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*
Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Division of Human Retrovirology, Dana Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115;
Epimmune, San Diego, CA 92121;
§
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, and Veteran’s Administration Medical Center, Palo Alto, CA 94304.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In support of the molecular mimicry model, peptides derived from measles, influenza, adenovirus, and EBV that share linear sequence homology to MBP have been identified (12). Furthermore, immunization of rabbits with a peptide derived from the hepatitis B viral polymerase, shown to have linear sequence homology with MBP, resulted in CNS inflammation but not clinical EAE (13). More recently, microbial peptides that share structural homology with an epitope of MBP (MBP84–102) were identified using motifs to search a protein database. Some of these peptides were then shown to activate human MBP84–102-specific T cell clones in vitro (14). Peptides that activate a human MBP-specific T cell clone have also been identified using a random peptide library approach (15).
Although it has been shown for B cell-mediated autoimmune disease that immunization of animals with streptococcal membrane Ags alone results in autoimmune myocarditis (16), it has not been conclusively shown for T cell-mediated autoimmune disease that immunization with cross-reactive Ags alone can induce clinical disease. To investigate the potential role of cross-reactive environmental Ags in the development of autoimmune disease, we performed a detailed analysis of the structural requirements for TCR recognition and MHC binding of PLP139–151, an encephalitogenic epitope of myelin proteolipid protein that induces severe EAE in SJL (H-2s) mice. Based on this analysis, we created motifs to search the SwissProt database for natural analogues of PLP139–151 and identified several bacterial and viral peptides that elicit immune responses that cross-react with PLP139–151. None of these peptides was able to induce clinical autoimmune disease in SJL mice on their own. However, immunization with one viral peptide predisposed mice for the development of EAE following active immunization with a suboptimal dose of PLP139–151. These results suggest that the induction of autoimmune disease via the mechanism of molecular mimicry may require a more complex series of events than previously postulated.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female SJL/J mice (4–6 wk) were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed under VAF conditions. They were maintained in accordance with the guidelines of the Committee on Animals of Harvard Medical School.
Ags
PLP139–151 (HSLGKWLGHPDKF), PLP139–151 altered peptides, and neuraminidase101–120 (NASE101–120; EALVRQGLAKVAYVYKPNNT) were synthesized by Dr. R. Laursen on a Milligen model 9050 synthesizer using F-moc chemistry. Natural analogues of PLP139–151 and pigeon cytochrome c88–104 (ADLIAYLKQATAK) were synthesized by Quality Controlled Biochemicals (Hopkinton, MA). Peptide purity was determined by HPLC, and peptide identity was confirmed by mass spectroscopy.
Culture media
T cell hybridomas (2) were cultured in DMEM supplemented with sodium pyruvate (1 mM), HEPES (1 mM), L-glutamine (2 mM), penicillin (100 U/ml), streptomycin (100 U/ml), gentamicin sulfate (0.1 mg/ml; BioWhittaker, Walkersville, MD), and 5% FBS (HyClone, Logan, UT). HT-2 cells were cultured in DMEM supplemented with sodium pyruvate, L-glutamine, penicillin, streptomycin, gentamicin sulfate, nonessential amino acids (0.1 mM), MEM essential vitamin mixture (1x; BioWhittaker), asparagine (0.1 mM), folic acid (0.1 mg/ml), 2-ME (5 x 10-5 M; Sigma, St. Louis, MO), 10% FBS (HyClone), and 10% T cell growth factor (T-stim, Collaborative Biomedical Products, Bedford, MA). Lymph node cells (LNC) were cultured in DMEM (as described above) without FBS.
Induction and assessment of EAE
Mice preimmunized with natural PLP analogues or control peptides (detailed in Results) received 100 µg of peptide emulsified in CFA (Difco, Detroit, MI) supplemented with Mycobaterium tuberculosis H37RA (400 µg/mouse; Difco) s.c. in the flanks. Mice were then challenged 2 to 4 wk later by injection with 100 µg of the relevant peptide emulsified in CFA supplemented with M. tuberculosis H37RA s.c. in the flanks. In the case of the challenge with PLP139–151, three different batches of peptide were used. Each batch was titrated to determine an optimal and a suboptimal dose (batch AI: suboptimal dose, 10 µg; optimal dose, 50–100 µg; batch CP40: suboptimal dose, 25 µg; optimal dose, 50–100 µg; batch CP114: suboptimal dose, 100 µg; optimal dose, >200 µg). On days 0 and 3, mice received 100 ng of pertussis toxin (List, Campbell, CA) or 109 heat-killed Bordetella pertussis bacilli (pertussis vaccine lot 285, Massachusetts Public Health Biologic Laboratories, Boston, MA) i.v. Mice preimmunized with PLP139–151 received 5 µg of peptide (batch QCB: optimal dose, 50–75 µg) emulsified in CFA supplemented with M. tuberculosis H37RA s.c. in the flanks. Mice were then challenged 2 wk later with 100 µg of natural PLP analogues or control peptides in CFA supplemented with M. tuberculosis H37RA s.c. in the flanks. On days 0 and 3, mice received 50 to 100 ng of pertussis toxin as described above. For the superantigen experiments, mice preimmunized with natural PLP analogues or control peptides received 40 µg of enterotoxin (SEA or SEB; Toxin Technology, Sarasota, FL) i.p. in PBS on day 14 along with 100 ng of pertussis toxin i.v. on days 0 and 3. For the LPS experiments, mice preimmunized with natural PLP analogues or control peptides received 50 µg of LPS (Sigma) i.p. in PBS on day 14. All mice were examined daily beginning on day 9 for disease, which was assessed clinically according to the following criteria: 0, no disease; 1, limp tail; 2, hindlimb weakness; 3, hindlimb paralysis; 4, hindlimb plus forelimb paralysis; and 5, moribund or dead. When animals were moribund or at the end of the experiment (generally day 30), they were sacrificed, and brains and spinal cords were fixed in 10% formalin, processed for histologic analysis, and evaluated as previously described (17).
Adoptive transfer of EAE
Mice were immunized s.c. at five sites with 100 µg of HAE, MHV, or PLP139–151 emulsified in CFA (Difco) containing a total of 250 µg of M. tuberculosis H37RA. Draining lymph nodes were harvested 10 days later. LNCs were cultured at 5 x 106/well in 24-well plates in the presence of HAE (20 µg), MHV (10 µg), or PLP139–151 (20 µg) for 4 days, then harvested and purified over a Ficoll-Hypaque gradient. Cells were resuspended in PBS at 108/ml and injected i.v. into mice (0.1 ml, 107/mouse). Recipient mice also received 100 ng of pertussis toxin (List) i.v. on days 0 and 3.
In vitro proliferation assays
Activation of T cell hybridomas. T cell hybridomas (5 x 104) were cultured in triplicate in 96-well round-bottom plates with 5 x 105 irradiated SJL spleen cells and various concentrations of Ag in a final volume of 0.2 ml. After 24 h, 0.1 ml of supernatant was transferred to 96-well flat-bottom plates, and the IL-2/IL-4-dependent HT-2 cell line was added at 104 cell/well. After 16 h, the cells were pulsed with 1 µCi of [3H]thymidine/well. Plates were harvested 6 h later. [3H]thymidine incorporation was determined in a Wallac scintillation counter (model 1250, Gaithersburg, MD).
LNC proliferation. Mice were immunized s.c. at five sites with 100 µg of Ag emulsified in CFA (Difco) containing a total of 250 µg of M. tuberculosis H37RA. Draining lymph nodes were harvested 10 days later. LNCs (4 x 105/well) were cultured in triplicate in 96-well round-bottom plates in the presence of various concentrations of peptide for 48 h and pulsed with 1 µCi of [3H]thymidine for the last 16 h. [3H]thymidine incorporation was determined as described above.
In vitro cytokine assays
Supernatants were collected from LNCs 40 h after activation
in vitro. The concentrations of IL-2, IL-4, IL-10, IFN-
, and TNF-
were measured by quantitative capture ELISA according to the guidelines
of the manufacturers. In brief, purified rat mAb to mouse IL-2 (clone
JES6-1A12), IL-4 (clone BVD4-1D11), IL-10 (clone JES5-2A5), IFN-
(clone R4-6A2), and TNF- (clone MP6-XT22) were obtained from
PharMingen (San Diego, CA) and were used to coat ELISA plates (Immulon
4, Dynatech, Chantilly, VA). Recombinant mouse cytokines (IL-2, IL-4,
IL-10, IFN-, and TNF-; PharMingen) were used to construct
standard curves, and biotinylated rat mAb to mouse IL-2 (clone
JES6-5H4), IL-4 (clone BVD6-24G2), IL-10 (clone SXC-1), and IFN-
(clone XMG1.2; PharMingen) were used as the second Ab. Detection of
TNF- was performed with biotinylated polyclonal rabbit IgG
(PharMingen). Plates were developed with TMB microwell peroxidase
substrate (Kirkegaard and Perry, Gaithersburg, MD) and read after the
addition of stop solution at 450 nm using a model 3550 microplate
Reader (Bio-Rad, Hercules, CA).
IAs binding assay
Purified IAs molecules (
5–10 nM) were incubated
with 5 nM 125I-radiolabeled peptide ROIV
(YAHAAHAAHAAHAAHAA) (18) for 48 h in PBS, which contained 5% DMSO
and 0.5% Nonidet P-40 in the presence of PMSF (1 mM),
1,10-phenanthroline (1.3 mM), pepstatin A (73 µM), EDTA (8 mM),
N-ethylmalemide (6 mM), and
Na-p-tosyl-L-lysine chloromethyl ketone (200
µM). IAs peptide complexes were separated from free
peptide by gel filtration on Sephadex G-50 or TSK columns. To test the
binding of PLP139–151 analogues, analogues were added to a
mixture of IAs molecules and radiolabeled standard peptide
before incubation. Analogs typically were tested at concentrations
ranging from 1.2 to 120 ng/ml. The concentration yielding 50%
inhibition (IC50) of binding of the radiolabeled peptide
was measured by plotting the percentage of inhibition vs the
concentration of analogue.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our previous studies using a panel of altered peptides bearing
alanine or conservative substitutions at each residue of the
PLP139–151 peptide (HSLGKWLGHPDKF) allowed the
assignment of W144 as the primary TCR contact residue, and L141 and
H147 as the secondary TCR contact residues for a panel of five
PLP139–151-specific T cell clones/hybridomas (2E5, 4E3,
5B6, 7A5, and SPL1.1) (19). Direct IAs binding and blocking
studies using the same panel of altered peptides allowed the assignment
of L145 and P148 as MHC binding residues
(19). To determine the degree of variability that could be accommodated
at each position along this peptide determinant, altered peptides
bearing various amino acid substitutions of the peptide core (residues
141–148) were synthesized and tested for their ability to activate the
panel of five T cell hybridomas. The data from the 4E3, 5B6, and 7A5
hybridomas are shown, since they represent the three different patterns
of reactivity that were observed (Table I
). The 5B6 hybridoma did not
tolerate any of the substitutions tested at residue 141. Likewise, the
7A5 hybridoma did not tolerate any substitutions at residue 147. All
three hybridomas tolerated to varying degrees substitutions at residues
142, 143, 145, and 148. Substitutions at residue 144 were not tolerated
by any of the hybridomas tested with the exception of P144 and Y144,
which stimulated 5B6, and Q144, which stimulated 7A5. At residue 146,
the conservative substitution of alanine for glycine was stimulatory
for all three hybridomas, whereas the conservative substitution of
valine for glycine was not tolerated. This suggests that substitution
of the glycine at residue 146 affects recognition of the peptide either
directly or indirectly by affecting the overall conformation of the
peptide in the MHC binding groove. Interestingly, some of the
substitutions tested were heteroclitic compared with the native
determinant.
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). Most substitutions, with the exception of A141, K141, A145,
A147, and K147, exhibited decreased binding compared with that of
native PLP139–151. The poor binding of all nonalanine
substitutions at residue 148 substantiates the assignment of this
residue as an MHC binding residue. Furthermore, the poor binding
exhibited by some of the substitutions at residues 142 and 143 suggests
that the residues at these positions may play a role either directly or
indirectly in binding to the MHC. Identification of natural analogues of PLP139–151
Based on the patterns of activating and nonactivating
substitutions and the MHC binding data, three motifs were created for
the 4E3, 5B6, and 7A5 T cell hybridomas to search for peptides bearing
structural homology to PLP139–151 (Fig. 1) in the SwissProt database using
Genetics Computer Group Software. Substituted peptides were scored as
activating if the proliferation observed was >20% of the
proliferation observed with native Ag. Substituted peptides that were
similar in charge, size, or chemical nature to activating substitutions
were included in the motifs. At positions where all the substitutions
tested were activating, no restriction was placed. These motifs were
then used to search the SwissProt database for peptide sequences
bearing structural homology to PLP139–151. The 4E3, 5B6,
and 7A5 motifs yielded 737, 1839, and 27 positives, respectively. From
the 2603 sequences, 33 sequences were chosen for further study (Table II). These sequences were chosen by two
criteria: the degree of sequence similarity to PLP139–151
and their origin, i.e., known pathogens or self peptides. Of the 33
sequences, 10 were identified using the 4E3 motif, and 23 were
identified using the 5B6 motif.
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First, the 33 peptides were tested for the ability to activate the
panel of PLP139–151-specific T cell hybridomas. None of
the 33 peptides was stimulatory for the panel of five
PLP139–151-specific T cell hybridomas (data not shown).
The peptides were then tested for the ability to immunize SJL
(IAs) mice. Five peptides, from murine hepatitis virus
(MHV), Haemophilus influenzae (HAE), Escherichia
coli (ECO-1), Salmonella typhimurium (SAL), and
Candida albicans (CAN), were able to elicit lymph node
responses that cross-reacted with PLP139–151, in that LNC
from mice immunized with these analogue peptides also reacted to
PLP139–151 in vitro (Table II). Of these five, MHV and HAE
gave the most potent cross-reactive immune responses. To further
analyze the cross-reactive T cell responses induced by these peptides,
a detailed dose-response analysis was undertaken. The data presented in
Figure 2 confirm that immunization with
MHV and HAE can induce T cells that cross-react with
PLP139–151. Moreover, cross-reactivity to HAE was seen in
the LNC of mice immunized with PLP139–151,
suggesting that the T cell repertoires that respond to HAE and
PLP139–151 overlap (Fig. 2). Thus, we chose to focus on
these two peptides for the rest of our study.
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in response to both MHV
and PLP139–151. HAE-immunized LNC made IL-2 and
IFN- in response to HAE, but made only IL-2 in response to
PLP139–151.
PLP139–151-immunized lymph nodes made IL-2 and
IFN- in response to both PLP139–151 and HAE
(Table III). The response to MHV in these
cells may be too low to detect any Ag-specific cytokine. The cytokine
production of LNC from mice immunized with an epitope of Theiler’s
murine encephalomyelitis virus (TMEV-2) that was identified in our
search is shown as a control. Since Th1 T cells have been shown to be
autopathogenic, the production of Th1 cytokines by MHV- and
HAE-immunized LNC that cross-react with
PLP139–151 suggested that these cells have the
potential to be encephalitogenic.
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The five analogues (MHV, HAE, ECO-1, SAL, and CAN) that induced immune responses cross-reactive with PLP139–151 varied in their degree of linear sequence homology to PLP139–151. HAE had the highest degree of linear sequence homology, with six residues in common with PLP139–151; ECO-1 and SAL had four residues in common; and MHV and CAN had three residues in common. All the analogues except CAN had a tryptophan in the center of the peptide sequence. As the tryptophan in the center of the PLP139–151 sequence is used as the primary TCR contact residue for PLP139–151-specific T cells, it is likely that the tryptophan in the center of the analogue peptide sequences is used as the primary TCR contact residue by T cells that recognize the analogue peptides and cross-react with PLP139–151. Interestingly, the most notable feature of both the MHV and HAE sequences is that they share a stretch of three residues (KWL) in the center of the peptide with PLP139–151. This may explain in part why MHV and HAE produced the most potent PLP139–151 cross-reactive immune responses.
The five analogue sequences also varied widely in their binding to
IAs (Table II). In fact, some of the analogues that failed
to elicit a PLP139–151 cross-reactive immune
response bound to the MHC more strongly than the five analogues that
gave positive results. Thus, there appears to be no strong correlation
between the MHC binding affinity and the ability to induce a
cross-reactive immune response.
In vivo effects of exposure to natural analogues of PLP139–151
To test whether MHV and HAE peptides could induce EAE, we
immunized SJL mice with these peptides and observed them for the
development of EAE for a period of 30 to 60 days. Immunization with MHV
or HAE in CFA with pertussis toxin did not induce clinical or
histologic EAE (Table IV). As
superantigens have been postulated to play a role in triggering
autoimmune disease (20, 21) and have been shown to trigger relapses of
EAE (22, 23), we postulated that two independent events, immunization
with a cross-reactive peptide followed by expansion by superantigen,
may induce EAE. Mice were immunized with either MHV or HAE and were
challenged 2 wk later with SEA or SEB. None of the mice in these groups
developed clinical disease. A few mice in the MHV group treated with
SEA or SEB had low numbers of inflammatory lesions in the CNS. As LPS
has been shown to promote a proinflammatory milieu and viral
penetration of the CNS (24), we immunized mice with either MHV or HAE
and challenged them 2 wk later with a dose of LPS. None of the mice in
these groups exhibited either clinical or histologic disease. Thus,
nonspecific immune system-activating events following exposure to
cross-reactive peptides were not able to trigger autoimmune disease in
mice primed with MHV or HAE.
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). The
incidence of EAE in the MHV-preimmunized mice (13 of 20) was
significantly higher (p < 0.01) than that in
mice that received a preimmunization with either of two different
IAs binding control peptides,
NASE101–120 or pigeon cytochrome
c88–104 (4 of 18). We also preimmunized mice
with an equivalent concentration of PLP139–151.
In this group, 40% of the animals (6 of 15) developed clinical disease
by day 21. These mice were not challenged with a suboptimal dose of
PLP139–151. Although preimmunization with MHV
increased disease incidence, it did not accelerate the day of disease
onset or enhance the severity of clinical disease in mice that did
develop disease. These mice also showed large numbers of inflammatory
foci in the CNS, confirming the presence of typical EAE (Table IV).
Four of eight HAE-preimmunized mice also developed EAE, although this
incidence is not significantly different compared with that in
controls.
To elucidate the mechanism further, we established short term T cell
lines from mice immunized with MHV, HAE, or
PLP139–151. LNCs from mice immunized with MHV
were activated with MHV or PLP139–151, LNCs from
mice immunized with HAE were activated with HAE or
PLP139–151, and LNCs from mice immunized with
PLP139–151 were activated with
PLP139–151. After 4 days in culture, T cell
blasts were harvested and transferred into naive mice. Mice that
received T cells from MHV- or HAE-primed mice and activated in vitro
with PLP139–151 developed clinical EAE (Fig. 3), whereas the mice that received T
cells activated in vitro with the natural analogue peptides did not
develop disease. This demonstrates that both in vivo and in vitro,
expansion of MHV- or HAE-specific T cells by
PLP139–151 can induce EAE.
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). Taken together the in vivo data suggest that although
cross-reactive Ags cannot induce EAE on their own, prior exposure to a
cross-reactive Ag can lower the threshold for induction of EAE by
autoantigenic peptides. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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None of the cross-reactive peptides we studied was able to induce EAE on their own, suggesting that the activation and expansion of the cross-reactive repertoire do not necessarily result in a disease-inducing repertoire. This finding argues against a simple molecular mimicry model of autoimmune disease and emphasizes that cross-reactivity with the autoantigen and the ability to produce Th1 cytokines may not be sufficient to break self tolerance and induce autoimmunity.
Furthermore, Ag nonspecific stimulation by the administration of superantigens was insufficient to induce disease in MHV- and HAE-primed mice. Because the cross-reactive T cells in these mice express multiple different Vß genes (data not shown), superantigen may not expand the appropriate Vß-expressing T cell subset required for disease to ensue. Similarly, treatment with LPS did not induce disease in MHV- and HAE-primed mice. This suggests that the inflammatory milieu that results from peripheral exposure to LPS does not render MHV- and HAE-reactive T cells encephalitogenic.
We were able to observe clinical and histologic disease in mice that
had been primed with MHV and then treated with a suboptimal dose of
PLP139–151. This raises an important issue: that
the selective expansion of pathogenic autoantigen-specific T cells from
a cross-reactive T cell repertoire may be essential to break the
threshold for induction of autoimmune disease. The transfer of disease
by cells from mice immunized with MHV or HAE and restimulated in vitro
with PLP139–151 (Fig. 3) confirms that T cells
are sufficient to mediate disease. It also strongly supports the
conclusion that selective expansion of cells that are cross-reactive
with PLP139–151 is necessary for the induction
of disease. Furthermore, although the increase in disease we observed
in HAE-preimmunized mice was not statistically significant, the EAE
observed in the mice that received HAE-primed T cells reactivated with
PLP139–151 suggests that HAE does lower the
threshold for the induction of autoimmune disease.
Although infection with neurotropic agents and molecular mimicry are the two proposed mechanisms by which environmental agents can induce EAE, our data raise a third possibility. First, exposure to an environmental Ag bearing structural homology to self primes and expands a T cell repertoire cross-reactive with self. No autoimmune disease may develop due to either low frequency of cells that are cross-reactive with self in the initial pool of responding T cells or to regulatory mechanisms that keep autoaggressive responses in check. However, a second event that specifically expands the self-reactive cells from this initial pool allows the cross-reactive T cells to induce clinical disease. This second event could be one that leads to tissue damage, thereby releasing autoantigen, or one that allows for extravasation of cross-reactive cells into the target organ. One can envision multiple different scenarios that would fit this model. For example, an infection with a neurotropic pathogen that expresses peptides that bear structural homology to self primes a cross-reactive T cell repertoire. Subsequent damage to myelin results in the release of self Ag that selectively expands autoreactive cells from this cross-reactive T cell repertoire. This would result in the establishment of a chronic autoimmune neuroinflammatory disease. A second scenario involves exposure to any environmental agent that bears structural homology to self, resulting in a primed cross-reactive T cell repertoire. Subsequent infection with a neurotropic agent that damages myelin and allows the release of self Ag into the periphery then selectively expands the self-reactive cells from the previously primed cross-reactive T cell repertoire. The pathogens responsible for priming cross-reactive T cell responses may be different from the pathogen responsible for releasing self Ag depending on the MHC haplotype and the T cell repertoire of a given individual. This is consistent with the lack of a strong correlation between any single pathogen and multiple sclerosis etiopathogenesis.
We cannot exclude the possibility that the present study may have failed to identify a ligand that when used alone would be sufficient to induce autoimmune disease, but given the increasing data supporting plasticity in the autoreactive T cell repertoire (14, 15) autoimmune disease would be much more prevalent if cross-reaction with self alone was sufficient to cause disease. Due to their cross-reactivity with self Ag and production of proinflammatory cytokines, it would be predicted that cross-reactive environmental Ags would induce disease, which is not the case. This raises an important issue that activation and expansion of a cross-reactive T cell repertoire are not sufficient to induce autoimmune disease. In conclusion, our data support a role for environmental Ags in predisposing toward autoimmune disease and suggest that infectious agents that affect target organs may induce autoimmune disease by releasing self Ag that then selectively expands autoreactive T cells from a pre-existing or expanded cross-reactive T cell repertoire.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 77 Louis Pasteur Ave., Boston, MA 02115. E-mail address:
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; CNS, central nervous system; MBP, myelin basic protein; NASE, neuraminidase; LNC, lymph node cells; IC50, 50% inhibiting concentration; SEA, staphylococcal enterotoxin A; SEB, staphylococcal enterotoxin B.
Received for publication February 6, 1998. Accepted for publication May 29, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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