| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
*
Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Martinsried, Germany;
Department of Neuroimmunology, Brain Research Institute University of Vienna, Vienna, Austria;
Department of Neurology, University of Graz, Graz, Austria; and
§
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A major target for the pathogenic autoimmune response in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), is the myelin oligodendrocyte glycoprotein (MOG). MOG is the only myelin autoantigen known to induce both a demyelinating autoantibody response (3, 4) and an encephalitogenic CD4+ T cell response (5, 6, 7, 8) in animals with EAE. The demyelinating potential of the MOG-specific Ab response has been studied extensively both in vivo and in vitro (4, 9, 10), and, in MOG-induced EAE, this humoral response acts synergistically with the encephalitogenic T cell response to induce a demyelinating pathology similar to that in MS (4, 11, 12, 13, 14). Although the encephalitogenic MOG-specific CD4+ T cell response initiates the recruitment of immune effector cells into the CNS and disrupts the blood brain barrier, demyelination in the rat is dependent on the presence of anti-MOG autoantibodies (4). These Abs bind to MOG exposed on the myelin surface (15) and mediate demyelination by a combination of complement and cell-mediated immune effector mechanisms (16, 17, 18). The observation that both MOG-specific T cell (19, 20) and Ab responses (21) are enhanced relative to other myelin Ags in MS suggests that demyelination involves a similar combination of immune effector mechanisms in the human disease. A concept supported by the recent demonstration that anti-MOG-Abs colocalize with myelin debris in actively demyelinating MS lesions (13, 22). However, the mechanism(s) that may initially disrupt self-tolerance to MOG in MS are obscure.
Intriguingly, sequence homologies involving its extracellular Ig-like
domain (MOGIgd) identified MOG as a member of an
extended family of "B7-like"proteins (23). Of
particular interest was the finding that the highest level of sequence
identity, 
50%, was with a homologous extracellular Ig domain of
butyrophilin (BTN) (24), a major protein of the milk fat
globule membrane (MFGM) (25, 26). This observation led us
to speculate that immunological cross-reactivity or "molecular
mimicry" with BTN may influence the function of the MOG-reactive
autoimmune repertoire.
In the current study, we report that this is indeed the case. In the context of a permissive MHC haplotype, we show that the CD4+ T cell response to BTN and MOG is mutually cross-reactive. Therefore, sensitization with native BTN can initiate an inflammatory response in the CNS mediated by a class II MHC-restricted MOG-reactive T cell response. Conversely, both intranasal and i.v. treatment with BTN peptide can abrogate MOG-induced EAE. The observation that transmucosal exposure to a BTN peptide can modulate disease activity in MOG-induced EAE suggests that, in the context of an appropriate HLA haplotype, dietary exposure to BTN may modulate the pathogenic autoimmune response to MOG in MS.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Dark Agouti (DA) and Brown Norway (BN) rats (120–200 g) were obtained from Charles River Breeding Laboratories (Sulzfeld, Germany), and Lewis (LEW) rats were obtained from the animal facility of the Max-Planck Institute for Biochemistry (Martinsried, Germany). CFA, IFA, and heat-killed Mycobacterium tuberculosis (H37Ra) were purchased from Difco (Detroit, MI). Purified protein derivative was purchased from the State Serum Institute (Copenhagen, Denmark). Recombinant MOGIgd (amino acids 1–120) (12) and BTNIgV (amino acids 27–144 notation including signal sequence) (26) corresponding to the N-terminal Ig-like domains of the two proteins with a C-terminal hexahistidine tag were expressed in Escherichia coli. The recombinant proteins were purified by chromatography on Ni-NTA agarose to a purity of >95% as assessed by SDS-PAGE (Qiagen, Chatsworth, CA) and stored at -20°C. MFGM was purified from fresh bovine milk as described previously (25). Synthetic peptides were purchased from Genosys (Cambridge, U.K.).
Immunization protocols and generation of Ag-specific T cell lines
Rats were immunized s.c. at the base of the tail with 100 µg Ag emulsified in CFA containing 225 µg of heat-killed M. tuberculosis (H37Ra) in a total volume of 100 µl. Ag-specific T cell lines were generated as described previously (12). Briefly, the draining lymph nodes were removed 10 days postimmunization (d.p.i.), and a single cell suspension was cultured for 72 h at a concentration of 107 cells/ml in DMEM supplemented with glutamine, penicillin, streptomycin, sodium pyruvate, essential amino acids (Life Technologies, Rockville, MD), and 1% rat serum in the presence of the selecting Ag (20 µg/ml). T cell blasts were then isolated by density gradient centrifugation and propagated for a further 5–10 days in medium containing IL-2. Ag-specific T cell lines were subsequently maintained by cycles of Ag-specific restimulation using irradiated (5000 rad) syngeneic thymus cells as APCs, followed by expansion in IL-2-containing medium.
Cytofluorometric analysis was performed using samples of 2 x 105 viable cells washed with PBS containing 0.2% BSA and 10 mM NaN3 and incubated with the primary mAb for 1 h on ice. After washing, the cells were stained with fluorescein-conjugated goat anti-mouse IgG (Dianova, Hamburg, Germany) for 1 h on ice. After removing unbound fluorescein-conjugate by washing, the cells were analyzed using a fluorescence-activated cell sorter (FACScan; Becton Dickinson, Heidelberg, Germany). A live gate was obtained by incubating the cells in PBS containing propidium iodide.
Proliferation assays were performed in flat-bottom 96-well tissue culture plates in a total volume of 200 µl using either 5 x 105 lymph node cells, or 2 x 104 T line cells plus 5 x 105 syngeneic, irradiated (5000 rad) thymus cells as APCs. Ag-specific proliferation was assessed by the incorporation of [3H]thymidine (10 µCi/well) during the final 16 h of a 72-h culture period using a Packard (Meriden, CT) Matrix 96 Direct ß counter.
EAE induction and treatment
Female DA rats (6–8 wk old) were treated intranasally daily for a period of 10 days with a dose of 50 µg of Ag (1 mg/ml in water), which was injected using a micropipette (25 µl per nostril). Three days after the last intranasal application of Ag, the animals were injected with 100 µg of MOGIgd in IFA. Adoptive transfer experiments were performed using activated T cell blasts isolated after 72 h restimulation with Ag in vitro. The T cell blasts were suspended in a volume of 1 ml DMEM and injected into the tail vein of female DA rats (6–8 wk old). Treatment with high-dose soluble Ag was performed using 500 µl of Ag (2 mg/ml in DMEM) injected in the tail vein 2 and 4 days after T cell transfer. Animals were weighed and examined daily for clinical signs of EAE that was scored on a scale of 0–5 as described previously.
Histopathological analysis
Histological evaluation was performed on paraformaldehyde-fixed, paraffin-embedded sections of brains and spinal cords sampled at various time points of disease. Paraffin sections were stained with hematoxylin-eosin, Luxol fast blue, and Bielschowsky silver impregnation to assess inflammation, demyelination, and axonal pathology. In adjacent serial sections, immunohistochemistry was performed with Abs against macrophages/activated microglia (ED1; Serotec, Oxford, U.K.) or T cells (W3/13; Seralab, Sussex, U.K.). Bound primary Ab was detected with a biotin-avidin technique as previously described in detail (27). Control sections were incubated in the absence of primary Ab or with nonimmune rabbit serum.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
LEW, BN, and DA rats were immunized with either MFGM, or
alternatively BTNIgV in CFA and monitored for the
development of clinical and/or histopathological evidence of EAE.
Strikingly, although neither immunogen induced clinical disease in
these rat strains, histopathological analysis identified a subclinical
inflammatory response in the CNS of DA rats that was absent in DA
controls immunized with PBS/CFA. This pathologic response was
characterized by the formation of scattered meningeal and perivascular
infiltrates of T cells and macrophages throughout the CNS (Fig. 1
a). This is in contrast to
the pathology of MOG-induced EAE in the rat that is dominated by
Ab-mediated demyelination (28). In contrast, neither
immunogen induced any CNS pathology in the other two rat strains.
Moreover, no pathology developed in the CNS of DA rats immunized with
PBS/CFA. These observations indicate that BTNIgV,
a major component of MFGM, can act as a strain-specific encephalitogen
in the rat.
|
To test the hypothesis that molecular mimicry with
MOGIgd at the level of the T cell response was
responsible for the CNS pathology induced by BTN, we investigated the
ability of BTN and synthetic BTN peptides to stimulate a panel of
encephalitogenic class II MHC-restricted MOG-specific T cell lines
(TCL) derived from LEW (MHC RT1l), BN (MHC
RT1n), and DA (MHC RT1av1)
rats. The encephalitogenic epitopes recognized by these TCLs are
strain-specific and together span 70% of the
MOGIgd sequence (Table I).
|
a).
|
a; Table I;
Stefferl and Schubart, unpublished observations). We investigated this
further using synthetic peptides corresponding to amino acids 74–90 of
the IgV-like domains of the two Ags. Strikingly both
MOG74–90 and BTN74–90
stimulated the MOG-specific TCL to a similar extent, inducing a
proliferative response similar to that obtained with the recombinant Ag
and the longer peptides (Fig. 2a). Active immunization with BTN induces an encephalitogenic MOG-reactive T cell response
Although the above observations demonstrate that the DA MOG-specific T cell response exhibits molecular mimicry with BTN in vitro, it remained uncertain whether this was responsible for the inflammatory pathology induced by active immunization with BTN in vivo. Therefore, we examined the BTN-specific T cell repertoire for evidence of a cross-reactive and encephalitogenic response to MOG74–90 using short-term TCLs obtained from BTNIgV immunized donors. Ag-specific TCLs were selected in vitro using a combination of the peptides BTN63–87 and BTN76–100 as the selecting Ag. After two rounds of restimulation in vitro, the encephalitogenic capacity of the TCLs was assessed by adoptive transfer into naive syngeneic recipients.
The i.v. injection of 5 x 106 to
107 T line cells induced an intense inflammatory
response in the CNS of all recipients (Fig. 1b), associated
with weight loss and hind limb paraparesis. Immunohistochemical
analysis of the lesions revealed that they consisted of large numbers
of T cells concentrated in the perivascular space. Migration of
infiltrating T cells into the parenchyma was restricted and the
recruitment of ED1+ macrophages into the CNS was minimal
(Fig. 1, c and d), a pathology similar to that
described previously in the Lewis rat following the adoptive transfer
of MOG-specific T cells (6).
The observation that
BTN63–87/BTN76–100-selected
TCLs proliferate in vitro in response to
MOG74–90 and MOGIgd, as
well as the selecting peptides and BTN, confirmed that the
pathogenicity of this T cell population could be attributed to
cross-reactivity with MOG (Fig. 2b). FACS analysis revealed
that the TCLs consisted predominantly (>90%) of
CD4+, CD45RO-,
ßTcR+ T cells (data not presented), and
blocking assays using the mAbs OX6 (RT1B), OX17 (RT1D), and OX18 (class
I MHC) demonstrated that their Ag-specific response to
B74–90 and M74–90 was
class II MHC (RT1B)-restricted (Fig. 2c). Therefore, BTN can
be processed and presented in vivo to stimulate a mutually
cross-reactive and encephalitogenic class II MHC-restricted T cell
response to MOG in the DA rat.
BTN peptide suppresses adoptively transferred MOG-EAE
It is now appreciated that molecular mimicry can induce either a pathogenic autoimmune response or, conversely, tolerance, depending on variables such as the route of sensitization, dose, and adjuvant effects (29). This is of particular relevance for peptides derived from ingested Ags, as these will cross the gut mucosal surface and provide tolerogenic signals in the periphery (30, 31). Therefore, could mimicry with BTN be exploited to suppress an autoaggressive MOG-reactive T cell response and abrogate clinical disease in EAE?
The tolerogenic potential of BTN74–90 was first
investigated in EAE induced by the adoptive transfer of
MOG74–90-specific T cells. In the DA rat, a dose
of 5 x 106
MOG74–90-specific T cells induced a maximal
clinical score of 2.5 ± 0.3 four days after transfer. Disease
severity was dramatically attenuated following i.v. treatment with
high-dose BTN74–90 given on days 2 and 4
following T cell transfer (Fig. 3). The
same treatment protocol using the nominal MOG peptide ligand
MOG74–90 was even more effective and completely
abrogated clinical disease (Fig. 3). This differential in vivo effect
was not reflected by the in vitro proliferative response of
MOG74–90-specific T cells to
MOG74–90 and BTN74–90,
which was similar over a wide concentration range (Fig. 2d).
We are currently investigating whether this reflects differences in the
pharmacological characteristics of the peptides in vivo, or
differential effects of the BTN peptide on individual
MOG74–90-specific T cell clones within the
TCLs.
|
; Stefferl and Schubart, unpublished observations). In view of
the complex immunopathogenesis of this model and that only one T cell
epitope exhibits molecular mimicry with BTN, it was not surprising that
intranasal treatment with any of the peptides when given individually
(MOG93–110, MOG74–90, or
BTN74–90) was unable to completely suppress
clinical disease.
Controls pretreated with OVA developed a biphasic disease
characterized by an initial episode of EAE that was rapidly followed by
a severe relapse that was normally fatal by day 25 p.i. (Fig. 4a). Nasal administration of
the individual peptides reduced disease severity, but failed to delay
disease onset or stop disease progression beyond day 15, as
demonstrated in Fig. 4b for animals treated with
MOG93–110. In contrast, the effect of treatment
with combinations of either MOG93–110 and
BTN74–90, or MOG93–110
and MOG74–90 was far more effective and both
combinations of peptides delayed disease onset, penetrance, and
severity (Fig. 4c). This effect was clearly seen 20
d.p.i. when all animals in the control group pretreated with OVA were
in relapse with a mean clinical score of 3.5 ± 0.32
(n = 6, Fig. 4c). In contrast, at this time
point, only two rats treated with
MOG93–110/BTN74–90
combination (n = 5) had developed EAE (grades 1 and 2).
A similar level of protection was also seen following intranasal
pretreatment with the combination
MOG93–110/MOG74–90 (data
not shown). Therefore, the BTN peptide could be used interchangeably
with the corresponding MOG epitope to modify the severity of actively
induced MOG-EAE.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Immunologic cross-reactivity, or molecular mimicry, involving microbial Ags and self is often discussed as one mechanism that may break self-tolerance to CNS myelin autoantigens in MS (35, 36, 37). This apparent lack of Ag specificity is a direct consequence of the degeneracy of TCR recognition of MHC/peptide complexes, resulting in the recognition of an extensive hierarchy of agonist and antagonist peptide ligands by a single TCR (38). Therefore, human T cell clones specific for MBP can be activated in vitro with synthetic viral peptides (39), and immunization with synthetic microbial peptides can induce an autoaggressive T cell response in vivo (35, 36, 37). However, whether or not mimicry involving microbial pathogens and myelin leads to autoaggression during the natural course of infection remains unknown. Our present study extends this concept to include mimicry with dietary Ags as a potential etiological factor in autoimmune diseases of the nervous system.
Autoaggression induced by BTN is T cell-mediated and restricted by
class II MHC. This limits the number of MHC haplotypes that are
permissive for the induction of an encephalitogenic response to MOG. In
our current study, we observed that only one of three rat haplotypes
supported this response. In the context of the permissive
RT1av1 haplotype, the cross-reactive T cell
epitopes of MOG and BTN share a core region (amino acids 74–86) of
which 8 of 12 residues are identical (Table I). Although at least two
other encephalitogenic epitopes of MOG in the rat exhibit similar
levels of gross sequence identity with BTN, this is not sufficient to
support a proliferative/encephalitogenic T cell response (Table I).
However, it is to be anticipated that non-MHC genes and environmental
factors, such as the intestinal flora, will also play a role in
determining the penetrance of this effect and the pathogenicity of the
BTN/MOG-reactive T cell response. These observations suggest that,
despite the extensive sequence identity that exists between the two
proteins, only a limited number of human MHC haplotypes may be
permissive for a similar cross-reactive T cell response.
However, although active immunization with BTN in CFA induces a pathogenic autoimmune response, this is not the route by which the immune system is exposed normally to this Ag. BTN is a sexually dimorphic protein that is only expressed in the lactating mammary gland (23, 26, 40), and, therefore, with exception of lactating females, the only route by which BTN-derived peptides can influence or trigger an immune response is via the diet. It is now known that immunogenic peptides can cross the gut mucosal surface to be presented to T cells in the periphery within hours of ingestion (30). This directly influences the selection, survival, and function of the T cell repertoire and contributes to "oral tolerance," the systemic suppression of potentially inflammatory responses to dietary Ags (29, 30, 31, 41, 42).
Applying Ag intranasally provides an alternative route to study the induction of transmucosal tolerance that avoids possible degradation of the target peptide in gastrointestinal tract (43, 44). In both cases, Ag-specific tolerance involves multiple mechanisms including "suppressor" T cell responses, anergy, and activation-induced cell death; the relative contribution of each depending on factors such as dose, timing, and the identity of the Ag (29, 30, 31, 41, 42, 43, 44). In the current study, we demonstrate that, despite the immunopathological complexity of MOG-induced EAE, intranasal application of a 1:1 mixture of the encephalitogenic MOG peptides, MOG74–90 and MOG93–110, has a dramatic effect on the severity and clinical course of MOG-induced EAE. Moreover, this effect is maintained when MOG74–90 is replaced by its BTN homologue, BTN74–90. The mechanistic details responsible for this clinical effect are currently being analyzed, but these results provide the first indication that transmucosal sensitization to a BTN peptide can modulate the effector T cell response to MOG. A suggestion supported by our observation that treatment with high doses of the BTN peptide also suppresses EAE mediated by the adoptive transfer of MOG74–90-specific T cells (45).
We anticipate that a similar tolerogenic effect may also occur in the adult following the consumption of bovine milk products, in which case BTN in the diet may not only induce oral tolerance to BTN itself, but also suppress cross-reactive and potentially encephalitogenic MOG-reactive T cell responses. However, such an effect will require a permissive MHC class II haplotype and be further complicated by factors effecting the degradation and uptake of BTN peptides in the gastrointestinal tract before its immunological processing and presentation. However, the mechanisms responsible for oral tolerance are poorly developed at birth, and, in the neonate, feeding Ags may initially prime the immune system rather than inducing tolerance, oral tolerance only developing if feeding is continued beyond a critical age (31). In the case of an autoantigen, this raises the possibility that neonatal exposure may enhance disease susceptibility later in life. This was clearly seen in rats fed MBP for a limited period immediately postpartum and then subsequently immunized with MBP in CFA in adulthood (46). These animals not only exhibited no tolerance to MBP-induced EAE, but also developed more severe disease than control littermates. In contrast, feeding MBP to adult rats induced oral tolerance and suppressed MBP-induced EAE (46). The role that timing of exposure and the differential effects of syngeneic BTN as opposed to xenogeneic BTN have on the T cell response to MOG is currently under investigation in BTN-/- and wild-type mice.
Intriguingly, the frequency of seropositive responders to milk proteins peaks in childhood and declines as puberty approaches (47), a time frame similar to that reported for the role of the environmental factors in the etiology of MS (1, 48). Moreover, epidemiological studies have identified an association between the consumption of milk and the prevalence of MS (32, 33, 34). However, whether or not this is related to molecular mimicry between BTN and MOG must remain a matter of speculation. Indeed, milk in the diet is only one of many environmental factors related to the prevalence of MS (48). Moreover, this simple explanation neglects the existence of multiple BTN homologues that are encoded together with BTN telomeric of the nonclassical class 1 MHC locus (23). Mimicry involving the N-terminal domains of these proteins, which are expressed in a wide variety of tissues, may also influence the composition and function of the BTN/MOG repertoire.
In conclusion, we identify BTN as an Ag that can influence the clinical outcome of autoimmune responses to MOG, an important antigenic target in EAE and MS. Modulation of the MOG-specific repertoire as a consequence of molecular mimicry with this dietary Ag BTN may be a significant factor in determining the role MOG plays as a target Ag in the immunopathogenesis of MS. Identification of those MHC haplotypes permissive for a cross-reactive T cell response between MOG and BTN may provide a strategy to identify those at risk of developing encephalitogenic responses to MOG following premature exposure to BTN.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 A.S. A.Sc. and M.S. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. C. Linington, Department of Neuroimmunology, Max-Planck Institute for Neurobiology, Am Klopferspitz 18a, 82152 Martinsried, Germany.
4 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; BTN, butyrophilin; MFGM, milk fat globule membrane; TCL, T cell line; d.p.i., days postimmunization; DA, Dark Agouti; BN, Brown Norway; LEW, Lewis.
Received for publication February 23, 2000. Accepted for publication June 14, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  K. A. McLaughlin, T. Chitnis, J. Newcombe, B. Franz, J. Kennedy, S. McArdel, J. Kuhle, L. Kappos, K. Rostasy, D. Pohl, et al. Age-Dependent B Cell Autoimmunity to a Myelin Surface Antigen in Pediatric Multiple Sclerosis J. Immunol., September 15, 2009; 183(6): 4067 - 4076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Jeong, A. U. Rao, J. Xu, S. L. Ogg, Y. Hathout, C. Fenselau, and I. H. Mather The PRY/SPRY/B30.2 Domain of Butyrophilin 1A1 (BTN1A1) Binds to Xanthine Oxidoreductase: IMPLICATIONS FOR THE FUNCTION OF BTN1A1 IN THE MAMMARY GLAND AND OTHER TISSUES J. Biol. Chem., August 14, 2009; 284(33): 22444 - 22456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Mathey, T. Derfuss, M. K. Storch, K. R. Williams, K. Hales, D. R. Woolley, A. Al-Hayani, S. N. Davies, M. N. Rasband, T. Olsson, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury J. Exp. Med., October 1, 2007; 204(10): 2363 - 2372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Otaegui, S. Mostafavi, C. C. A. Bernard, A. L. de Munain, P. Mousavi, J. R. Oksenberg, and S. E. Baranzini Increased Transcriptional Activity of Milk-Related Genes following the Active Phase of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis J. Immunol., September 15, 2007; 179(6): 4074 - 4082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R P Lisak, J A Benjamins, B Bealmear, B Yao, S Land, L Nedelkoska, and D Skundric Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures Multiple Sclerosis, April 1, 2006; 12(2): 149 - 168. [Abstract] [PDF]
|
|
|
|
 |
|
 K. L. Reichelt and O. Skjeldal IgA antibodies in Rett syndrome Autism, March 1, 2006; 10(2): 189 - 197. [Abstract] [PDF]
|
|
|
|
 |
|
 I. Tsunoda, J. E. Libbey, L.-Q. Kuang, E. J. Terry, and R. S. Fujinami Massive Apoptosis in Lymphoid Organs in Animal Models for Primary and Secondary Progressive Multiple Sclerosis Am. J. Pathol., December 1, 2005; 167(6): 1631 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L. Spitsberg Invited Review: Bovine Milk Fat Globule Membrane as a Potential Nutraceutical J Dairy Sci, July 1, 2005; 88(7): 2289 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bischof, A. Bins, M. Durr, Y. Zevering, A. Melms, and A. M. Kruisbeek A Structurally Available Encephalitogenic Epitope of Myelin Oligodendrocyte Glycoprotein Specifically Induces a Diversified Pathogenic Autoimmune Response J. Immunol., July 1, 2004; 173(1): 600 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Mana, M. Goodyear, C. Bernard, R. Tomioka, M. Freire-Garabal, and D. Linares Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin Int. Immunol., March 1, 2004; 16(3): 489 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kawakami, S. Lassmann, Z. Li, F. Odoardi, T. Ritter, T. Ziemssen, W. E.F. Klinkert, J. W. Ellwart, M. Bradl, K. Krivacic, et al. The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis J. Exp. Med., January 20, 2004; 199(2): 185 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Guggenmos, A. S. Schubart, S. Ogg, M. Andersson, T. Olsson, I. H. Mather, and C. Linington Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis J. Immunol., January 1, 2004; 172(1): 661 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Breithaupt, A. Schubart, H. Zander, A. Skerra, R. Huber, C. Linington, and U. Jacob Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein PNAS, August 5, 2003; 100(16): 9446 - 9451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bourquin, A. Schubart, S. Tobollik, I. Mather, S. Ogg, R. Liblau, and C. Linington Selective Unresponsiveness to Conformational B Cell Epitopes of the Myelin Oligodendrocyte Glycoprotein in H-2b Mice J. Immunol., July 1, 2003; 171(1): 455 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Weissert, J. Kuhle, K. L. de Graaf, W. Wienhold, M. M. Herrmann, C. Muller, T. G. Forsthuber, K.-H. Wiesmuller, and A. Melms High Immunogenicity of Intracellular Myelin Oligodendrocyte Glycoprotein Epitopes J. Immunol., July 1, 2002; 169(1): 548 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Winer, I. Astsaturov, R. K. Cheung, K. Schrade, L. Gunaratnam, D. D. Wood, M. A. Moscarello, P. O'Connor, C. McKerlie, D. J. Becker, et al. T Cells of Multiple Sclerosis Patients Target a Common Environmental Peptide that Causes Encephalitis in Mice J. Immunol., April 1, 2001; 166(7): 4751 - 4756. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and
BTN74–90-specific (
) TCLs is restricted by class II MHC
(I-A). Addition of the mAb OX6 (anti-I-A), but not mAbs OX 17
(anti-I-E) or OX18 (anti-class I MHC), blocks proliferation in
vitro (mAb concentration 10 µg/ml) The purified OX mAbs were kindly
provided by Dr. R. Weissert, Stockholm. d, The peptides
MOG74–90 and BTN74–90 stimulate
MOG74–90-specific T cells to a similar extent over a broad
range of peptide concentrations.
) 2 and 4 days after T cell transfer
significantly inhibited disease. Injections were performed under light
ether anesthesia; control animals were treated with OVA. *,
p < 0.05; Duncan’s post hoc test.