Proteasome Is A Major AutoAntigen In Multiple Sclerosis
Mayo I, Arribas J, Villoslada P, Alvarez DoForno R, Rodriguez-Vilarino S, Montalban X, De Sagarra MR, Castano JG.
Brain 2002 Dec;125(Pt 12):2658-2667
Instituto de Investigaciones Biomedicas 'Alberto Sols', UAM-CSIC, Facultad de Medicina, UAM, Servicio de Inmunologia, Hospital Universitario 'La Paz', Madrid and Unitat de NeuroImmunologia Clinica. Hospital Vall d'Hebron, Barcelona, Spain
Multiple Sclerosis seems to be an AutoImmune Disease of unknown Etiology affecting the White Matter of the CNS. It is generally accepted that the AutoImmune Response is directed against specific components of Myelin.
We show here that Proteasome, a ubiquitous Protease complex composed of 14 different subunits, is a target for AutoAntibodies (IgG and IgM classes) present in the Serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with Multiple Sclerosis.
Using recombinant Proteasomal subunits we demonstrate the presence of specific AutoAntibodies against subunits C2, C8, C9 and C5 in Multiple Sclerosis patients.
Recombinant C2 constructs allow us to localize an ImmunoDominant AutoEpitope recognized by the Sera of Multiple Sclerosis patients within the C-terminal of C2 Proteasomal subunit (251-Depaekadepmeh-263).
In addition, two constructs of the recombinant Proteasomal subunits C2 and C8 were also used to study the proliferation of peripheral blood MonoNuclear Cells from Multiple Sclerosis patients; 12 out of 30 (40%) Multiple Sclerosis patients show positive proliferation with one or both of these recombinant subunits.
The high prevalence of AntiProteasome AutoAntibodies in Multiple Sclerosis Sera compared with Sera from patients with other chronic inflammatory conditions:
- Systemic Lupus Erythematosus (35%, 35 out of 100)
- primary Sjogren's Syndrome (16%, 5 out of 31)
- Vasculitis (0 out of 20)
- Sarcoidosis (7%, 1 out of 13)
- Behcet's Disease (19%, 4 out of 21)
Suggest that Humoral AutoReactivity to Proteasome could be a useful test in Multiple Sclerosis patients that may be of help in the diagnosis and/or progression of this chronic inflammatory disease.
Finally, these results suggest that some global abnormality in B and/or T-Cell function is also involved in the chronic inflammatory response observed in Multiple Sclerosis patients, as it is frequently observed in other human organ-specific AutoImmune Diseases.
Evidence For The Genetic Role of Human Leukocyte Antigens In Low Frequency DRB1*1501 Multiple Sclerosis Patients In Israel
Karni A, Kohn Y, Safirman C, Abramsky O, Barcellos L, Oksenberg JR, Kahana E, Karussis D, Chapman J, Brautbar C
Mult Scler 1999 Dec;5(6):410-5
Hadassah University Hospital, Hebrew University Hadassah Medical School, Department of Neurology, Jerusalem, Israel
PMID# 10618697; UI# 20087448
A strong association exists between Multiple Sclerosis (MS) and the DRB1*1501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on Chromosome 6p21 has previously been observed in DRB1*1501 positive MS families.
A group of 13 Israeli multiplex MS families with a very low frequency of DRB1*1501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1501 effect of HLA on susceptibility for MS.
MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248.
Data analyzes included:
- An association study comparing the patient group with both healthy relative, and healthy control groups
- Transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families
- Multipoint non-parametric linkage (NPL) and parametric LOD score analyzes using the GENEHUNTER program
The DRB1*1303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB1*1303, but was not statistically significant.
Allele sharing and LOD score analyzes revealed no evidence for linkage. The high frequency of DRB1*1303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients.
Thus, DRB1*1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.
MRI Techniques To Monitor MS Evolution: The Present And The Future
Filippi M, Grossman RI
Neurology 2002 Apr 23;58(8):1147-53
NeuroImaging Research Unit, Department of NeuroScience, Scientific Institute and University Ospedale San Raffaele, Milan, Italy
PMID# 11971079, UI# 21966380
Conventional MRI (cMRI) is limited in its ability to provide specific information about pathology in MS.
Measures commonly derived from cMRI include T2 lesions, T1-enhanced lesions, Atrophy, and possibly T1-HypoIntense lesions, which have been extensively investigated in many clinical trials.
Better MRI measures are needed to advance our understanding of MS and design ideal clinical trials. This article reviews the strengths and weaknesses of the major MRI-based methods used to monitor MS evolution and submits that
1) metrics derived from Magnetization Transfer MRI, Diffusion-weighted MRI, and Proton MRS should be implemented to achieve reliable specific in vivo quantification of MS pathology;
2) targeted multiparametric MRI protocols rather than generic application of cMRI should be used in all possible clinical circumstances and trials; and
3) reproducible quantitative MR measures should ideally be used for the assessment of patients but are essential for clinical trials.
Glatiramer Acetate-Specific T-Helper 1- And 2-Type Cell Lines Produce BDNF: Implications For Multiple Sclerosis Therapy
Ziemssen T, Kumpfel T, Klinkert WE, Neuhaus O, Hohlfeld R
Brain 2002 Nov;125(Pt 11):2381-2391
Max Planck Institute of NeuroBiology, Department of NeuroImmunology, Martinsried; Ludwig Maximilians University, Institute for Clinical NeuroImmunology and Department of Neurology, Klinikum Grosshadern, Munich, Germany; and Karl-Franzens-University Graz, Department of Neurology, Austria
The clinical effects of Glatiramer Acetate (GA), an approved therapy for Multiple Sclerosis, are thought to be largely mediated by a T-Helper 1 (Th1) to T-Helper 2 (Th2) shift of GA-reactive T-Lymphocytes.
Current theories propose that activated GA-reactive Th2 cells penetrate the CNS, release AntiInflammatory Cytokines such as InterLeukin (IL-4), IL-5, and IL-10.
And thus inhibit neighboring inflammatory cells by a mechanism termed 'Bystander Suppression'.
We demonstrate that both GA-specific Th2 and Th1 Cells produce the NeuroTrophin Brain-Derived NeuroTrophic Factor (BDNF).
As the signal-transducing receptor for BDNF, the full-length 145 Tyrosine Kinase Receptor (trk) B, is expressed in Multiple Sclerosis lesions.
It is likely that the BDNF secreted by GA-reactive Th2 and Th1 has NeuroTrophic effects in the Multiple Sclerosis target tissue.
This may be an additional mechanism of action of GA, and may be relevant for therapies with altered Peptide Ligands in general.
To demonstrate that GA-reactive T-Cells produce BDNF, we selected four GA-specific, long-term T-Cell lines (TCLs).
Which were characterized according to their Cytokine profile by IntraCellular double-fluorescence flow cytometry.
Three TCLs (isolated from a normal subject) had the phenotypes Th1, Th1/Th0, and Th0; the fourth, derived from a GA-treated patient, had the phenotype Th2.
To demonstrate BDNF production, we used a combination of RT-PCR (Reverse Transcription-Polymerase Chain Reaction) and two specially designed techniques for BDNF protein detection:
One was based on ELISA (Enzyme-Linked Immunosorbent Assay) of supernatants from co-cultures of GA-specific TCLs plus GA-pulsed Antigen-Presenting Cells.
And, the other on the direct IntraCellular staining of BDNF in individual T-Cells and flow cytometric analysis.
The different assays and different TCLs yielded similar, consistent results.
All four GA-specific T-Cell lines, representing the major different TH phenotypes, could be stimulated to produce BDNF.