Another 2 of 12
IL-6-/- mice developed grade 1 EAMG after the second
boost with AChR. Overall, 3 (25%) of 12 IL-6-/- mice
developed clinical EAMG. In the second experiment, the incidence of
EAMG in WT and IL-6-/- mice was similar to that in the
first experiment, except none of the IL-6 KO mice developed clinical
EAMG after the first AChR boost. The kinetics of the incidence and mean
severity of clinical EAMG are illustrated in Fig. 1
, A and B, for
experiment 1 and D and E for experiment 2. In
both of the experiments, IL-6-/- mice had a delayed
onset, lower total incidence (p = 0.0058), and
less severe clinical EAMG (p < 0.05) compared
to WT mice. The data demonstrated the first direct genetic evidence for
the involvement of IL-6 in the development of clinical EAMG after
immunization with AChR.
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-bungarotoxin binding sites in
the muscles, which reflect the amount of functionally available muscle
AChR, were measured in AChR-immunized WT and IL-6-/-
mice. The functional AChR in AChR-immunized IL-6-/- mice
was significantly higher (p < 0.05) than that
of WT mice (Fig. 1
, C, Expt. 1, and F, Expt. 2).
Therefore, the lower incidence of EAMG in IL-6-/- mice
correlated with higher available functional muscle AChR. Although mice
with disease have significantly more AChR loss compared to mice without
disease (27), the muscle AChR levels do not reveal a
significant correlation with severity of disease. This could be due to
the differential neuromuscular transmission safety margin in each
mouse. Predominant suppression of secondary anti-AChR IgG2 in AChR-immunized IL-6-/- mice
Sera from individual mice were collected at various time points
after the first immunization with AChR. The anti-AChR IgG Ab
response was measured first by RIA. In both of the experiments,
compared to AChR-immunized WT mice, AChR-immunized
IL-6-/- mice had reduced anti-mouse AChR IgG at most
of the time points tested (Fig. 2). ELISA
was adopted to measure serum anti-AChR IgM and IgG isotypes. After
the third AChR immunization (day 74), when a significant number of WT
mice developed clinical EAMG, the anti-AChR Abs belonging to the
IgG, IgG2b, and IgG2c isotypes, but not IgM
isotype, were significantly reduced in AChR-immunized
IL-6-/- mice compared to AChR-immunized WT mice in both
experiments (Fig. 3). After the primary
AChR immunization or after boosting with AChR, no significant
suppression of anti-AChR IgM Abs was observed in
IL-6-/- mice compared to WT mice (data not shown).
Therefore, IL-6 deficiency could have led to defective T cell help
and/or defective class switching of anti-AChR IgM to IgG2 isotype,
thus contributing to the resistance of clinical EAMG. Our data imply
that IL-6 is critical for producing the secondary anti-AChR Ab
response.
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146–162
To test the lymphocyte response to AChR and its peptides, LNC from
AChR-immunized IL-6-/- and WT mice were stimulated in
vitro with AChR and 146–162 peptide. Proliferation of AChR and
146–162 peptide-specific lymphocyte and production of IFN-,
IL-10, and IL-4 were measured. At termination of the short-term (day 7)
and long-term experiments (day 90), IL-6-/- mice
demonstrated a reduced proliferative response to AChR and 146–162
peptide compared to the proliferative response of cells from WT mice
(Fig. 4, A and D).
AChR and 146–162 peptide-specific IFN- and IL-10 production were
also significantly suppressed in IL-6-/- mice compared to
WT mice in the long-term assay (Fig. 4, E and F).
AChR-specific IFN- and IL-10 production were also suppressed in the
short-term assay (Fig. 4, B and C). Although
146–162 peptide-specific IL-10 production was suppressed in
IL-6-/- mice, 146–162 peptide-specific IFN-
production was not significantly suppressed in IL-6-/-
mice compared to WT mice in the day 7 assay. In all cultures, IL-4 was
undetectable in ELISA. These data suggest that the primary and
established lymphocyte responses to AChR and its peptide were
suppressed in IL-6-/- mice. Furthermore, the data
implicate IL-6 as having an in vivo regulatory role in AChR and
146–162 peptide-specific IFN- and IL-10 production, especially
in the established (long-term) immune response, since these cytokines
were suppressed in AChR-immunized IL-6-/- mice.
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146–162
peptide-challenged AChR immune lymphocytes (long term). AChR and
146–162 peptide-specific WT lymphocytes produced detectable levels
of IL-6 and logically very little IL-6 was produced by AChR and
146–162 peptide-specific IL-6-/- lymphocytes (Fig. 5A). A significant level of
serum IL-6 was observed in WT, but not in IL-6-/- mice
(Fig. 5B), tested at various time points after immunizations
with AChR.
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The total axillary and inguinal LNC numbers (Fig. 6, B and D) and the
expression of cell surface markers, MHC class II, B220, B7-2, B7-1,
CD40, and CD4 were measured in IL-6-/- and WT mice 7 days
after a single immunization (Fig. 6A) with AChR in CFA and
at termination of the long-term experiment (Fig. 6C; 90 days
after the first immunization with AChR in CFA). On day 90, we also
detected CD3 expression. These data suggested that expansion of
lymphoid cells after AChR/CFA immunization was not impaired in
IL-6-/- mice. The total number of draining LNC was
comparable to those in AChR-immunized WT and IL-6-/- mice
both on days 7 and 90 (Fig. 6, B and D). There
were no obvious differences in the cell surface expression of MHC class
II, B220, B7-1, B7-2, and CD40 molecules between AChR-immunized
IL-6-/- and WT mice (Fig. 6C). The cell
surface molecule expression on normal B6 and IL-6-/- mice
(for day 90 age matched) is given in the legend to Fig. 6. MHC class
II, CD40, and B220 molecule expression were augmented and CD3 and CD4
molecule expression were reduced in both B6 and IL-6-/-
mice after AChR immunization. There was no change in the expression of
B7-2 and B7-1 molecules on day 90 after AChR immunizations. A similar
result was obtained in the second long-term experiment (data not
shown). In both B6 and IL-6-/- mice, B cells have
expanded and T cells are reduced after AChR immunization.
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Spleens from IL-6-/- and WT mice were isolated at
day 90 after primary immunization with AChR/CFA and prepared for
immunohistochemistry using PNA as the marker for GC. A
significant reduction in the number and size of GC in AChR-immunized
IL-6-/- mice was observed compared to WT mice (Table I and Fig. 7).
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Serum C3 levels of AChR-immunized WT and IL-6-/-
mice were measured by ELISA in serum samples obtained 2 wk after the
first, second, and third AChR immunizations. This complement component
was chosen for its key role in the complement activation cascade. C3
levels were found to be elevated in WT mice after the third
immunization. By contrast, serum C3 levels of IL-6-/-
mice revealed a slight downward, steady-state deviation from initial
levels (Fig. 8). The failure of
up-regulation of C3 could have contributed to the resistance to EAMG
induction in the IL-6-/- mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-, 
-, -, and 
-chains, CD4, and CD8 molecules
(29). B cells in the bone marrow and spleens of
IL-6-/- mice expressed B220, IgM, IgD, and CD23 within
normal ranges (29). The T cell-dependent IgM response to
vesicular stomatitis virus was normal, but the IgG response was 5–10
times reduced in IL-6-/- mice compared to B6 mice
(29). The polyclonal T cell responses were comparable
between IL-6-/- and WT mice (30).
IL-6-/- mice had a reduced Ag-specific, T
cell-proliferative response, but a normal response to mitogen
(30). IL-6-/- mice were resistant to
experimental autoimmune encephalomyelitis (EAE); however, in vivo IL-6
reconstitution into IL-6-/- mice could recover their
susceptibility to EAE (31). These data suggest that
IL-6-/- mice did not have embryonic or postnatal
developmental defects, but rather that IL-6 promotes both the cellular
and humoral immune responses. IL-6 has been shown to be involved in the
development of myelin oligodendrocyte glycoprotein-induced EAE
(30), Ag-induced arthritis (32), lupus in
NZB/W F1 mice (33), and
cyclophosphamide-induced autoimmune diabetes in nonobese diabetic/WEHI
mice (34). Approximately 15% of MG patients have thymomas (35, 36). Secondary lymphoid follicles or GC are found in hyperplastic MG thymi, and thymic epithelial cells from hyperplastic and neoplastic thymi express mRNA for AChR (36). Interestingly, IL-6 mRNA and protein were up-regulated in MG thymic epithelial cells (22). The IL-6 up-regulation in MG patients’ thymi might contribute to the development of thymic hypertrophy and GC formation because of its effect on B cell maturation and differentiation. The reduced size of the GC in IL-6-/- mice (37) further supports the above possibility. Therefore, our evidence on the critical role of IL-6 in EAMG development has important implications in MG pathogenesis, including the development of thymic hypertrophy and thymomas. We have not observed any histological changes in the thymi of AChR-immunized B6 mice (data not shown). Also, we do not know whether IL-6 is produced by thymic epithelial cells of AChR-immunized B6 mice. In EAMG the site of autosensitization is AChR draining lymph node and spleen in B6 mice. In MG the site of autosensitization could be the thymus and/or the peripheral lymphoid organs. Therefore, the thymic pathology seen in most MG patients may not be evident in B6 mice with EAMG. Whether thymic changes could be observed after a long time (4–6 mo) following AChR immunizations is yet to be studied in B6 mice.
There is strong evidence for a facilitative role for IFN- (8, 9) and IL-10 (38) in EAMG pathogenesis. IL-12 and
IL-18 also participate in the development of EAMG (10, 39). It appears that IL-6 in vivo could regulate production of
AChR and 146–162-specific IL-2, IFN-, and IL-10 production. It
is possible that down-regulation of IL-6 could suppress the production
of IL-2, IFN-, IL-10, and other cytokines which facilitate the
development and maintenance of the autoimmune response to AChR. TNFR
p55 and p75 gene KO mice were also resistant to EAMG and
blocking endogenous TNF function by soluble human recombinant TNFR:Fc
suppressed ongoing clinical EAMG, thus implicating TNF as an important
cytokine in EAMG pathogenesis (40, 41). We have also
demonstrated evidence for a role for lymphotoxin in the development of
EAMG (42). None of the lymphotoxin (TNF-)-deficient
mice immunized with AChR developed clinical EAMG and failed to switch
anti-AChR IgM isotype to IgG (42). From our published
and unpublished studies on various cytokines or their receptor KO mice,
we suggest that a cytokine hierarchy exists in the development of EAMG,
with IL-6, TNF, and IL-18 playing the hierarchal role in its
development. Dissecting out the role of these cytokines in the afferent
and effector phase of autoimmune response to AChR would pave the way
for effectively treating the disease by therapeutic down-regulation of
the cytokines involved in the effector phase. Further studies will
suggest whether IL-6 and TNF act in concert or one of them regulates
the production of the other.
The serum C3 levels of AChR-immunized IL-6-/- mice were reduced gradually, whereas those of B6 mice increased considerably after a brief period of decline. Serum C3 levels of AChR-immunized mice seldom drop off to very low levels after the second immunization, probably due to the fact that repetitive immunizations increase the rate of serum C3 consumption and therefore reduce serum C3 levels. However, the C3-producing cells of WT mice can easily cope with the increased demand and after a short period of time serum C3 levels even exceed the previous level. The lack of this capability of catching up with the increased demand kept serum C3 levels of IL-6-/- mice decreasing steadily despite successive immunizations. IL-6 has been proven to influence the GC development and Ab production (37). Moreover, complement C3 mRNA expression in GC has been shown to be regulated by IL-6 (37). It is therefore not surprising that serum C3 levels were reduced in IL-6-deficient mice. Additionally, IL-6 is important in B cell differentiation and plays a crucial role in T cell-dependent or -independent polyclonal IgG production (43). Therefore, IL-6 deficiency could also have led to reduced anti-AChR IgG production and caused a decline in circulating immune complex levels and consequently diminished activation of classical complement pathway and thus decreased C3 activation.
AChR-immunized IL-6-/- mice had a significantly reduced
anti-AChR level of IgG and IgG2 isotype compared to
AChR-immunized B6 mice. Thus, suppression of anti-AChR
IgG2 isotype could have contributed to the suppression of
EAMG in IL-6-/- mice. The importance of anti-AChR
IgG2b in EAMG pathogenesis was first demonstrated in our
previous study (7), in which tolerance to AChR 146–162
peptide significantly suppressed anti-AChR IgG2b Abs.
Furthermore, one should note that IgG2b is a
complement-fixing Ab. However, the primary IgM anti-AChR Ab
response was comparable between AChR-immunized IL-6-/-
and B6 mice. These data are consistent with the observation
in NZB/W F1 mice (44) and suggest that
AChR-immunized IL-6-/- mice have an impaired ability to
switch to the anti-AChR IgG isotype, especially IgG2b.
The reduction in serum C3 in IL-6-/- mice could have
contributed to the lower muscle AChR loss. Because anti-AChR IgG
Abs and C3 activation contribute to the autoimmune destruction of AChR,
therapeutic down-regulation of IL-6 could control the onslaught of an
autoimmune attack at the NMJ in EAMG and probably in MG. After
induction of EAMG/MG remission via IL-6 down-regulation by IL-6
antagonists, Ag-specific tolerance (e.g., high-dose AChR T cell epitope
tolerance (7)) could be used as a maintenance therapy. A
similar therapeutic approach could be attempted in other Ab-mediated
autoimmune diseases.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Neurology, University of Texas Medical Center, Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9036.
3 Address correspondence and reprint requests to Dr. Premkumar Christadoss, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070. E-mail address: pchrista{at}utmb.edu
4 Abbreviations used in this paper: MG, myasthenia gravis; EAMG, experimental autoimmune MG; AChR, acetylcholine receptor, NMJ, neuromuscular junction; GC, germinal center; LNC, lymph node cell; PNA, peanut agglutinin, WT, wild type; EAE, experimental autoimmune encephalomyelitis.
Received for publication February 5, 2002. Accepted for publication May 14, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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therapy is effective in suppressing the clinical experimental myasthenia gravis. J. Immunol. 157:5675.[Abstract]
(IFN-) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J. Exp. Med. 186:385. receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis. J. Immunol. 162:3775.. Microbiol. Immunol. 40:443.[Medline]
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) and IL-6-deficient (•) mice 2 wk after the
first, second, and third immunizations with 20 µg AChR/CFA. The serum
C3 levels were determined by ELISA and the data are expressed as mean
OD values ± SE for each group.