This Is MS Multiple Sclerosis Knowledge & Support Community

http://www.medpagetoday.com/clinical-co ... id=5517461

KIR4.1 appears to represent the first autoantigen associated with multiple sclerosis, as reported online in the New England Journal of Medicine.

"The antibody is present in a subgroup of persons with multiple sclerosis -- 47% of the group that we analyzed -- and it has biologic effects in vivo," Bernhard Hemmer, MD, of the Technical University of Munich, and co-authors wrote in their summation.

It's possible that CCSVI sets up conditions that weaken the blood-brain barrier due to known effects of low shear such as the increase adhesion molecules that transport leukocytes across to the brain. An autoimmune reaction can start that would never have started if the access had not been granted by the weakened blood-brain barrier.

"Even if autoantibodies are secondary to the pathology of multiple sclerosis, it is conceivable that they may perpetuate destruction of the central nervous system," wrote editorialists Anne H. Cross, MD, of Washington University in St. Louis, and Emmanuelle Waubant, MD, PhD, of the University of California San Francisco.

Now the question is if these autoantibodies can be targeted directly
Great research. I am tired of reading that MS is a disease of unknown etiology. Let's get some more knowns in there.

The statement that:

Even if autoantibodies are secondary to the pathology of multiple sclerosis, it is conceivable that they may perpetuate destruction of the central nervous system.

is not shown anywhere, is it? I am also tired of "unknown etiology". In contrast, it must be easy to show that hypoxia causes a similar perpetuation.

Is this an antigen without a real target? Or do we just not know what it is?

weird, the potassium channel. i'm thinking about protein misfolding a lot lately, so when i did a little reading on Kir4.1, the protein connection stood out.

Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90.
http://www.ncbi.nlm.nih.gov/pubmed/9148889
Abstract
An inwardly rectifying potassium channel predominantly expressed in glial cells, Kir4.1/KAB-2, has a sequence of Ser-Asn-Val in its carboxyl-terminal end, suggesting a possible interaction with an anchoring protein of the PSD-95 family. We examined the effects of PSD-95 on the distribution and function of Kir4.1 in a mammalian cell line. When Kir4.1 was expressed alone, the channel immunoreactivity was distributed homogeneously. In contrast, when co-expressed with PSD-95, prominent clustering of Kir4.1 in the cell membrane occurred. Kir4.1 was co-immunoprecipitated with PSD-95 in the co-expressed cells. Glutathione S-transferase-fusion protein of COOH terminus of Kir4.1 bound to PSD-95. These interactions disappeared when the Ser-Asn-Val motif was deleted. The magnitude of whole-cell Kir4.1 current was increased by 2-fold in cells co-expressing Kir4.1 and PSD-95 compared with cells expressing Kir4. 1 alone. SAP97, another member of the PSD-95 family, showed similar effects on Kir4.1. Furthermore, we found that Kir4.1 as well as SAP97 distributed not diffusely but clustered in retinal glial cells. Therefore, PSD-95 family proteins may be a physiological regulator of the distribution and function of Kir4.1 in glial cells.

went looking for more on PSD-95/SAP-90. it's a "scaffolding protein". encoded by DLG4 gene. looked up DLG4. seems more like i looked up PSD-95, but still interesting:

http://en.wikipedia.org/wiki/DLG4
"PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the DLG4 (disks large homolog 4) gene...
PSD-95 is the best studied member of the MAGUK-family of PDZ domain-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an SH3 domain, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of neurons,[4] and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels.[5]"

okay. next i found this
http://www.nextbio.com/b/search/da/DLG4 ... ry=1206167

from that page i zeroed in on prion disease:

Disease Atlas for DLG4 (gene)
Name...........: :.....Score 0/ 50/ 100.....: :.....Supporting Data Types.....: :.....# Studies.....: :.....Effect on Query
Prion disease..: :......................99.....: :.............................RE......................2.....: :.....down-regulated

there's even a study linking DLG4 and zinc (scroll down to nutritional/metabolic diseases - zinc deficiency) but, not being a member of the disease atlas web site, i will have to dig that up on my own.


then, seeing if there's a connection between DLG4 and MS, found this:

T-cell regulation by CD46 and its relevance in multiple sclerosis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566619/
"CD46 is a complement regulatory molecule expressed on every cell type, except for erythrocytes. While initially described as a regulator of complement activity, it later became a ‘magnet for pathogens’, binding to several viruses and bacteria. More recently, an alternative role for such complement molecules has emerged: they do regulate T-cell immunity, affecting T-cell proliferation and differentiation. In particular, CD46 stimulation induces Tr1 cells, regulatory T cells characterized by massive production of interleukin-10 (IL-10), a potent anti-inflammatory cytokine. Hence, CD46 is likely to control inflammation. Indeed, data from CD46 transgenic mice highlight a role for CD46 in inflammation, with antagonist roles depending on the cytoplasmic tail being expressed. Furthermore, recent data have shown that CD46 is defective in multiple sclerosis, IL-10 production being severely impaired in these patients. This lack of IL-10 production probably participates in the inflammation observed in patients with multiple sclerosis. This review will summarize the data on CD46 and T cells, and how CD46 is likely involved in multiple sclerosis."

i had picked up the abstract above because of some text in the google results, which i guess were a citation..

A functional interaction between CD46 and DLG4: a role for DLG4 in epithelial polarization
http://www.ncbi.nlm.nih.gov/pubmed/11714708
"Using a yeast two-hybrid screen, we identified a physical interaction between CD46 and DLG4. CD46 is a ubiquitous human cell-surface receptor for the complement components C3b and C4b and for measles virus and human herpesvirus 6. DLG4 is a scaffold protein important for neuronal signaling and is homologous to the Drosophila tumor suppressor DLG. We show that an interaction between CD46 and DLG4 is important for polarization in epithelial cells. Specifically, we show (i) biochemical evidence for an interaction between CD46 and DLG4, (ii) that this interaction is specific for the Cyt1 (but not Cyt2) domain of CD46, (iii) that both CD46 and an alternatively spliced isoform of DLG4 are polarized in normal human epithelial cells, and (iv) that the polarized expression of CD46 in epithelial cells requires the DLG4-binding domain and alters with expression of a truncated form of DLG4. This is the first identification of a direct and cytoplasmic domain-specific interaction between CD46 and an intracellular signaling molecule and provides a molecular mechanism for the polarization of CD46. These data also indicate that, in addition to the known role for DLG4 in neuronal cells, DLG4 may be important for polarization in epithelial cells."

quite interesting.

main article abstract:

Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis
http://www.nejm.org/doi/full/10.1056/NEJMoa1110740
Background
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known.
Methods
We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo.
Results
Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum.
Conclusions
KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis.

Jimmylegs,

Very interesting info indeed. I'm such a lay person when reading through the MS related research though. And as an MS patient, I have followed both the Swank Diet (Low Fat) and the Ann Borash diet (Candia albicans overgrowth)

As CD46 and DLG4 are both monoclonal antibodies, are they somehow related to Candida albicans?
http://www.labinova.se/media/downloads/9/ip.pdf

or better yet, how about this article titled, How fungi steal zinc from your body, I know you often mention the importance of our Zinc levels.

http://blogs.scientificamerican.com/lab ... your-body/


I know from personal experience that I felt sooooooooooo much better when I followed the Candida albicans elemination diet and completely eliminated sugar from my diet. Now I've let sugar re-enter my diet and I have been steadily going down hill. Guess I already know what I need to do.

PURGE the pantry of POISON (sugar)


Respectfully,
Lora

Is Sugar Toxic to Your Body, to your blood vessels? - Yes Lora!
Best Arne

'The Video shows how sugar not only causes heart disease and diabetes, but also feeds tumors and is as addictive as Cocaine to your brain.' http://www.truthaboutabs.com/toxic-sugar.html

jimmylegs, I have some reading to do if I'm going to keep up.

These data also indicate that, in addition to the known role for DLG4 in neuronal cells, DLG4 may be important for polarization in epithelial cells

Rather fitting for a disease that is both neurological and vascular.

hi lora, trust me i'm no pro! :S just rounding another interesting new learning curve

that said, i need clarification on CD46 and DLG4, because i'm not sure they are essentially monoclonal antibodies, rather genes and proteins encoded by said genes, with related antibodies.

according to the esteemed wikipedia:

The CD46 gene encodes CD46 complement regulatory protein.
The DLG4 gene encodes PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-
associated protein 90).

there are monoclonal antibodies to both CD46 and PSD-95 proteins.

i can't click through right now, but as for fungi stealing zinc, that's interesting since i have this strong impression that crimini mushrooms are one of the decent dietary sources of zinc.

and as for candida albicans, back in '06 my naturopath gave me some dietary recommendations which made no sense to me having been a long term vegan, along the lines of no eggs, no dairy, the familiar stuff. i had trouble with candida back then, regularly. i thought candida was causal, meanwhile my naturopath said no, it's opportunistic. conclusion 6 years later, she was right. because i realized i was zinc deficient, corrected it (in the context of correcting suboptimal uric acid status), and the candida problem resolved simultaneously as a nice little perk.

the really interesting part is, that the candida diets just remove all the things that are known to drain zinc out of your system. adequate zinc provides a ph environment that is inhospitable to overgrowth by candida albicans. if you let your zinc status get down enough that candida becomes an issue, then you have the potential for additional nutrient losses.

now sugar is a double whammy because sure it would feed candida, but it also is one of those pesky zinc-draining foods (with a wide spectrum of potential consequences). i eat sugar pretty much daily, but i also take my zinc pretty regularly. and here i am with no candida issues, last few years have been the first time in my life. i'd been dealing with candida since i was a kid. my mom had me on an anti-candida diet forever ago. but we didn't know then what we know now. so, the ms dx was good for something

how's your diet for zinc-rich foods normally? eg venison, calf liver, beef, scallops, oysters etc? also, do you happen to supplement zinc? and if so, what form, how much, what timing, and in combination with which other supplements?

hi cece, i feel the same way! lots of reading to do on this new (to me) tangent.

Hi Legs,

It was this link, http://www.labinova.se/media/downloads/9/ip.pdf that said, CD46 and DLG4 are both monoclonal antibodies, but now that I went back there again, I think I was out of my scope of understanding, and that web site is not revelant to this discussion. My oops!

looks like those are products which can be used to isolate CD46 protein for research purposes, a la:

http://www.ncbi.nlm.nih.gov/pubmed/12882822
"Immunoprecipitation experiments demonstrated that CD46 and beta1 integrin coprecipitated from RPE cell lysates when either protein was used as the precipitating antibody. The adhesion assay showed that antibodies to either CD46 or beta1 integrin reduced RPE adhesion to the surface of Bruch's membrane compared with the control."

I think these guys use all kinds of fancy techniques like PCR (Polymerase chain reaction (PCR) enables researchers to produce millions of copies of a specific DNA sequence in approximately two hours. -- http://www.dnalc.org/resources/animations/pcr.html) or this "immunoprecipitation" to make manufacturing quantities of drugs. I understood that the monoclonal antibody is such a human-expanded copy of some DNA or a protein or something.

Correct me if wrong. See: http://www.pacificimmunology.com/types- ... bodies.asp

If there are monoclonal antibodies, there are likely non-manufactureable quantities being produced naturally by some human or other mammal (I understood hamster were used for some "MS" drugs), of the non-cloned variety of the antibody..

okay so going back to CD46 and defective IL-10 production in MS (abstract above), found this:

CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome, and defective IL-10 expression from CD4 lymphocytes
http://www.jacionline.org/article/S0091 ... 1/abstract

wonder if that could be the case for ms patients too?

Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423259/

hmm ... too much of a newb at this stuff to figure out how a CD25 antibody would help to correct defective IL-10 production in MS.. how might this piece fit in?

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis
http://www.ncbi.nlm.nih.gov/pubmed/16206232
"Whereas Treg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived (CD4+)CD25high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals."

Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis
http://www.jci.org/articles/view/29251
"There were striking defects in the induction of Tr1 cells with CD46 costimulation as measured by IL-10 but not IFN-γ secretion in patients with MS compared with healthy subjects. This loss of Tr1 cell–associated IL-10 secretion was specific to CD46 and not CD28 costimulation and was associated with an altered regulation of the CD46-Cy2 isoform that differentially regulates T cell function in a CD46-transgenic murine model. These data demonstrate a second major Treg defect in human autoimmune disease associated with the CD46 pathway."

bringing in CD4+

Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype
http://www.ncbi.nlm.nih.gov/pubmed/12540904
"Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype..."

wouldn't be me if i didn't bring a nutrient into play, guess which one

Effects of zinc deficient diet on development of atopic dermatitis-like eruptions in DS-Nh mice
http://www.ncbi.nlm.nih.gov/pubmed/18248795
"...The number of CD25+CD4+ T cells in spleen was significantly decreased, while the percentage of Foxp3 positive cells in the CD25+CD4+ T cells was comparable to those of the controls. CD25+CD4+ T cells from mice fed the zinc deficient diet maintained a suppressive function compared with those from the controls. These findings indicate that zinc deficiency influences the skin barrier system and immune system, and suggests that zinc deficiency acts as an exacerbation factor of atopic dermatitis."

pretty interesting, although (besides everything else..!) i need to spend some more time on genetic expression effects of nutrients other than zinc.

What the hell is an auto antibody?

http://en.wikipedia.org/wiki/Autoantibody

also,

http://en.wikipedia.org/wiki/Monoclonal_antibodies

oh interesting!

"Given almost any substance, it is possible to produce monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. Monoclonal antibodies can serve as a recognition element for assay of antigen using a suitable analytical method.[1] When used as medications, the non-proprietary drug name ends in -mab"

eg tysabri (Natalizumab)

http://en.wikipedia.org/wiki/List_of_mo ... antibodies