Dual Implication Of 2',3'-Cyclic Nucleotide 3' Phosphodiesterase As Major AutoAntigen And C3 Complement-Binding Protein In The Pathogenesis Of Multiple Sclerosis
Multiple Sclerosis (MS) is characterized by intra-Blood-Brain Barrier ImmunoGlobulin synthesis that persists lifelong.
SubCellular fractionation and two-dimensional ElectroPhoresis were used in conjunction with Immune precipitation and ImmunoBlotting to identify Antigenic Determinants for this ImmunoGlobulin.
We report that 2', 3'-Cyclic Nucleotide 3'-Phosphodiesterase (CNP), a protein associated with Oligodendrocyte/Myelin membranes, also present in Lymphocytes and Retina, is one major target for the Humoral Response.
AntiBodies to CNP are detected in Sera of 74% of MS patients. The AntiBodies are IgM and are present in Serum in high Titer as well as in CerebroSpinal Fluid.
The AntiBody response is temporally persistent, consistent with Systemic Immune Activation and persistent Antigenic stimulation. Moreover, CNP is isolated as an Immune complex from MS Brain.
CNP is expressed as two isoforms, with CNPII identical to CNPI but with a 20-Amino Acid extension at the Amino terminus of CNPII; however, the AntiBody response is exclusively restricted to CNPI.
In contrast, both isoforms bind the C3 Complement, providing a plausible mechanism in MS Central Nervous System (CNS) for Opsonization of Myelin membrane CNP, mediated via the C3 Receptor, and Phagocytosis of CNP-Ig Immune complexes, mediated by membrane Ig Fc Receptors of Macrophages and CNS Microglia.
MIP-1 And MIP-1ß Differentially Mediate Mucosal And Systemic Adaptive Immunity
James W Lillard, Udai P Singh, Prosper N Boyaka, Shailesh Singh, Dennis D Taub, and Jerry R McGhee
Blood First Edition Paper September 12, 2002
Morehouse School of Medicine, Department of Microbiology, Atlanta, GA, USA; University of Alabama at Birmingham, Department of Microbiology, Birmingham, AL, USA;
Morehouse School of Medicine, Department of Microbiology, Atlanta, GA, USA;
University of Alabama at Birmingham, Department of Microbiology, Birmingham, AL, USA;
National Institutes of Health, National Institute on Aging, Laboratory of Immunology, Baltimore, MD, USA
Macrophage Inflammatory Protein - 1 (MIP-1) and MIP-1ß are, distinct but highly homologous CC Chemokines, produced by a variety of host cells in response to various external stimuli, and share affinity for CCR5.
To better elucidate the role of these CC Chemokines in Adaptive Immunity, we have characterized the affects of MIP-1alpha and MIP-1ß on Cellular and Humoral Immune Responses.
MIP-1 stimulated strong Antigen (Ag)-specific Serum IgG and IgM responses, while MIP-1ß promoted lower IgG and IgM, but higher Serum IgA and IgE AntiBody (Ab) responses.
MIP-1 elevated Ag-specific IgG1 and IgG2b followed by IgG2a and IgG3 subclass responses, while MIP-1ß only stimulated IgG1 and IgG2b subclasses. Correspondingly, MIP-1ß produced higher Titers of Ag-specific Mucosal secretory-IgA Ab levels when compared to MIP-1.
Splenic T-Cells from MIP-1- or MIP-1ß- treated mice displayed higher Ag-specific Th1 (IFN-γ) as well as selective Th2 (IL-5 and IL-6) Cytokine responses than did T-Cells from control groups.
Interestingly, Mucosally derived T-Cells from MIP-1ß-treated mice displayed higher levels of IL-4 and IL-6 compared to MIP-1-treated mice. However, MIP-1 effectively enhanced Ag-specific Cell-mediated Immune Responses.
In correlation with their selective effects on Humoral and Cellular Immune Responses, these Chemokines also differentially attract CD4+ versus CD8+ T-Cells and modulate CD40, CD80, and CD86 expressed by B220+ Cells as well as CD28, 4-1BB, and gp39 expression by CD4+ and CD8+ T-Cells in a dose-dependent fashion.
Taken together, these studies suggest that these CC Chemokines differentially enhance Mucosal and Serum Humoral as well as Cellular Immune Responses.
Polyclonal IgM Influence Oligodendrocyte Precursor Cells In Mixed Glial Cell Cultures: Implications For ReMyelination
Stangel M, Bernard D
J NeuroImmunol 2003 May;138(1-2):25-30
Universitatsklinikum Benjamin Franklin, Department of Neurology, Freie Universitat Berlin, Berlin, Germany
Polyclonal ImmunoGlobulins for IntraVenous use (IVIg) are a potent ImmunoModulator and have been shown to be effective in several Immune-mediated diseases. This includes Inflammatory DeMyelinating Diseases of the Central Nervous System (CNS) like Multiple Sclerosis (MS).
Besides their ImmunoModulatory function, IVIg have been proposed to enhance ReMyelination based on studies in the animal model of Theiler's Murine Encephalomyelitis Virus (TMEV).
Disappointingly, recent treatment trials in patients with MS have failed to demonstrate repair of longstanding deficits.
Since the clinical trials have used IVIg that contained nearly exclusively IgG, whereas the most pronounced effect in TMEV was seen with IgM, this could be a possible explanation for the negative outcome in the MS trials.
Here we have examined the effects of a new PolyClonal IgM preparation (IVIgM) on cultured Oligodendrocyte Precursor Cells (OPCs).
To achieve successful ReMyelination, OPCs proliferate, migrate, and differentiate into mature myelinating Oligodendrocytes.
IVIgM and commercial IVIg preparations had no influence on proliferation and differentiation of either isolated OPCs or OPCs in coculture with Microglia.
In contrast, IVIgM inhibited the proliferation of OPCs in mixed Glial cultures containing Astrocytes and Microglia.
This was not seen in cultures treated with IVIg, Albumin, or Interferon-gamma (IFN-γ), suggesting that this is a specific effect of IVIgM.
Differentiation was slightly delayed by IVIgM in mixed Glial cultures, but this was not statistically significant and Interferon-γ had a similar effect.
These results underline the importance of IgM in influencing OPCs and corroborate the in vivo findings that PolyClonal IgM are more potent than IgG in their capacity to influence ReMyelination.
The exact mechanism of how this modulation of OPCs is achieved remains unknown, but a complex interaction among all cells present in the CNS has to be postulated.
A Randomized Trial Of IntraVenous ImmunoGlobulin In Inflammatory DeMyelinating Optic Neuritis
Noseworthy JH, O'Brien PC, Petterson TM, Weis J, Stevens L, Peterson WK, Sneve D, Cross SA, Leavitt JA, Auger RG, Weinshenker BG, Dodick DW, Wingerchuk DM, Rodriguez M
Neurology 2001 Jun 12;56(11):1514-22
Mayo Clinic and Mayo Foundation, Department of Neurology, Rochester, MN 55905, USA
To determine whether IV ImmunoGlobulin (IVIg) reverses chronic Visual Impairment in MS patients with Optic Neuritis (ON).
In this double-blind, placebo-controlled Phase II trial, 55 patients with persistent Acuity Loss after ON were randomized to receive either IVIg 0.4 g/kg daily for 5 days followed by three single infusions monthly for 3 months, or placebo.
The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled.
Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up.
Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR Visual scores at 6 months (p = 0.766).
Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in Visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable MS during the trial.
IVIg administration does not reverse persistent Visual loss from ON to a degree that merits general use.