This Is MS Multiple Sclerosis Knowledge & Support Community

alemtuzumab = Campath
daclizumab = Zenapax
interesting that Efalizumab = Raptiva for psoriasis blocks T-cell migration. Ain't that just what natalizumap does, too?
why have I heard of Infliximab = Remicade?
anybody know rituximab = Rituxan?

Billmeik wrote:What the hell is an auto antibody?

from jimmylegs' link

An autoantibody is an antibody (a type of protein) manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body". Many autoimmune diseases, notably lupus erythematosus, are caused by such autoantibodies.

Up until now, MS has been called autoimmune but with no evidence of any autoantigen. The lack of an autoantigen called into question whether or not MS is an autoimmune condition, especially if we can look to alternate explanations such as CCSVI. Now if there's an autoantigen and people can be tested for it and about 45% or whatever the number was from the first post will have this autoantigen. This opens up new lines of inquiry such as what if the people who have this autoantigen do not have as good of a neurological response to venoplasty as the patients who do not have the autoantigen? What if the people with the autoantigen are the ones who respond better to DMDs? Will the autoantigen still be present in the blood a year or two after venoplasty, or if the blood-brain barrier tightens, will the amount of autoantigen in the blood diminish? It has been said that MS may be a heterogenous bunch of diseases clumped together under one label, and this autoantigen may separate out a subset of patients with MS who have a true autoimmunity component to their disease which may persist even after CCSVI is treated. Too many 'mays' in that sentence because, as always, research is needed.

But as for what the hell is an autoantibody:
just as the body makes antibodies to a cold virus in sufficient quantity to kill off the cold virus, our bodies may be making antibodies to components of our own brain matter

wiki CD46:
http://en.wikipedia.org/wiki/CD46
"CD46 complement regulatory protein, also known as CD46 (cluster of differentiation 46) and Membrane Cofactor Protein, is a protein which in humans is encoded by the CD46 gene.[1] CD46 is an inhibitory complement receptor.[2]"

so if defective CD46 is a problem, and it's a protein, could protein misfolding be the defect? investigating the structure of CD46... ow my brain...

Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens
http://www.plospathogens.org/article/in ... at.1001122
"Common to all the proteins expressed from the RCA cluster is their modular construction, which is primarily based on concatenated short consensus repeats (SCR) [3]. Each SCR module contains about 60 amino acids that fold into a compact β-barrel domain surrounded by flexible loops [27]. While the modules display high sequence variability, they all contain four conserved cysteine residues that form two disulfide bridges at the top and bottom of the repeat. The number of repeats present in the members of the RCA family ranges from four in CD55 and CD46 to 30 in CD35. Many structures of fragments of RCA family members are known, and they exhibit significant diversity both in their loop structures and also in their interdomain orientation [28], [29]. The four SCRs in CD46 constitute the bulk of its extracellular region. The repeats are connected to a short linker region rich in serines, threonines and prolines (STP region), a single membrane-spanning segment, and a cytoplasmic tail. Alternative splicing generates multiple isoforms of CD46 that all have identical N-terminal repeats but exhibit variation in the STP region and the cytoplasmic tail [30].

The crystal structure of the N-terminal two repeats, SCR1 and SCR2, of CD46 (CD46-2D) revealed essential features of this region, including a pronounced bend between the two repeats and significant flexibility at the interdomain interface [31]. Although CD46-2D is heavily glycosylated, one side of the two-domain fragment was found to be entirely devoid of glycans. Subsequent crystal structures of CD46-2D in complex with the Adv fiber knob [32], [33] and with the MV hemagglutinin [34] demonstrated that both viral attachment proteins bind to this glycan-free surface. In both cases, engagement by the virus leads to “straightening” of the CD46-2D protein into a linear conformation. Furthermore, both viral attachment proteins form contacts with CD46-2D that predominantly involve residues at the SCR1-SCR2 interface. The implications of the structural rearrangement of CD46 upon ligand binding are not understood."

here we are at membranes and tight junctions again...

A novel Role for the complement regulator CD46 in epithelial tight junction formation/regulation
https://wao.confex.com/wao/2010isc/webp ... r1705.html
"...we found that CD46 interacts with E-cadherin and SPAK, both vital proteins in the maintenance of epithelial cell layer integrity. Mutations in either protein cause colon cancer or IBD, respectively. Further, we observed that CD46 regulates tight junctions and by this transepithelial resistance and paracellular permeability. Based on these data we hypothesize that complement/CD46 communicates with the E-cadherin/catenin network in epithelial cells (via interaction/activation of SPAK) and contributes to normal epithelial cell barrier integrity."

taking it back to some earlier thoughts (2008) i had on intestinal membrane integrity and zinc...

http://www.thisisms.com/forum/general-d ... tml#p34958

Trace Elements in Human Health and Disease: An Update
The many functions of zinc in inflammatory conditions of the gastrointestinal tract
Keywords
gastric diseases; inflammatory bowel disease; intestinal permeability; inflammation; zinc
Abstract
A variety of inflammatory gastrointestinal diseases are associated with altered zinc metabolism or deficiency. Acute and chronic diarrheal disorders may cause deficiency because of increased losses, altered immunity or decreased absorption. When the small intestinal barrier is altered by inflammation, zinc supplementation may be beneficial not only in correcting the deficiency but also because it improves the small bowel mucosal capacity of absorbing water and electrolytes. Zinc is known to have antioxidant properties being a membrane stabilizer, scavenging reactive oxygen metabolites and regulating cytokine synthesis through the activation of transcription factors and this has relevant potential in inflammatory bowel diseases. Moreover, the element stimulates tissue healing and repair in experimental ulcers directly through promoting cell proliferation, protein synthesis and growth factors production and scavenging free radicals. Interest is growing in supplementary therapies with elements and vitamins but current research suggests great caution and to balance the benefits and dangers of uncontrolled administration, since zinc can also stimulate an increased acute phase response and this can exacerbate chronic relapsing diseases. Zinc plays an important role in inflammation. The metal has catalytic, co-catalytic and structural functions in many zinc-dependent enzymes of the body through the regulation of gene expression. Moreover, the involvement of zinc finger proteins in the genetic expression of growth factors has been established. Zinc stabilizes cellular membranes especially interacting at the SH levels and preventing depolarization of phospholipids. The effects on cellular immunity and especially on the activity of serum thymulin and natural killer cells, T-lymphocyte proliferation and interleukin-2 production are also well-known. A growing body of evidence suggests a role for zinc in antioxidant defence systems. The metal has only one stable oxidation state (divalent) and is not affected by free radicals or oxidative stress. It may act as a scavenger of radical products through the synthesis of enzymes such as superoxide dismutase (SOD) and metallothionein (MT) or it may affect cytokine-activated transcription factors. J. Trace Elem. Exp. Med. 13:33-39, 2000. © 2000 Wiley-Liss, Inc.

i've posted elsewhere on zinc and protein misfolding, but it's going to take me a while to figure out if any of this hangs together...

Thanks to jimmylegs I began using zinc over a year ago for IBD (Crohns) and had complete symptom resolution. I've since learned that zinc is useful for combatting the common cold. For the first time in years, possibility decades, I had no colds this past year. I've been having troubles lately with zinc in terms of the return of bowel issues, so I've switched to zinc pocolinate in hopes that I can continue my "zinc run". I shall post my complete regimen shortly for comment.

looking forward to it, PN, hope we can get you sorted. remind me if you were getting bloodwork done?

i think i'll have a lot of reading to do, in order to pull together coherent thoughts on CD46, KIR4.1, DLG4, PSD-95/SAP90, etc!!!

http://neuro.cjb.net/content/21/15/5429.short

Kir4.1 Potassium Channel Subunit Is Crucial for Oligodendrocyte Development and In Vivo Myelination

Abstract

To understand the cellular and in vivo functions of specific K+ channels in glia, we have studied mice with a null mutation in the weakly inwardly rectifying K+ channel subunit Kir4.1. Kir4.1−/− mice display marked motor impairment, and the cellular basis is hypomyelination in the spinal cord, accompanied by severe spongiform vacuolation, axonal swellings, and degeneration. Immunostaining in the spinal cord of wild-type mice up to postnatal day 18 reveals that Kir4.1 is expressed in myelin-synthesizing oligodendrocytes, but probably not in neurons or glial fibrillary acidic protein-positive (GFAP-positive) astrocytes. Cultured oligodendrocytes from developing spinal cord of Kir4.1−/− mice lack most of the wild-type K+ conductance, have depolarized membrane potentials, and display immature morphology. By contrast, cultured neurons from spinal cord of Kir4.1−/− mice have normal physiological characteristics. We conclude that Kir4.1 forms the major K+ conductance of oligodendrocytes and is therefore crucial for myelination.The Kir4.1 knock-out mouse is one of the few CNS dysmyelinating or demyelinating phenotypes that does not involve a gene directly involved in the structure, synthesis, degradation, or immune response to myelin. Therefore, this mouse shows how an ion channel mutation could contribute to the polygenic demyelinating diseases.

Lack of KIR4.1 certainly could explain an MS white matter lesion or two.

Is the Kir4.1 mRNA itself regulated by hypoxia? Cultured astrocytes were placed in an
environmental chamber for 4 or 16 h in 5% CO 2 /95% N 2 . Under the microscope, the 4-h hypoxic
cultures appeared normal, whereas after 16 h there was obvious cell death

http://tinyurl.com/cbq27gn
If the KIR4.1 mRNA is regulated by hypoxia, perhaps it dies naturally under our CCSVI hypoxic conditions, and the immune system cleans up, thus generating antigens to KIR4.1 in 45% of pwMS?

Downregulation of KIR4.1 is also seen in autoimmune uveitis, which I have and which is associated with MS but without good explanation for that assocation:
http://onlinelibrary.wiley.com/doi/10.1 ... ated=false

nice finds cece

PSD-95 and SAP97 Exhibit Distinct Mechanisms for Regulating K+ Channel Surface Expression and Clustering
http://jcb.rupress.org/content/148/1/147.full

"ion channel clustering by PSD-95 and SAP97 occurs by distinct mechanisms, and suggests that these channel-clustering proteins may play diverse roles in regulating the abundance and distribution of channels at synapses and other neuronal membrane specializations...
Previous studies showed that coexpression of either PSD-95 or SAP97 increased the density of Kir4.1 currents in transfected cells by increasing the number of functional channels (Horio et al., 1997). The authors proposed that PSD-95 and SAP97 may play an important biosynthetic role in facilitating the surface expression of Kir4.1."

so now i wonder, what induces biosythesis of the Kir4.1 autoantigen? are there good reasons for autoantigens, under healthy conditions? is it just when they get out of control that they're a problem? or is the mere fact that they exist, evidence of a broken system? thoughts?

Writing up a note about this discovery for FB--

We see an immune reaction towards this protein in the rat brain with hydrocephalus.
KIR4.1 is a potassium channel protein which is involved in "water flux"

Hydrocephalus is characterized by impaired cerebrospinal fluid (CSF) flow with enlargement of the ventricular cavities of the brain and progressive damage to surrounding tissue. Bulk water movement is altered in these brains. We hypothesized that increased expression of aquaporins, which are water-permeable channel proteins, would occur in these brains to facilitate water shifts. We used quantitative (real-time) RT-PCR, Western blotting and immunohistochemistry to evaluate the brain expression of aquaporins (AQP) 1, 4, and 9 mRNA and protein in Sprague–Dawley rats rendered hydrocephalic by injection of kaolin into cistern magna. AQP4 mRNA was significantly up-regulated in parietal cerebrum and hippocampus 4 weeks and 9 months after induction of hydrocephalus (P < 0.05). Although Western blot analysis showed no significant change, there was more intense perivascular AQP4 immunoreactivity in cerebrum of hydrocephalic brains at 3–4 weeks after induction. We did not detect mRNA or protein changes in AQP1 (located in choroid plexus) or AQP9 (located in select neuron populations). Kir4.1, a potassium channel protein linked to water flux, exhibited enhanced immunoreactivity in the cerebral cortex of hydrocephalic rats; the perineuronal distribution was entirely different from that of AQP4. These results suggest that brain AQP4 up-regulation might be a compensatory response to maintain water homeostasis in hydrocephalus.

http://www.ncbi.nlm.nih.gov/pubmed/16819982

In normal brain tissue, AQP4 and Kir4.1 were detected around the microvessels. In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770130/
Maybe CCSVI creates venous congestion--a situation akin to hydocephalus--with swelling and an interruption in cerebral spinal fluid and a break in the BBB, and this activates the immune reaction to KIR4.1??
cheer

CSF flow is very relevant to CCSVI. great find.