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Bourdette, D. N., E. Edmonds, C. Smith, J. D. Bowen, C. RG Guttmann, Z. P. Nagy, J. Simon et al. « A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis ». Multiple Sclerosis Journal 11, no 5 (octobre 2005) : 552–61. http://dx.doi.org/10.1191/1352458505ms1225oa.
Texte intégralRésumé :
Background: T cell receptor (TCR) peptide vaccination is a novel approach to treating multiple sclerosis (MS). The low immunogenicity of previous vaccines has hindered the development of TCR peptide vaccination for MS. Objective: To compare the immunogenicity of intramuscular injections of TCR BV5S2, BV6S5 and BV13S1 CDR2 peptides in incomplete Freund’s adjuvant (IFA) with intradermal injections of the same peptides without IFA. Methods: MS subjects were randomized to receive TCR peptides/IFA, TCR peptides/saline or IFA alone. Subjects were on study for 24 weeks. Results: The TCR peptides/IFA vaccine induced vigorous T cell responses in 100% of subjects completing the 24-week study (9/9) compared with only 20% (2/10) of those receiving the TCR peptides/saline vaccine (P =0.001). IFA alone induced a weak response in only one of five subjects. Aside from injection site reactions, there were no significant adverse events attributable to the treatment. Conclusions: The trivalent TCR peptide in IFA vaccine represents a significant improvement in immunogenicity over previous TCR peptide vaccines and warrants investigation of its ability to treat MS.
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Matsoukas, John, George Deraos, Kostas Kelaidonis, Md Kamal Hossain, Jack Feehan, Andreas G. Tzakos, Elizabeth Matsoukas, Emmanuel Topoglidis et Vasso Apostolopoulos. « Myelin Peptide–Mannan Conjugate Multiple Sclerosis Vaccines : Conjugation Efficacy and Stability of Vaccine Ingredient ». Vaccines 9, no 12 (8 décembre 2021) : 1456. http://dx.doi.org/10.3390/vaccines9121456.
Texte intégralRésumé :
Myelin peptide–mannan conjugates have been shown to be potential vaccines in the immunotherapy of multiple sclerosis. The conjugates are comprised from the epitope peptide and the polysaccharide mannan which transfers as a carrier the antigenic peptide to dendritic cells that process and present antigenic peptides at their surface in complex with MHC class I or class II resulting in T-cell stimulation. The conjugation of antigenic peptide with mannan occurs through the linker (Lys–Gly)5, which connects the peptide with the oxidized mannose units of mannan. This study describes novel methods for the quantification of the vaccine ingredient peptide within the conjugate, a prerequisite for approval of clinical trials in the pursuit of multiple sclerosis therapeutics. Myelin peptides, such as MOG35–55, MBP83–99, and PLP131–145 in linear or cyclic form, as altered peptide ligands or conjugated to appropriate carriers, possess immunomodulatory properties in experimental models and are potential candidates for clinical trials.
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Bourdette, D. N., R. H. Whitham, Y. K. Chou, W. J. Morrison, J. Atherton, C. Kenny, D. Liefeld, G. A. Hashim, H. Offner et A. A. Vandenbark. « Immunity to TCR peptides in multiple sclerosis. I. Successful immunization of patients with synthetic V beta 5.2 and V beta 6.1 CDR2 peptides. » Journal of Immunology 152, no 5 (1 mars 1994) : 2510–19. http://dx.doi.org/10.4049/jimmunol.152.5.2510.
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Abstract Immunization with disease-associated TCR V region peptides is an effective treatment for experimental autoimmune encephalomyelitis. Myelin basic protein-specific T cells, which induce experimental autoimmune encephalomyelitis in many animal strains, may be important in the pathogenesis of multiple sclerosis. Myelin basic protein-specific T cell clones from some multiple sclerosis patients preferentially use TCR V genes from the V beta 5.2 and V beta 6.1 families. To assess the safety and immunogenicity of TCR V beta 5.2 and V beta 6.1 peptides, we injected 11 multiple sclerosis patients with varying doses of two synthetic peptides, TCR V beta 5.2(39-59) and V beta 6.1(39-59), encompassing the CDR2 region of these V gene families. Low doses (100 to 300 micrograms) of peptide induced T cell immunity in 7 of 11 patients to one or both peptides. Delayed type hypersensitivity skin responses to the peptides were observed in three of seven responders, and TCR peptide-specific Ab occurred in two of seven T cell responders. Low doses of TCR peptides produced no side effects and did not cause broad spectrum immunosuppression. Synthetic TCR V region peptides can induce T cell immunity safely in humans and may prove useful in treating human autoimmune diseases.
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Planas, Raquel, Radleigh Santos, Paula Tomas-Ojer, Carolina Cruciani, Andreas Lutterotti, Wolfgang Faigle, Nicole Schaeren-Wiemers et al. « GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis ». Science Translational Medicine 10, no 462 (10 octobre 2018) : eaat4301. http://dx.doi.org/10.1126/scitranslmed.aat4301.
Texte intégralRésumé :
Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.
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Owens, Gregory P., Andrew J. Shearer, Xiaoli Yu, Alanna M. Ritchie, Kathryne M. Keays, Jeffrey L. Bennett, Donald H. Gilden et Mark P. Burgoon. « Screening Random Peptide Libraries with Subacute Sclerosing PanencephalitisBrain-Derived Recombinant Antibodies Identifies Multiple Epitopes in the C-Terminal Region of the Measles Virus Nucleocapsid Protein ». Journal of Virology 80, no 24 (15 décembre 2006) : 12121–30. http://dx.doi.org/10.1128/jvi.01704-06.
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ABSTRACT Infectious and inflammatory diseases of the CNS are often characterized by a robust B-cell response that manifests as increased intrathecal immunoglobulin G (IgG) synthesis and the presence of oligoclonal bands. We previously used laser capture microdissection and single-cell PCR to analyze the IgG variable regions of plasma cells from the brain of a patient with subacute sclerosing panencephalitis (SSPE). Five of eight human IgG1 recombinant antibodies (rAbs) derived from SSPE brain plasma cell clones recognized the measles virus (MV) nucleocapsid protein, confirming that the antibody response in SSPE targets primarily the agent causing disease. In this study, as part of our work on antigen identification, we used four rAbs to probe a random phage-displayed peptide library to determine if epitopes within the MV nucleocapsid protein could be identified with SSPE brain rAbs. All four of the SSPE rAbs enriched phage-displayed peptide sequences that reacted specifically to their panning rAb by enzyme-linked immunosorbent assay. BLASTP searches of the NCBI protein database revealed clear homologies in three peptides and different amino acid stretches within the 65 C-terminal amino acids of the MV nucleocapsid protein. The specificities of SSPE rAbs to these regions of the MV nucleocapsid protein were confirmed by binding to synthetic peptides or to short cDNA expression products. These results indicate the feasibility of using peptide screening for antigen discovery in central nervous system inflammatory diseases of unknown etiology, such as multiple sclerosis, neurosarcoidosis, or Behcet's syndrome.
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Beddow, Sara A., Tobias Neef, Igal Ifergan, Joseph R. Podojil, Daniel Getts et Stephen D. Miller. « Treatment with Multiple-linked Myelin Peptides Encapsulated within Nanoparticles Induces Antigen-specific Tolerance in SJL/J Relapsing-remitting Experimental Autoimmune Encephalomyelitis ». Journal of Immunology 204, no 1_Supplement (1 mai 2020) : 160.10. http://dx.doi.org/10.4049/jimmunol.204.supp.160.10.
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Abstract Experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a demyelinating disease of the central nervous system (CNS), and serves as a fit-for-purpose pre-clinical model of Multiple Sclerosis (MS). Data show that tolerogenic immune-modifying nanoparticles (TIMPs) encapsulating peptides/proteins is an effective therapeutic that induces antigen-specific tolerance to the encapsulated peptide/protein. The effectiveness of this therapeutic platform has been be demonstrated in multiple mouse models, as well as in a recently completed phase 2 double-blinded placebo-controlled clinical trial for the treatment of celiac disease. While previous EAE studies have utilized single peptides, the present study utilized a polypeptide containing the SJL/J mouse dominant encephalitogenic peptides (PLP139–151, PLP178–191, MBP84–104, and MOG92-10) linked together with intervening capsaicin S cleavage sites. The use of the multiple-linked myelin peptides was produced to achieve broader coverage of myelin-derived epitopes, which will be required for the treatment of MS. The present data show that this multiple-linked myelin peptide emulsified in CFA induced both CD4+ T cell responses and EAE in SJL/J mice similar to PLP139–151/CFA. Our data go on to show that treatment of SJL/J mice with multiple-linked myelin peptide TIMP inhibited both PLP139–151/CFA-induced R-EAE, as well as multiple-linked myelin peptide/CFA-induced EAE. Furthermore, treatment of SJL/J mice with multiple-linked myelin peptide TIMP significantly decreased TH17 cell responses and increased Tr1 cell responses. The present findings suggest that utilizing multiple-linked peptides may be clinically translatable for the treatment of autoimmune disease.
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Bronstein, J. M., R. Lallone, R. S. Seitz, G. W. Ellison et L. W. Myers. « A humoral response to OSP in multiple sclerosis : A molecular mimic ? » Multiple Sclerosis Journal 2, no 5 (décembre 1996) : 250. http://dx.doi.org/10.1177/135245859600200512.
Texte intégralRésumé :
Oligodendrocyte-specifie protein (OSP) is a recently isolated novel protein found only in CNS laminar myelin and therefor is a good candidate as an autoantigen in patients with MS. In order to determine the humoral response in patients with MS. Westren blot analysis was performed on CSF from 6 patients with clinically stable relapsing MS (rMS) and 2 normal controls. All 6 of the CSF samples from rMS patients contained anti-OSP antibodies and none were detected in controls. Peptide mapping determined that the antigenic response was directed at a 7 amino acid peptide (OSP 114-120) which was 71% homologous with several common viral and bacterial proteins and 100% identical to the human OSP protein. ELISAs were performed using OSP 114-20 as antigen on a total 32 MS patints followed at UCLA, 53 MS patients from the National Neurological Rescarch Specimen Bank (NNRSB), and on 51 neurological control samples. Eighty % of UCLA rMS patients had an OSP ELISA reading above 0.55 OD units (median ± SD, 0.94 ± .35) while 0 of 14 CSF samples from HTLV-1 patients and normal controls had values above 0.55 units (0.28 ± .12; p<.01). Similar results were found in specimens from the NNRSB. No differences in anti-OSP titers were found in serum of MS and control patients. ELISAs performed on CSF samples using homologus viral peptieds as antigen (e.g. EBV, HSV HIV) showed a close correlation with anti-OSP 114-120 titers, and in some, the anti-viral titers far exceeded them. These data demonstrate a specific humoral response directed against a region of OSP in rMS patinets which cross reacts with several common viral peptides and suggests a possible role of molecular mimicry in the development of MS.
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Matsoukas, John M., Irene Ligielli, Christos T. Chasapis, Konstantinos Kelaidonis, Vasso Apostolopoulos et Thomas Mavromoustakos. « Novel Approaches in the Immunotherapy of Multiple Sclerosis : Cyclization of Myelin Epitope Peptides and Conjugation with Mannan ». Brain Sciences 11, no 12 (29 novembre 2021) : 1583. http://dx.doi.org/10.3390/brainsci11121583.
Texte intégralRésumé :
Multiple Sclerosis (MS) is a serious autoimmune disease. The patient in an advanced state of the disease has restrained mobility and remains handicapped. It is therefore understandable that there is a great need for novel drugs and vaccines for the treatment of MS. Herein we summarise two major approaches applied for the treatment of the disease using peptide molecules alone or conjugated with mannan. The first approach focuses on selective myelin epitope peptide or peptide mimetic therapy alone or conjugated with mannan, and the second on immune-therapy by preventing or controlling disease through the release of appropriate cytokines. In both approaches the use of cyclic peptides offers the advantage of increased stability from proteolytic enzymes. In these approaches, the synthesis of myelin epitope peptides conjugated to mannan is of particular interest as this was found to protect mice against experimental autoimmune encephalomyelitis, an animal model of MS, in prophylactic and therapeutic protocols. Protection was peptide-specific and associated with reduced antigen-specific T cell proliferation. The aim of the studies of these peptide epitope analogs is to understand their molecular basis of interactions with human autoimmune T-cell receptor and a MS-associated human leucocyte antigen (HLA)-DR2b. This knowledge will lead the rational design to new beneficial non-peptide mimetic analogs for the treatment of MS. Some issues of the use of nanotechnology will also be addressed as a future trend to tackle the disease. We highlight novel immunomodulation and vaccine-based research against MS based on myelin epitope peptides and strategies developed in our laboratories.
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Androutsou, Maria-Eleni, Agathi Nteli, Areti Gkika, Maria Avloniti, Anastasia Dagkonaki, Lesley Probert, Theodore Tselios et Simona Golič Grdadolnik. « Characterization of Asparagine Deamidation in Immunodominant Myelin Oligodendrocyte Glycoprotein Peptide Potential Immunotherapy for the Treatment of Multiple Sclerosis ». International Journal of Molecular Sciences 21, no 20 (13 octobre 2020) : 7566. http://dx.doi.org/10.3390/ijms21207566.
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Mannan (polysaccharide) conjugated with a myelin oligodendrocyte glycoprotein (MOG) peptide, namely (KG)5MOG35–55, represents a potent and promising new approach for the immunotherapy of Multiple Sclerosis (MS). The MOG35–55 epitope conjugated with the oxidized form of mannan (poly-mannose) via a (KG)5 linker was found to inhibit the symptoms of MOG35–55-induced experimental autoimmune encephalomyelitis (EAE) in mice using prophylactic and therapeutic vaccinated protocols. Deamidation is a common modification in peptide and protein sequences, especially for Gln and Asn residues. In this study, the structural solution motif of deaminated peptides and their functional effects in an animal model for MS were explored. Several peptides based on the MOG35–55 epitope have been synthesized in which the Asn53 was replaced with Ala, Asp, or isoAsp. Our results demonstrate that the synthesized MOG peptides were formed to the deaminated products in basic conditions, and the Asn53 was mainly modified to Asp. Moreover, both peptides (wild type and deaminated derivative) conjugated with mannan (from Saccharomyces cerevisiae) independently inhibited the development of neurological symptoms and inflammatory demyelinating spinal cord lesions in MOG35–55-induced EAE. To conclude, mannan conjugated with a deamidated product did not affect the efficacy of the parent peptide.
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Bourdette, Dennis N., Yuan K. Chou, Ruth H. Whitham, Jane Buckner, Hi Jong Kwon, Gerald T. Nepom, Abigail Buenafe et al. « Immunity to T Cell Receptor Peptides in Multiple Sclerosis. III. Preferential Immunogenicity of Complementarity-Determining Region 2 Peptides from Disease-Associated T Cell Receptor BV Genes* ». Journal of Immunology 161, no 2 (15 juillet 1998) : 1034–44. http://dx.doi.org/10.4049/jimmunol.161.2.1034.
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Abstract Vaccination with synthetic TCR peptides from the BV5S2 complementarity-determining region 2 (CDR2) can boost significantly the frequency of circulating CD4+ peptide-specific Th2 cells in multiple sclerosis (MS) patients, with an associated decrease in the frequency of myelin basic protein (MBP)-reactive Th1 cells and possible clinical benefit. To evaluate the immunogenicity of CDR2 vs other regions of the TCR, we vaccinated seven MS patients with overlapping BV5S2 peptides spanning amino acids 1–94. Six patients responded to at least one of three overlapping or substituted CDR2 peptides possessing a core epitope of residues 44–52, and one patient also responded to a CDR1 peptide. Of the CDR2 peptides, the substituted (Y49T)BV5S2-38–58 peptide was the most immunogenic but cross-reacted with the native sequence and had the strongest binding affinity for MS-associated HLA-DR2 alleles, suggesting that position 49 is an MHC rather than a TCR contact residue. Two MS patients who did not respond to BV5S2 peptides were immunized successfully with CDR2 peptides from different BV gene families overexpressed by their MBP-specific T cells. Taken together, these results suggest that a widely active vaccine for MS might well involve a limited set of slightly modified CDR2 peptides from BV genes involved in T cell recognition of MBP.
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Chou, Y. K., W. J. Morrison, A. D. Weinberg, R. Dedrick, R. Whitham, D. N. Bourdette, G. Hashim, H. Offner et A. A. Vandenbark. « Immunity to TCR peptides in multiple sclerosis. II. T cell recognition of V beta 5.2 and V beta 6.1 CDR2 peptides. » Journal of Immunology 152, no 5 (1 mars 1994) : 2520–29. http://dx.doi.org/10.4049/jimmunol.152.5.2520.
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Abstract The biased expression of V beta 5.2 and V beta 6.1 by T cells specific for myelin basic protein (BP) has led to our use of TCR peptides from these V gene sequences to induce anti-TCR immunity in patients with multiple sclerosis (MS). Injection of V beta 5.2-39-59 or V beta 6.1-39-59 peptides significantly increased the peptide specific T cell frequency in 7 of 11 MS patients, often with an accompanying delayed hypersensitivity reaction at the injection site. Here, we validate these cellular immune responses by characterizing TCR peptide specific T cells from an MS patient with biased V beta 5.2 expression in BP reactive T cells before treatment with TCR peptides, and from two MS patients in whom the frequencies of anti-TCR peptide specific T cells were significantly boosted after injection with low doses of TCR peptides. In both cases, T cell lines were established with relative ease, especially after boosting with the peptides. A V beta 5.2-39-59 reactive line responded selectively to the boosting peptide and was restricted by both MHC class I (HLA-B7) and MHC class II (HLA-DR2) molecules. Characterization of 22 clonal isolates revealed that the responding T cells were predominantly activated CD4+CD8lo, circulating memory cells restricted by either HLA-B7 or HLA-DR2, that utilized mainly V beta 4, V beta 6, V beta 12, and V beta 14, but not V beta 5.2 in their TCR. T cell isolates specific for V beta 6.1-39-59 possessed similar characteristics but contained specificities cross-reactive with an N-terminal sequence on V beta 5.2-39-59. Upon stimulation with peptide or Con A, the TCR peptide specific T cell lines had increased message production for IFN-gamma, GM-CSF, IL-4, IL-5, and to a lesser degree, IL-2. This lymphokine mRNA profile differed from a BP-specific T cell line that produced message for IFN-gamma and GM-CSF but low or absent levels of IL-4 and IL-5. The extensive parallels between human T cells specific for V beta 5.2 and V beta 6.1 CDR2 peptides and rat T cells specific for V beta 8.2 CDR2 peptide that are highly protective against experimental encephalomyelitis strengthen the rationale for the therapeutic use of TCR peptides in human autoimmunity.
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Augutis, Kristin, Markus Axelsson, Erik Portelius, Gunnar Brinkmalm, Ulf Andreasson, Mikael K. Gustavsson, Clas Malmeström et al. « Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis ». Multiple Sclerosis Journal 19, no 5 (15 octobre 2012) : 543–52. http://dx.doi.org/10.1177/1352458512460603.
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Background: Amyloid precursor protein (APP) and amyloid β (Aβ) peptides are intensely studied in neuroscience and their cerebrospinal fluid (CSF) measurements may be used to track the metabolic pathways of APP in vivo. Reduced CSF levels of Aβ and soluble APP (sAPP) fragments are reported in inflammatory diseases, including multiple sclerosis (MS); but in MS, the precise pathway of APP metabolism and whether it can be affected by disease-modifying treatments remains unclear. Objective: To characterize the CSF biomarkers of APP degradation in MS, including the effects of disease-modifying therapy. Methods: CSF samples from 87 MS patients (54 relapsing–remitting (RR) MS; 33 secondary progressive (SP) MS and 28 controls were analyzed for sAPP and Aβ peptides by immunoassays, plus a subset of samples was analyzed by immunoprecipitation and mass spectrometry (IP-MS). Patients treated with natalizumab or mitoxantrone were examined at baseline, and after 1–2 years of treatment. Results: CSF sAPP and Aβ peptide levels were reduced in MS patients; but they increased again towards normal, after natalizumab treatment. A multivariate model of IP-MS-measured Aβ species separated the SPMS patients from controls, with RRMS patients having intermediate levels. Conclusions: We confirmed and extended our previous observations of altered CSF sAPP and Aβ peptide levels in MS patients. We found that natalizumab therapy may be able to counteract the altered APP metabolism in MS. The CSF Aβ isoform distribution was found to be distinct in SPMS patients, as compared to the controls.
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Karin, Nathan, Ofer Binah, Nir Grabie, Dennis J. Mitchell, Bella Felzen, Matthew D. Solomon, Paul Conlon, Amitabh Gaur, Nicholas Ling et Lawrence Steinman. « Short Peptide-Based Tolerogens Without Self-Antigenic or Pathogenic Activity Reverse Autoimmune Disease ». Journal of Immunology 160, no 10 (15 mai 1998) : 5188–94. http://dx.doi.org/10.4049/jimmunol.160.10.5188.
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Abstract An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87–99), is a major target of T cells in brain lesions of multiple sclerosis (MS), and this peptide can trigger experimental autoimmune encephalomyelitis (EAE). We designed truncated peptides based on this pathogenic 13-mer that are not antigenic. These short peptides reduced production of IFN-γ and TNF-α in vivo. Moreover, paraplegic rats given the 7-mer FKNIVTP in soluble form showed total reversal of paralysis in 24 h. Truncated peptides that are too small to stimulate antigenic responses to pathogenic regions of myelin basic protein are nevertheless effective tolerogens and are able to anergize autoreactive T cells. Short peptide-based tolerogens, devoid of immunogenic and pathogenic potential, may be attractive for therapy of autoimmune diseases.
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Grau-López, L., D. Raïch, C. Ramo-Tello, M. Naranjo-Gómez, A. Dàvalos, R. Pujol-Borrell, F. E. Borràs et E. Martínez-Cáceres. « Myelin peptides in multiple sclerosis ». Autoimmunity Reviews 8, no 8 (juillet 2009) : 650–53. http://dx.doi.org/10.1016/j.autrev.2009.02.013.
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Robinson, Rachel R., Elba M. Rojano et Thomas Forsthuber. « Small numbers of T cells specific to different myelin-antigens cooperate to induce autoimmunity in a murine model of multiple sclerosis ». Journal of Immunology 202, no 1_Supplement (1 mai 2019) : 180.3. http://dx.doi.org/10.4049/jimmunol.202.supp.180.3.
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Abstract T cells play a crucial role in many autoimmune diseases including multiple sclerosis (MS). Despite this, mechanisms of peripheral tolerance and dysregulation of these mechanisms during autoimmunity remain elusive. Myelin-reactive T cells are present in the blood of both healthy controls and patients with MS and T cells from patients with MS react to many different myelin peptides. The strongest genetic risk factor for developing MS is the HLA-DRB1*1501 haplotype, indicating that peptide binding to this MHC aids in disease induction. It is unlikely and not supported by current human studies that patients exhibit large populations of T cells specific for a single myelin-antigen. In contrast, a quorum of 2–5 low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides, particularly in genetically susceptible individuals. We utilized wild-type C57BL/6 mice and transgenic mice expressing the human MHC HLA-DRB1*1501 allele to assess the effect of inducing experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis, with low numbers of different myelin peptide-specific T cells or myelin peptides at suboptimal doses. In this proof-of-principle study, we found that EAE can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. The results support the hypothesis that a quorum of T cells could be reached by multiple antigen-specific T cells and could suffice to initiate autoimmune disease.
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Lee, Hye Lim, Jin-Woo Park, Jin Myoung Seok, Mi Young Jeon, Hojin Kim, Young-Min Lim, Ha Young Shin et al. « Serum Peptide Immunoglobulin G Autoantibody Response in Patients with Different Central Nervous System Inflammatory Demyelinating Disorders ». Diagnostics 11, no 8 (26 juillet 2021) : 1339. http://dx.doi.org/10.3390/diagnostics11081339.
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Previous efforts to discover new surrogate markers for the central nervous system (CNS) inflammatory demyelinating disorders have shown inconsistent results; moreover, supporting evidence is scarce. The present study investigated the IgG autoantibody responses to various viral and autoantibodies-related peptides proposed to be related to CNS inflammatory demyelinating disorders using the peptide microarray method. We customized a peptide microarray containing more than 2440 immobilized peptides representing human and viral autoantigens. Using this, we tested the sera of patients with neuromyelitis optica spectrum disorders (NMOSD seropositive, n = 6; NMOSD seronegative, n = 5), multiple sclerosis (MS, n = 5), and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD, n = 6), as well as healthy controls (HC, n = 5) and compared various peptide immunoglobulin G (IgG) responses between the groups. Among the statistically significant peptides based on the pairwise comparisons of IgG responses in each disease group to HC, cytomegalovirus (CMV)-related peptides were most clearly distinguishable among the study groups. In particular, the most significant differences in IgG response were observed for HC vs. MS and HC vs. seronegative NMOSD (p = 0.064). Relatively higher IgG responses to CMV-related peptides were observed in patients with MS and NMOSD based on analysis of the customized peptide microarray.
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Hanson, Gunnar J. « DR (MHC Class 11) Ligands : an Approach to Rheumatoid Arthritis Therapeutics ». Current Pharmaceutical Design 4, no 5 (octobre 1998) : 397–402. http://dx.doi.org/10.2174/138161280405221010162755.
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Abstract: The presentation of peptide antigens to T-cells by MHC Class II proteins is a central process in cellular and humoral immune responses. Blockade of this presentation event via synthetic ligands that bind to disease-associated MHCs (such as DR1 and DR4 l may be useful for the treatment of autoimmune diseases such as rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erthymatosis and Graves disease. Recently reported synthetic ligands for DR1 and DR4 are short modified peptides (2-7mers) capable of competing at nanomolar concentrations with antigenic peptides for the DR (MHC) binding groove.
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Ufret-Vincenty, Rafael L., Laura Quigley, Nancy Tresser, Seong Hee Pak, Ameer Gado, Stefan Hausmann, Kai W. Wucherpfennig et Stefan Brocke. « In Vivo Survival of Viral Antigen–specific T Cells that Induce Experimental Autoimmune Encephalomyelitis ». Journal of Experimental Medicine 188, no 9 (2 novembre 1998) : 1725–38. http://dx.doi.org/10.1084/jem.188.9.1725.
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A peptide derived from the human papillomavirus L2 protein is recognized by a myelin basic protein (MBP)-specific T cell clone from a multiple sclerosis patient and by MBP-specific autoantibodies purified from multiple sclerosis brain tissue. We now show in mice that low doses of this papillomavirus peptide were optimal in selecting a subpopulation of papillomavirus peptide–specific T cells that cross-reacted with MBP(87–99) and with an unrelated viral peptide derived from the BSLF1 protein of Epstein-Barr virus (EBV). These low dose viral peptide– specific T cell lines were highly encephalitogenic. Splenocytes from mice transferred with viral peptide–specific T cells showed a vigorous response to both the papillomavirus and MBP peptides, indicating that viral antigen–specific T cells survived for a prolonged time in vivo. The EBV peptide, unable to prime and select an autoreactive T cell population, could still activate the low dose papillomavirus peptide–specific cells and induce central nervous system (CNS) autoimmunity. Cytokine profiles of papillomavirus peptide–specific encephalitogenic T cells and histopathology of CNS lesions resembled those induced by MBP. These results demonstrate conserved aspects in the recognition of the self-antigen and a cross-reactive viral peptide by human and murine MBP-specific T cell receptors. We demonstrate that a viral antigen, depending on its nature, dose, and number of exposures, may select autoantigen-specific T cells that survive in vivo and can trigger autoimmune disease after adoptive transfer.
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Marquez-Manriquez, Juan P., JOSE ANTONIO MATUTE-BRISENO, PEDRO ALEJANDRO Alejandro Lucero-Diaz et ALEJANDRO CAMACHO-HERNANDEZ. « T regulatory antigen-specific multi-peptide immunotherapy induce clinical responses in autoimmune diseases ». Journal of Immunology 202, no 1_Supplement (1 mai 2019) : 68.10. http://dx.doi.org/10.4049/jimmunol.202.supp.68.10.
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Abstract Background The current treatment for several fatal autoimmune diseases is mainly palliative with minimal clinical benefit. By other hand the biological and clinically relevant potential targets to stop the auto immune response are mainly unknown, including the innate and adaptive auto-immune micro-environment. We performed a pilot trial with (n=5) progressive patients with myasthenia gravis (MG), multiple sclerosis (MS) and amyotrophic sclerosis lateral (ASL) using a multi-peptide T regulatory immunotherapy. Methods We performed a systematic review to found potential proteins involved in the auto-immune response in these three autoimmune diseases using the terms “misfolded proteins and autoimmune disease and prognosis and multivariate analysis”. initially N=25 repository samples from autoimmune disease patients were analyzed to test the predicted T regulatory peptides immunogenicity for ELISA, IL-10 ELISPOT and T –cell expansion. Results We found that predicted T regulatory peptides from Bcl-2, peptide C (p=0.001), survivi, peptide A (0.001) and VCP, peptide 8 = (P=0.005) were able to expand antigen-specific T regulatory cells and there was a clinical correlation in symptoms improvement in all the three diseases (mOS=28 months). Discussion The multi-peptide T regulatory peptide immunotherapy is feasible therapeutic approach to treat incurable autoimmune diseases and this data could be used as proof of principle to prepare a large clinical study in order to potentially improve clinical outcomes in combination with other approaches that may impact the clinical scenario in autoimmune diseases with limited or nor therapeutic options. No clinical toxicity was observed.
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Rojano, Elba Mirelle, Rachel R. Robinson et Thomas Forsthuber. « T cells directed against different myelin antigen epitopes cooperate to induce autoimmune encephalomyelitis in mice ». Journal of Immunology 200, no 1_Supplement (1 mai 2018) : 176.13. http://dx.doi.org/10.4049/jimmunol.200.supp.176.13.
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Abstract Multiple Sclerosis (MS) is the most common demyelinating autoimmune disease of the central nervous system (CNS). Important insights have emerged into the pathogenic mechanisms that drive the inflammatory events and demyelination in MS, however, much less is known about the events initiating this disease. The murine model of MS, experimental autoimmune encephalomyelitis (EAE), is usually induced through injection with a high dose of single immunodominant peptides found on the myelin sheath of the CNS. Low doses of single peptide do not induce EAE or result in very low disease incidence. In individual MS patients, autoimmune T cell-reactivity is usually directed against multiple myelin antigen epitopes and fluctuates significantly over the course of disease. Thus, we hypothesize that MS is triggered by the emergence of autoreactive T cells directed against multiple myelin epitopes, which together synergize to induce the disease. To test this concept in an animal model of EAE, we explored the effect of induction of EAE using combinations of low dose peptides akin to a “multiple hit” mechanism implicated in other disease conditions. We found that EAE can be induced through the immunization of mice with a combination of low dose myelin peptides from different myelin proteins, which individually are suboptimal to induce disease. The disease observed after multi-peptide immunization is comparable or more severe than with optimal doses of peptide traditionally used to induce EAE. This research provides new insights into the potential mechanisms underlying the induction of MS and could lead to novel approaches for immunotherapy.
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Moldovan, I. R., R. A. Rudick, A. C. Cotleur, S. E. Born, J.-C. Lee, M. T. Karafa et C. M. Pelfrey. « Longitudinal single-cell cytokine responses reveal recurrent autoimmune myelin reactivity in relapsing-remitting multiple sclerosis patients ». Multiple Sclerosis Journal 11, no 3 (juin 2005) : 251–60. http://dx.doi.org/10.1191/1352458505ms1165oa.
Texte intégralRésumé :
The relationship between multiple sclerosis (MS) disease activity and myelin protein-induced cytokine responses over time is not elucidated. We addressed this relationship by examining longitudinal cytokine responses to myelin proteins every three months for one year, in the context of gadolinium (gad)-enhancing brain lesions and of clinical relapses. The ELISPOT assay was used to determine the ex vivo cytokine production in response to nine amino acid long peptides spanning the entire proteolipid protein (PLP) and myelin basic protein (MBP) molecules in relapsing—remitting (RR) MS patients and matched healthy controls. We identified three longitudinal levels of myelin-induced cytokine secretion by adding up the positive responses for all PLP or MBP peptides obtained for five timepoints, at three- month intervals: low reactivity (<200 cumulative cytokine-secreting cells), isolated peptide reactivity (201-450 cumulative cytokine- secreting cells) and recurrent protein-wide bursts of cytokine reactivity (> 451 cumulative cytokine-secreting cells). The majority of MS patients showed recurrent bursts to PLP and MBP. In contrast, controls showed a more even distribution between all levels of cytokine reactivity. The majority of patients with gad-enhancing lesions showed PLP/IFNg and MBP/IFNg recurrent burst responses. This is the first longitudinal study on MS patients in which nine amino acid long myelin peptides are used to reveal the broad range of PLP- and MBP- peptide cytokine reactivity across the whole molecule of these two major myelin proteins. This study also reveals the extremely dynamic nature of the immune reactivity to numerous regions of myelin, which can fluctuate dramatically over time. Such fluctuation could hamper the efficacy of antigen-based therapies for MS.
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Deskoulidis, Efstathios, Souzana Petrouli, Vasso Apostolopoulos, John Matsoukas et Emmanuel Topoglidis. « The Use of Electrochemical Voltammetric Techniques and High-Pressure Liquid Chromatography to Evaluate Conjugation Efficiency of Multiple Sclerosis Peptide-Carrier Conjugates ». Brain Sciences 10, no 9 (21 août 2020) : 577. http://dx.doi.org/10.3390/brainsci10090577.
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Recent studies have shown the ability of electrochemical methods to sense and determine, even at very low concentrations, the presence and quantity of molecules or analytes including pharmaceutical samples. Furthermore, analytical methods, such as high-pressure liquid chromatography (HPLC), can also detect the presence and quantity of peptides at very low concentrations, in a simple, fast, and efficient way, which allows the monitoring of conjugation reactions and its completion. Graphite/SiO2 film electrodes and HPLC methods were previously shown by our group to be efficient to detect drug molecules, such as losartan. We now use these methods to detect the conjugation efficiency of a peptide from the immunogenic region of myelin oligodendrocyte to a carrier, mannan. The HPLC method furthermore confirms the stability of the peptide with time in a simple one pot procedure. Our study provides a general method to monitor, sense and detect the presence of peptides by effectively confirming the conjugation efficiency. Such methods can be used when designing conjugates as potential immunotherapeutics in the treatment of diseases, including multiple sclerosis.
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Varga, Zoltan, Gabor Tajti et Gyorgy Panyi. « The Kv1.3 K+ channel in the immune system and its “precision pharmacology” using peptide toxins ». Biologia Futura 72, no 1 (6 février 2021) : 75–83. http://dx.doi.org/10.1007/s42977-021-00071-7.
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AbstractSince the discovery of the Kv1.3 voltage-gated K+ channel in human T cells in 1984, ion channels are considered crucial elements of the signal transduction machinery in the immune system. Our knowledge about Kv1.3 and its inhibitors is outstanding, motivated by their potential application in autoimmune diseases mediated by Kv1.3 overexpressing effector memory T cells (e.g., Multiple Sclerosis). High affinity Kv1.3 inhibitors are either small organic molecules (e.g., Pap-1) or peptides isolated from venomous animals. To date, the highest affinity Kv1.3 inhibitors with the best Kv1.3 selectivity are the engineered analogues of the sea anemone peptide ShK (e.g., ShK-186), the engineered scorpion toxin HsTx1[R14A] and the natural scorpion toxin Vm24. These peptides inhibit Kv1.3 in picomolar concentrations and are several thousand-fold selective for Kv1.3 over other biologically critical ion channels. Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here. These include the conjugation of the peptides to carriers to increase the residency time of the peptides in the circulation (e.g., PEGylation and engineering the peptides into antibodies), use of rational drug design to create novel peptide inhibitors and understanding the potential off-target effects of Kv1.3 inhibition.
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Fanelli, Ilaria, Paolo Rovero, Paul Robert Hansen, Jette Frederiksen, Gunnar Houen et Nicole Hartwig Trier. « Specificity of Anti-Citrullinated Protein Antibodies to Citrullinated α-Enolase Peptides as a Function of Epitope Structure and Composition ». Antibodies 10, no 3 (21 juillet 2021) : 27. http://dx.doi.org/10.3390/antib10030027.
Texte intégralRésumé :
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1–2% of the world population. In addition to the first discovered serologic markers for RA, the rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPAs) are even more specific for the disease compared to RFs and are found in 70–80% of RA patient sera. RA etiopathogenesis still needs to be elucidated, as different factors are proposed to be involved, such as Epstein–Barr virus infection. Hence, understanding the interaction between ACPAs and their citrullinated peptide targets is relevant for a better knowledge of RA pathophysiology and for diagnostic purposes. In this study, a cohort of RA sera, healthy control sera and multiple sclerosis sera were screened for reactivity to a variety of citrullinated peptides originating from α-enolase, pro-filaggrin, proteoglycan and Epstein–Barr nuclear antigen-2 by enzyme-linked immunosorbent assay. ACPA reactivity to citrullinated α-enolase peptides was found to depend on peptide length and peptide conformation, favouring cyclic (disulfide bond) conformations for long peptides and linear peptides for truncated ones. Additional investigations about the optimal peptide conformation for ACPA detection, employing pro-filaggrin and EBNA-2 peptides, confirmed these findings, indicating a positive effect of cyclization of longer peptides of approximately 20 amino acids. Moreover, screening of the citrullinated peptides confirmed that ACPAs can be divided into two groups based on their reactivity. Approximately 90% of RA sera recognize several peptide targets, being defined as cross-reactive or overlapping reactivities, and whose reactivity to the citrullinated peptide is considered primarily to be backbone-dependent. In contrast, approximately 10% recognize a single target and are defined as nonoverlapping, primarily depending on the specific amino acid side-chains in the epitope for a stable interaction. Collectively, this study contributed to characterize epitope composition and structure for optimal ACPA reactivity and to obtain further knowledge about the cross-reactive nature of ACPAs.
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Singh, Rana A. K., Ying C. Q. Zang, Anju Shrivastava, Jian Hong, George T. Wang, Sufang Li, Maria V. Tejada-Simon, Milena Kozovska, Victor M. Rivera et Jingwu Z. Zhang. « Th1 and Th2 Deviation of Myelin-Autoreactive T Cells by Altered Peptide Ligands Is Associated with Reciprocal Regulation of Lck, Fyn, and ZAP-70 ». Journal of Immunology 163, no 12 (15 décembre 1999) : 6393–402. http://dx.doi.org/10.4049/jimmunol.163.12.6393.
Texte intégralRésumé :
Abstract Th0 clones recognizing an immunodominant peptide of myelin basic protein (residues 83–99) were derived from patients with multiple sclerosis. We demonstrate that analogue peptides with alanine substitution at Val86 and His88 had a unique partial agonistic property in inducing Th0 →Th1 and Th0 →Th2 deviation of the myelin basic protein-reactive T cell clones, respectively. Th0 to Th1 deviation induced by peptide 86V→A correlated with up-regulation of Fyn and ZAP-70 kinase activities. Conversely, Th0 to Th2 deviation induced by peptide 88H→A was associated with complete failure to activate Fyn and ZAP-70 kinases. The observed Th1 and Th2 shift also correlated, to a lesser extent, with Lck kinase activity that was down-regulated with Th1 deviation and increased with Th2 deviation in some T cell clones. We demonstrated that the Th1 and Th2 shift induced by the analogue peptides was a reversible process, as the T cell clones previously exposed to either 86V→A or 88H→A peptide could revert to an opposite phenotype when rechallenged reciprocally with a different analogue peptide. The study has important implications in our understanding of regulation of TCR-associated tyrosine kinases by altered peptide ligands and its role in cytokine regulation of autoreactive T cells.
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Whitham, R. H., D. N. Bourdette, G. A. Hashim, R. M. Herndon, R. C. Ilg, A. A. Vandenbark et H. Offner. « Lymphocytes from SJL/J mice immunized with spinal cord respond selectively to a peptide of proteolipid protein and transfer relapsing demyelinating experimental autoimmune encephalomyelitis. » Journal of Immunology 146, no 1 (1 janvier 1991) : 101–7. http://dx.doi.org/10.4049/jimmunol.146.1.101.
Texte intégralRésumé :
Abstract Relapsing experimental autoimmune encephalomyelitis (R-EAE) can be induced in SJL/J mice by immunization with spinal cord homogenate and adjuvant. The specific Ag(s) responsible for acute disease and subsequent relapses in this model is unknown. Myelin basic protein (BP), an encephalitogenic peptide of BP (BP 87-99), and proteolipid protein (PLP) can each induce R-EAE in SJL/J mice, and a peptide of PLP (PLP 139-151) has been reported to induce acute EAE. To determine the encephalitogens in cord-immunized mice with R-EAE, the in vitro proliferative responses of lymph node cells (LNC) and central nervous system mononuclear cells to BP, BP peptides, and PLP peptides were examined during acute EAE and during relapses. LNC responded only to PLP peptides 139-151 and 141-151 and did not respond to BP or its peptides during acute or chronic disease. Central nervous system mononuclear cells also preferentially responded to PLP 139-151 and 141-151 during acute and relapsing disease. A PLP 139-151 peptide-specific Th cell line was selected from LNC of cord-immunized donors. Five million peptide-specific line cells transferred severe relapsing demyelinating EAE to naive recipients. We conclude that PLP peptide 139-151 is the major encephalitogen for R-EAE in cord-immunized SJL/J mice. We demonstrate for the first time that Th cells specific for this peptide are sufficient to transfer relapsing demyelinating EAE. The predominance of a PLP immune response rather than a BP response in SJL/J mice suggests that genetic background may determine the predominant myelin Ag response in human demyelinating diseases such as multiple sclerosis.
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Sclavons, Coralie, Carmen Burtea, Sébastien Boutry, Sophie Laurent, Luce Vander Elst et Robert N. Muller. « Phage Display Screening for Tumor Necrosis Factor-α-Binding Peptides : Detection of Inflammation in a Mouse Model of Hepatitis ». International Journal of Peptides 2013 (26 février 2013) : 1–9. http://dx.doi.org/10.1155/2013/348409.
Texte intégralRésumé :
TNF-α is one of the most abundant cytokines produced in many inflammatory and autoimmune conditions such as multiple sclerosis, chronic hepatitis C, or neurodegenerative diseases. These pathologies remain difficult to diagnose and consequently difficult to treat. The aim of this work is to offer a new diagnostic tool by seeking new molecular probes for medical imaging. The target-specific part of the probe consists here of heptameric peptides selected by the phage display technology for their affinity for TNF-α. Several affinity tests allowed isolating 2 peptides that showed the best binding capacity to TNF-α. Finally, the best peptide was synthesized in both linear and cyclic forms and tested on the histological sections of concanavalin-A-(ConA-)treated mice liver. In this well-known hepatitis mouse model, the best results were obtained with the cyclic form of peptide 2, which allowed for the staining of inflamed areas in the liver. The cyclic form of peptide 2 (2C) was, thus, covalently linked to iron oxide nanoparticles (magnetic resonance imaging (MRI) contrast agent) and tested in the ConA-induced hepatitis mouse model. The vectorized nanoparticles allowed for the detection of inflammation as well as of the free peptide. These ex vivo results suggest that phage display-selected peptides can direct imaging contrast agents to inflammatory areas.
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Samson, M. F., et D. E. Smilek. « Reversal of acute experimental autoimmune encephalomyelitis and prevention of relapses by treatment with a myelin basic protein peptide analogue modified to form long-lived peptide-MHC complexes. » Journal of Immunology 155, no 5 (1 septembre 1995) : 2737–46. http://dx.doi.org/10.4049/jimmunol.155.5.2737.
Texte intégralRésumé :
Abstract Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease induced by immunization with myelin basic protein (MBP), proteolipid protein, or encephalitogenic peptides from these myelin components. EAE resembles basic protein multiple sclerosis in some of its clinical and histologic features, and serves as an experimental model for this and other autoimmune diseases. In this study, we examine i.v. peptide therapy of EAE in detail, and show that repeated i.v. injections of MBP peptides effectively treat EAE in (PLJxSJL)F1 mice. In this study, administration of the immunodominant epitope (MBP Ac1-11) prevents MBP-induced disease, whereas the subdominant epitope MBP 31-47 is neither required nor sufficient. Intravenous administration of substituted MBP peptide analogues is also effective in treating EAE, provided the peptide side chains presumed to be involved in TCR contact and MHC binding are preserved. A substituted MBP peptide analogue that forms long-lived peptide-MHC complexes in vivo is more effective than the unmodified MBP peptide. Lower doses of the substituted peptide analogue are effective, and the effect is longer lasting than treatment with the unmodified peptide. Clinical signs of EAE are reversed by injection of the substituted peptide during the acute phase of disease. Moreover, treatment of mice in the remission phase of EAE results in a dramatically reduced incidence of relapse. In summary, we have shown that EAE can be reversed after onset and treated during remission with an MBP peptide analogue that has been modified for improved therapeutic potency.
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Alcaro, Maria Claudia, et Anna Maria Papini. « Contribution of peptides to multiple sclerosis research ». Biopolymers 84, no 4 (2006) : 349–67. http://dx.doi.org/10.1002/bip.20498.
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Blanchette, F. « Clinical significance of glatiramer acetate antibodies ». Multiple Sclerosis Journal 13, no 1_suppl (mai 2007) : 28–35. http://dx.doi.org/10.1177/1352458507076994.
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Glatiramer acetate is a mixture of synthetic peptides that are cross-reactive with MBP. The antigen-based therapy induces a shift to an anti-inflammatory Th2 bias and is used in the treatment of relapsing-remitting multiple sclerosis. Like other peptide antigens, GA induces an antibody response in all patients. In contrast to biologically active agents, such as the recombinant interferon beta drugs, GA is a peptide antigen that lacks intrinsic biological activity. In vitro and in vivo data have shown that GA-reactive antibodies are not neutralizing. Antibodies do not alter the principal immunological effects of GA, including binding to MHC Class II molecules, activation and proliferation of GA-reactive T cells, and the release of anti-inflammatory Th2 cytokines. Higher antibody titres do not appear to be associated with a deterioration in clinical endpoints, such as relapse rate, EDSS progression or the occurrence of side effects in MS patients treated with GA. The presence of GA-reactive antibodies may promote remyelination and enhance the immunological and clinical effects of GA, indicating that they may be part of GA's mechanism of action. Multiple Sclerosis 2007; 13: S28—S35. http://msj.sagepub.com
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Zubizarreta, Irati, Georgina Flórez-Grau, Gemma Vila, Raquel Cabezón, Carolina España, Magi Andorra, Albert Saiz et al. « Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial ». Proceedings of the National Academy of Sciences 116, no 17 (8 avril 2019) : 8463–70. http://dx.doi.org/10.1073/pnas.1820039116.
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There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.
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Del Gatto, Annarita, Michele Saviano et Laura Zaccaro. « An Overview of Peptide-Based Molecules as Potential Drug Candidates for Multiple Sclerosis ». Molecules 26, no 17 (28 août 2021) : 5227. http://dx.doi.org/10.3390/molecules26175227.
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Multiple sclerosis (MS) belongs to demyelinating diseases, which are progressive and highly debilitating pathologies that imply a high burden both on individual patients and on society. Currently, several treatment strategies differ in the route of administration, adverse events, and possible risks. Side effects associated with multiple sclerosis medications range from mild symptoms, such as flu-like or irritation at the injection site, to serious ones, such as progressive multifocal leukoencephalopathy and other life-threatening events. Moreover, the agents so far available have proved incapable of fully preventing disease progression, mostly during the phases that consist of continuous, accumulating disability. Thus, new treatment strategies, able to halt or even reverse disease progression and specific for targeting solely the pathways that contribute to the disease pathogenesis, are highly desirable. Here, we provide an overview of the recent literature about peptide-based systems tested on experimental autoimmune encephalitis (EAE) models. Since peptides are considered a unique therapeutic niche and important elements in the pharmaceutical landscape, they could open up new therapeutic opportunities for the treatment of MS.
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Leadbetter, Elizabeth A., Cheryl R. Bourque, Brigitte Devaux, Carl D. Olson, Geoffrey H. Sunshine, Shirish Hirani, Barbara P. Wallner, Dawn E. Smilek et Mary Pat Happ. « Experimental Autoimmune Encephalomyelitis Induced with a Combination of Myelin Basic Protein and Myelin Oligodendrocyte Glycoprotein Is Ameliorated by Administration of a Single Myelin Basic Protein Peptide ». Journal of Immunology 161, no 1 (1 juillet 1998) : 504–12. http://dx.doi.org/10.4049/jimmunol.161.1.504.
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Abstract Multiple sclerosis is an autoimmune disease of the central nervous system in which T cell reactivity to several myelin proteins, including myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG), has been implicated in the perpetuation of the disease state. Experimental autoimmune encephalomyelitis (EAE) is used commonly as a model in which potential therapies for multiple sclerosis are evaluated. The ability of T cell epitope-containing peptides to down-regulate the disease course is well documented for both MBP- and proteolipid protein-induced EAE, and recently has been shown for MOG-induced EAE. In this study, we describe a novel EAE model, in which development of severe disease symptoms in (PL/J × SJL)F1 mice is dependent on reactivity to two different immunizing Ags, MBP and MOG. The disease is often fatal, with a relapsing/progressive course in survivors, and is more severe than would be predicted by immunization with either Ag alone. The MOG plus MBP disease can be treated postinduction with a combination of the MOG 41–60 peptide (identified as the major therapeutic MOG epitope for this strain) and the MBP Ac1–11[4Y] peptide. A significant treatment effect can also be obtained by administration of the MBP peptide alone, but this effect is strictly dose dependent. This MBP peptide does not treat the disease induced only with MOG. These results suggest that peptide immunotherapy can provide an effective means of mitigating disease in this model, even when the treatment is targeted to only one component epitope or one component protein Ag of a diverse autoimmune response.
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Esposito, Maria, Vijay Venkatesh, Laszlo Otvos, Zhiping Weng, Sandor Vajda, Katalin Banki et Andras Perl. « Human Transaldolase and Cross-Reactive Viral Epitopes Identified by Autoantibodies of Multiple Sclerosis Patients ». Journal of Immunology 163, no 7 (1 octobre 1999) : 4027–32. http://dx.doi.org/10.4049/jimmunol.163.7.4027.
Texte intégralRésumé :
Abstract Multiple sclerosis is mediated by an autoimmune process causing selective destruction of oligodendrocytes. Transaldolase, which is expressed in the brain selectively in oligodendrocytes, is a target of high affinity autoantibodies in serum and cerebrospinal fluid of multiple sclerosis patients. A three-dimensional model of human transaldolase was developed based on the crystal structure of the enzyme from Escherichia coli. To identify immunodominant epitopes, 33 peptides overlapping human transaldolase by 5 amino acids were synthesized. Ab 12484, raised against enzymatically active human transaldolase, recognized antigenic determinants corresponding to linear epitopes (residues 27–31 and 265–290) and α helices (residues 75–98 and 302–329). Four immunodominant peptides harboring charged amino acid residues with topographically exposed side chains were identified by sera from 13 multiple sclerosis patients with predetermined autoreactivity to transaldolase. Autoantibodies binding to the most prominent human transaldolase epitope, between residues 271 and 285, showed cross-reactivity with Epstein-Barr and herpes simplex virus type 1 capsid-derived peptides. Molecular mimicry between immunodominant autoepitopes and viral Ags may be a decisive factor in directing autoimmunity to transaldolase in multiple sclerosis patients.
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Mustafa, Ghulam, Hafiza Salaha Mahrosh, Mahwish Salman, Sumaira Sharif, Raheela Jabeen, Tanveer Majeed et Hafsah Tahir. « Identification of Peptides as Novel Inhibitors to Target IFN-γ, IL-3, and TNF-α in Systemic Lupus Erythematosus ». BioMed Research International 2021 (13 novembre 2021) : 1–11. http://dx.doi.org/10.1155/2021/1124055.
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Autoimmune disorder is a chronic immune imbalance which is developed through a series of pathways. The defect in B cells, T cells, and lack of self-tolerance has been greatly associated with the onset of many types of autoimmune complications including rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy. The SLE is an autoimmune disease with a common type of lupus that causes tissue and organ damage due to the wide spread of inflammation. In the current study, twenty anti-inflammatory peptides derived from plant and animal sources were docked as ligands or peptides counter to proinflammatory cytokines. Interferon gamma (IFN-γ), interleukin 3 (IL-3), and tumor necrosis factor alpha (TNF-α) were targeted in this study as these are involved in the pathogenesis of SLE in many clinical studies. Two docking approaches (i.e., protein-ligand docking and peptide-protein docking) were employed in this study using Molecular Operating Environment (MOE) software and HADDOCK web server, respectively. Amongst docked twenty peptides, the peptide DEDTQAMMPFR with S -score of -11.3018 and HADDOCK score of − 10.3 ± 2.5 kcal/mol showed the best binding interactions and energy validation with active amino acids of IFN-γ protein in both docking approaches. Depending upon these results, this peptide could be used as a potential drug candidate to target IFN-γ, IL-3, and TNF-α proteins to control inflammatory events. Other peptides (i.e., QEPQESQQ and FRDEHKK) also revealed good binding affinity with IFN-γ with S -scores of -10.98 and -10.55, respectively. Similarly, the peptides KHDRGDEF, FRDEHKK, and QEPQESQQ showed best binding interactions with IL-3 with S -scores of -8.81, -8.64, and -8.17, respectively.
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Wagley, Sariqa, Monika Bokori-Brown, Helen Morcrette, Andrea Malaspina, Caroline D’Arcy, Sharmilee Gnanapavan, Nicholas Lewis et al. « Evidence of Clostridium perfringens epsilon toxin associated with multiple sclerosis ». Multiple Sclerosis Journal 25, no 5 (21 avril 2018) : 653–60. http://dx.doi.org/10.1177/1352458518767327.
Texte intégralRésumé :
Background: It was recently reported that, using Western blotting, some multiple sclerosis (MS) patients in the United States had antibodies against epsilon toxin (Etx) from Clostridium perfringens, suggesting that the toxin may play a role in the disease. Objective: We investigated for serum antibodies against Etx in UK patients with clinically definite multiple sclerosis (CDMS) or presenting with clinically isolated syndrome (CIS) or optic neuritis (ON) and in age- and gender-matched controls. Methods: We tested sera from CDMS, CIS or ON patients or controls by Western blotting. We also tested CDMS sera for reactivity with linear overlapping peptides spanning the amino acid sequence (Pepscan) of Etx. Results: Using Western blotting, 24% of sera in the combined CDMS, CIS and ON groups ( n = 125) reacted with Etx. In the control group ( n = 125), 10% of the samples reacted. Using Pepscan, 33% of sera tested reacted with at least one peptide, whereas in the control group only 16% of sera reacted. Out of 61 samples, 21 (43%) were positive to one or other testing methodology. Three samples were positive by Western blotting and Pepscan. Conclusion: Our results broadly support the previous findings and the role of Etx in the aetiology of MS warrants further investigation.
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Monti, Lucia, Umberto Arrigucci et Alessandro Rossi. « Insights into Endothelin-3 and Multiple Sclerosis ». Biomolecular Concepts 11, no 1 (25 juin 2020) : 137–41. http://dx.doi.org/10.1515/bmc-2020-0012.
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AbstractEndothelins are powerful vasoconstrictor peptides that play numerous other roles. Endothelin-1 (ET1) is the principal isoform produced by the endothelium in the human cardiovascular system. Endothelin-3 (ET3) and its rPptor affinity have been demonstrated to support neuronal repair mechanisms throughout life. In multiple sclerosis (MS), the role of vasoactive peptides are not well defined. Here we focus on ET3, specifically the plasma levels between MS patients and healthy subjects. Furthermore, we evaluated the changes in ET1 and ET3 plasma levels during different disease phases, the correlation between ET3 and cerebral circulation time, and the relationship between ET1 and ET3. In MS patients, the ET3 plasma levels were altered in a time-dependent manner. These results could support a putative role of ET3 in neuroprotection and/or neuroimmune modulation over time.
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Martin, R., U. Utz, J. E. Coligan, J. R. Richert, M. Flerlage, E. Robinson, R. Stone, W. E. Biddison, D. E. McFarlin et H. F. McFarland. « Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87-106. » Journal of Immunology 148, no 5 (1 mars 1992) : 1359–66. http://dx.doi.org/10.4049/jimmunol.148.5.1359.
Texte intégralRésumé :
Abstract Multiple sclerosis (MS), a human demyelinating disease, is thought to be caused by an autoimmunologic process, and myelin basic protein (MBP) is considered a likely autoantigen. Studies of T cell lines (TCL) responding to different parts of the MBP molecule have indicated that amino acids 87 through 106 contain an immunodominant epitope of MBP. We have demonstrated previously that amino acids 89 through 99 represent the core of this 87-106 peptide epitope. Importantly, this epitope is not only encephalitogenic in SJL/J mice and Lewis rats but also has been shown to be recognized by human cytotoxic TCL in the context of four HLA-DR molecules that are associated with MS in different geographic areas. If the immune response to MBP peptide 87-106 was homogeneous with respect to epitope specificity and TCR usage, specific immunotherapies targeting the interaction of peptide, MHC, and TCR might be possible. In this study, the fine specificity of 29 CD4+ cytotoxic, long term, and limiting dilution TCL that had been generated against whole MBP and were derived from four MS patients and two healthy relatives was dissected using truncated and alanine-substituted peptides for the 87-106 peptide. In addition, the TCR alpha and beta chain usage of 15 CD4+ TCL was determined. Using truncated peptides, the presence of several nested immunogenic epitopes within amino acids 87 to 106 was demonstrated. TCL with identical restriction elements and similar responses to truncated peptides could be differentiated further using alanine-substituted peptides. Finally, heterogeneity of TCR usage was shown not only for those lines that differed in their peptide specificity but also for some that showed identical responses and were restricted by the same HLA-DR antigen. In conclusion, the CD4+ cytotoxic T cell response to the immunodominant MBP peptide 87-106 demonstrates a high degree of heterogeneity at the level of fine specificity and TCR usage. These findings indicate that specific immunotherapies aimed at TCR in MS will probably be more complicated than previously anticipated.
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Zhu, Shaochun, Anna Wuolikainen, Junfang Wu, Anders Öhman, Gunnar Wingsle, Thomas Moritz, Peter M. Andersen, Lars Forsgren et Miles Trupp. « Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS ». Journal of Molecular Neuroscience 69, no 4 (12 novembre 2019) : 643–57. http://dx.doi.org/10.1007/s12031-019-01411-y.
Texte intégralRésumé :
Abstract The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) share some common molecular deficits including disruption of protein homeostasis leading to disease-specific protein aggregation. While insoluble protein aggregates are the defining pathological confirmation of diagnosis, patient stratification based on early molecular etiologies may identify distinct subgroups within a clinical diagnosis that would respond differently in therapeutic development programs. We are developing targeted multiple reaction monitoring (MRM) mass spectrometry methods to rigorously quantify CSF proteins from known disease genes involved in lysosomal, ubiquitin-proteasomal, and autophagy pathways. Analysis of CSF from 21 PD, 21 ALS, and 25 control patients, rigorously matched for gender, age, and age of sample, revealed significant changes in peptide levels between PD, ALS, and control. In patients with PD, levels of two peptides for chromogranin B (CHGB, secretogranin 1) were significantly reduced. In CSF of patients with ALS, levels of two peptides from ubiquitin carboxy-terminal hydrolase like protein 1 (UCHL1) and one peptide each for glycoprotein non-metastatic melanoma protein B (GPNMB) and cathepsin D (CTSD) were all increased. Analysis of patients with ALS separated into two groups based on length of survival after CSF sampling revealed that the increases in GPNMB and UCHL1 were specific for short-lived ALS patients. While analysis of additional cohorts is required to validate these candidate biomarkers, this study suggests methods for stratification of ALS patients for clinical trials and identifies targets for drug efficacy measurements during therapeutic development.
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null. « Novel peptides for the treatment of multiple sclerosis ». Expert Opinion on Therapeutic Patents 13, no 1 (2003) : 119–23. http://dx.doi.org/10.1517/eotp.13.1.119.20923.
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Kammona, Olga, et Costas Kiparissides. « Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis ». Brain Sciences 10, no 6 (29 mai 2020) : 333. http://dx.doi.org/10.3390/brainsci10060333.
Texte intégralRésumé :
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and is considered to be the leading non-traumatic cause of neurological disability in young adults. Current treatments for MS comprise long-term immunosuppressant drugs and disease-modifying therapies (DMTs) designed to alter its progress with the enhanced risk of severe side effects. The Holy Grail for the treatment of MS is to specifically suppress the disease while at the same time allow the immune system to be functionally active against infectious diseases and malignancy. This could be achieved via the development of immunotherapies designed to specifically suppress immune responses to self-antigens (e.g., myelin antigens). The present study attempts to highlight the various antigen-specific immunotherapies developed so far for the treatment of multiple sclerosis (e.g., vaccination with myelin-derived peptides/proteins, plasmid DNA encoding myelin epitopes, tolerogenic dendritic cells pulsed with encephalitogenic epitopes of myelin proteins, attenuated autologous T cells specific for myelin antigens, T cell receptor peptides, carriers loaded/conjugated with myelin immunodominant peptides, etc.), focusing on the outcome of their recent preclinical and clinical evaluation, and to shed light on the mechanisms involved in the immunopathogenesis and treatment of multiple sclerosis.
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Lobell, Anna, Robert Weissert, Maria K. Storch, Cecilia Svanholm, Katrien L. de Graaf, Hans Lassmann, Roland Andersson, Tomas Olsson et Hans Wigzell. « Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis ». Journal of Experimental Medicine 187, no 9 (4 mai 1998) : 1543–48. http://dx.doi.org/10.1084/jem.187.9.1543.
Texte intégralRésumé :
We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68–85 (MBP68–85), before induction of EAE with MBP68–85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon γ production after challenge with MBP68–85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.
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Martin, R., D. Jaraquemada, M. Flerlage, J. Richert, J. Whitaker, E. O. Long, D. E. McFarlin et H. F. McFarland. « Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. » Journal of Immunology 145, no 2 (15 juillet 1990) : 540–48. http://dx.doi.org/10.4049/jimmunol.145.2.540.
Texte intégralRésumé :
Abstract Myelin basic protein (MBP) is a candidate Ag for the autoimmune process believed to be involved in the pathogenesis of multiple sclerosis (MS). To investigate the fine specificity and HLA restriction of human MBP-specific CTL, long term T cell lines (TCL) were established from 22 MS patients and 16 healthy individuals by repeated antigenic restimulation. By using this approach, MBP-specific cytotoxic TCL were generated from 81% of the lines from MS patients and 69% of those from controls. TCL from both groups expressed the CD3+, CD4+, CD8- phenotype and secreted substantial amounts of IFN-gamma. By using large enzymatic and small synthetic peptides of MBP, TCL were primarily specific for the C-terminal part of the molecule and to a lesser extent for the N-terminal portion. Two regions of the molecule, MBP peptide 87-106 and MBP peptide 154-172, were recognized by the majority of the polyspecific lines and by four and three of 14 monospecific TCL, respectively. These highly immunogenic regions are of interest because they include sequences encephalitogenic in other species. The HLA restriction of each line was determined by using antibody blocking as well as various target cells including EBV-transformed B cells, homozygous typing cells, and fibroblasts transfected with cDNA for DR-alpha and DR-beta genes. All TCL were restricted by HLA-DR Ag. Several HLA-DR molecules restricted multiple cathepsin D-derived and synthetic MBP peptides, including the regions of peptides 87-106 and 154-172 which, respectively, were recognized in conjunction with four and three HLA-DR types. Three of these HLA-DR types are overrepresented in MS patients in different geographic regions. Together, these findings suggest that the MBP-specific cytotoxic T cell response, although not sufficient for disease, may be important for the pathogenesis of MS.
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Teunissen, CE, MJA Koel-Simmelink, TV Pham, JC Knol, M. Khalil, A. Trentini, J. Killestein et al. « Identification of biomarkers for diagnosis and progression of MS by MALDI-TOF mass spectrometry ». Multiple Sclerosis Journal 17, no 7 (19 avril 2011) : 838–50. http://dx.doi.org/10.1177/1352458511399614.
Texte intégralRésumé :
Introduction: Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of considerable interest in multiple sclerosis (MS). Proteomics tools are optimal for the unbiased simultaneous detection of large series of peptides and proteins. Objectives: To identify novel candidate biomarkers discriminating patients with MS from patients with other neurological diseases (OND), and for subtyping of relapsing–remitting (RR), secondary progressive (SP) and primary progressive (PP) MS patients using a high-throughput MALDI-TOF-based mass spectrometry method. Methods: Paired cerebrospinal fluid (CSF) and serum samples of 41 RRMS, 30 SPMS, 13 PPMS patients and 25 patients with OND were analysed. Results: Out of a total of 100 detected peptides in CSF and 200 peptides in serum, 11 peptides were differentially regulated in serum and two in CSF between patients with MS and the OND control group. Eleven peptides were differentially regulated in both serum and CSF between relapse-onset MS and PPMS patients. Lastly, four peptides were differentially regulated in serum and two in CSF between RRMS and SPMS patients. Specific peaks regulated in MS were tentatively identified as fragments of secretogranin III and complement C3. The peak intensity of the CSF peptide ion with m/z value 8607.7 correlated to atrophy ( r = −0.27, p < 0.005), black hole volumes ( r = 0.31, p < 0.008) and total lesion load ( r = 0.34, p < 0.003). A serum peptide with m/z value of 872.4 elevated in SPMS correlated to Expanded Disability Status Scale ( r = 0.341, p < 0.005) and atrophy ( r = −0.286, p < 0.028). Conclusions: Using high-throughput body fluid profiling by MALDI-TOF mass spectrometry, small proteins and peptides were detected as promising candidate biomarkers for diagnosis and disease progression of MS.
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Weissert, Robert, Anders Svenningsson, Anna Lobell, Katrien L. de Graaf, Roland Andersson et Tomas Olsson. « Molecular and Genetic Requirements for Preferential Recruitment of TCRBV8S2+ T Cells in Lewis Rat Experimental Autoimmune Encephalomyelitis ». Journal of Immunology 160, no 2 (15 janvier 1998) : 681–90. http://dx.doi.org/10.4049/jimmunol.160.2.681.
Texte intégralRésumé :
Abstract The underlying mechanisms behind the preferential expression of select TCRBV products in certain autoimmune illnesses, such as multiple sclerosis and some models of experimental autoimmune encephalomyelitis (EAE), have principally remained enigmatic. In this study, we examined the mutual role of nonself- vs self-origin of antigenic myelin basic protein (MBP) peptides and given MHC haplotypes in relation to the relative frequency of activated TCRBV8S2+ T lymphocytes in the Lewis (LEW) rat EAE model. Inbred MHC (RT1) congenic LEW rats (LEW (RT1l), LEW.1AV1 (RT1av1), and LEW.1W (RT1u)) were immunized with the 63 to 88 peptide of the guinea pig MBP (MBPGP63-88). Additionally, LEW rats were immunized with the corresponding autologous rat sequence (MBPRAT63-88). Although EAE ensued in all MBP peptide/LEW rat strain combinations, only LEW rats immunized with the heterologous MBPGP63-88 peptide elicited T cell responses encompassing a bias toward TCRBV8S2 expression, as determined by flow cytometric analyses. Reduction of TCRBV8S2+ T cells led to mitigation of disease severity in LEW rats immunized with MBPGP63-88, but not with MBPRAT63-88, indicating that critical encephalitogenic characteristics are associated with this T cell subset. We conclude that the preferential recruitment of TCRBV8S2+ T cells in the LEW rat EAE model is due to selective, high-avidity recognition of the nonself-MBPGP63-88 in the context of the RT1.Bl molecule. This inference lends support to the notion that the highly restricted TCR repertoire of the self-MBP-reactive T cells in certain genetically predisposed multiple sclerosis patients may have its source in a multistep molecular mimicry event.
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Mamedov, Azad E., Ioanna N. Filimonova, Ivan V. Smirnov et Alexey A. Belogurov. « Peculiarities of the Presentation of the Encephalitogenic MBP Peptide by HLA-DR Complexes Providing Protection and Predisposition to Multiple Sclerosis ». Acta Naturae 13, no 1 (15 mars 2021) : 127–33. http://dx.doi.org/10.32607/actanaturae.11008.
Texte intégralRésumé :
Predisposition to multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system, is due to various factors. The genetic component is considered one of the most important factors. HLA class II genes contribute the most to the development of MS. The HLA-DRB1*15 allele group is considered one of the main genetic risk factors predisposing to MS. The group of HLA-DRB1*01 alleles was shown to have a protective effect against this disease in the Russian population. In this work, we compared the binding of the encephalitogenic fragment of the myelin basic protein (MBP) to two HLA-DR complexes that provide protection against and predisposition to MS: HLA-DR1 (HLA-DRB1*0101) and HLA-DR15 (HLA-DRB1*1501), respectively. We found that the myelin peptide MBP88-100 binds to HLA-DR1 at a rate almost an order of magnitude lower than the viral peptide of hemagglutinin (HA). The same was true for the binding of MBP85-97 to HLA-DR15 in comparison with viral pp65. The structure of the C-terminal part of the peptide plays a key role in the binding to HLA-DR1 for equally high-affinity N-terminal regions of the peptides. The IC50 of the myelin peptide MBP88-100 competing with viral HA for binding to HLA-DR1 is almost an order of magnitude higher than that of HA. As for HA, the same was also true for the binding of MBP85-97 to HLA-DR15 in comparison with viral pp65. Thus, autoantigenic MBP cannot compete with the viral peptide for binding to protective HLA-DR1. However, it is more competitive than viral peptide for HLA-DR15.
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Mor, F., et I. R. Cohen. « Pathogenicity of T cells responsive to diverse cryptic epitopes of myelin basic protein in the Lewis rat. » Journal of Immunology 155, no 7 (1 octobre 1995) : 3693–99. http://dx.doi.org/10.4049/jimmunol.155.7.3693.
Texte intégralRésumé :
Abstract The cellular immunology of experimental autoimmune encephalomyelitis, a model for multiple sclerosis, has been studied, for the most part, using T cells directed to dominant epitopes of the Ag myelin basic protein (MBP). To characterize T cells reactive to cryptic epitopes of MBP, we immunized Lewis rats with each of 17 overlapping peptides of the 18.5-kDa isoform of rat MBP. We found that, in addition to the known 71-90 epitope, six other peptides induced active encephalomyelitis in the majority the injected rats. T cell lines raised to six different MBP epitopes were encephalitogenic upon adoptive transfer to naive rats. In contrast to the T cells specific for the dominant 71-90 peptide, the T cell lines reactive to cryptic epitopes were not restricted in their TCR genes to V beta 8.2, and some of the lines caused prolonged disease. Thus, T cells of different specificities and TCR usage can be pathogenic.
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Garza, Celeste, Rachel Robinson Joern, Elba Mirelle Rojano et Thomas Forsthuber. « T cell cooperation in the induction of autoimmunity in a murine model of multiple sclerosis ». Journal of Immunology 204, no 1_Supplement (1 mai 2020) : 142.20. http://dx.doi.org/10.4049/jimmunol.204.supp.142.20.
Texte intégralRésumé :
Abstract Multiple sclerosis (MS) is a T cell-driven autoimmune disease. There are many unknowns regarding the disease etiology and pathogenesis. Importantly, the mechanisms of peripheral tolerance and dysregulation of pathogenic mechanisms are poorly understood. It is known that patients with MS exhibit myelin reactive T cells in the blood; however healthy controls also show myelin reactive T cells in the blood. Additionally, T cells from patients with MS react to many different myelin peptides. Current human studies do not support that patients exhibit large populations of T cells specific for a single myelin-antigen responsible for the induction of autoimmune pathology. In contrast, a quorum of several low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides. We found that disease in the experimental autoimmune encephalomyelitis (EAE) model of MS can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. These results support the hypothesis that a quorum of autoreactive T cells could suffice to initiate autoimmune disease. We have developed a system whereby T cells of different antigen specificities can be traced in order to track the dynamics and kinetics of those T cells in disease initiation and progression. The results of this study provide further insights into the dynamic interactions between T cells of different antigen specificities.
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Fanelli, Ilaria, Paolo Rovero, Paul Robert Hansen, Jette Lautrup Frederiksen, Gunnar Houen et Nicole Hartwig Trier. « Reactivity of Rheumatoid Arthritis-Associated Citrulline-Dependent Antibodies to Epstein-Barr Virus Nuclear Antigen1-3 ». Antibodies 11, no 1 (11 mars 2022) : 20. http://dx.doi.org/10.3390/antib11010020.
Texte intégralRésumé :
Rheumatoid arthritis (RA) is a chronic disease which causes joint inflammation and, ultimately, erosion of the underlying bone. Diagnosis of RA is based on the presence of biomarkers, such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factors, along with clinical symptoms. Much evidence points to a link between the Epstein-Barr virus and RA. In this study, we analyzed ACPA reactivity to citrullinated peptides originating from Epstein-Barr nuclear antigens (EBNA1, EBNA2, and EBNA3) in order to elaborate the diagnostic potential of citrullinated EBNA peptides. Moreover, ACPA cross-reactivity to citrullinated peptides from myelin basic protein (MBP) was analyzed, as citrullinated MBP recently was described to be associated with multiple sclerosis, and some degree of sequence homology between MBP and citrullinated EBNA exists. A peptide from EBNA2, (EBNA2-A, GQGRGRWRG-Cit-GSKGRGRMH) reacted with approximately 70% of all RA sera, whereas only limited reactivity was detected to EBNA1 and EBNA3 peptides. Moreover, screening of ACPA reactivity to hybrid peptides of EBNA3-A (EPDSRDQQS-Cit-GQRRGDENRG) and EBNA2-A and peptides containing citrulline close to the N-terminal confirmed that ACPA sera contain different populations of ACPAs. No notable ACPA reactivity to MBP peptides was found, confirming that ACPAs are specific for RA, and that other factors than the presence of a central Cit-Gly motif are crucial for antibody binding. Collectively, these findings illustrate that citrullinated EBNA2 is an optimal candidate for ACPA detection, supporting current evidence that EBV is linked to RA onset.
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Fridkis-Hareli, Masha, et Jack L. Strominger. « Promiscuous Binding of Synthetic Copolymer 1 to Purified HLA-DR Molecules ». Journal of Immunology 160, no 9 (1 mai 1998) : 4386–97. http://dx.doi.org/10.4049/jimmunol.160.9.4386.
Texte intégralRésumé :
Abstract Copolymer 1 (Cop 1) is a random synthetic amino acid copolymer of l-alanine, l-glutamic acid, l-lysine, and l-tyrosine, effective both in suppression of experimental allergic encephalomyelitis and in the treatment of relapsing forms of multiple sclerosis. Cop 1 binds promiscuously and very efficiently to living APCs of various HLA haplotypes. In the present study, a substantial part of the whole mixture of random polypeptides that compose Cop 1 was shown to bind to purified human HLA-DR1, DR2, and DR4 with high affinity in a temperature- and time (and, in the case of DR4, pH)-dependent manner, and was competitively inhibited by DR-restricted peptides, but not by peptide derivatives that bind with low affinity. Bacterial superantigens inhibited Cop 1 binding only at very high concentrations. The formation of the Cop 1-DR1 complex was also shown by SDS-PAGE. These findings represent the first direct evidence for interactions of Cop 1 with purified DR molecules, and suggest that its effectiveness in experimental allergic encephalomyelitis and multiple sclerosis may be directly related to its binding in the groove of HLA-DR proteins.