Research points way to 'holy grail' therapy for autoimmune diseases

Interesting. I think IBD research is often hampered by not thinking outside the box, as in researching IBD only. I do think the answer to all this crap is to look at the whole ball of wax (all autoimmune diseases) when doing research. When we figure out autoimmune diseases in general, we will have the answer to IBD.

Sounds great but, maybe im wrong, don't neutrophils start to do damage before T cells even come to the tissues? So even with this there would still be damage from the neutrophills...

Marauder93 said...
I too could be wrong, but I believe the T cells are the immune cells that cause the main/most damage. They are typically more potent then neutrophils

Yet the can halt a flare in Japan by filtering out neutros which are replaced in hours but new ones have no orders to attack. Flares are long lasting too.

I watch neutros carefully when flaring, they went down hard/fast from Asacol HD.

@Concour

Mauruder is basically right. "Activated" T-cell are responsible for most of the damage BUT not so much first hand but through signalling. Here's roughly how it works:

We all have T-Cell and B-Cells along with other immune cells such as macrophages, neutrophils etc etc.

T & B cells can be thought of as the "Bosses" I guess, and the others like macrophages and neutrophils etc as the "Workers". So the "Bosses" not only tell the others when to start working, but where to actually do this work and on what.

Every B-cell has what's called a variable membrane bound antibody. So think of it like a receptor sticking out from it's surface. So different B-cells respond to different antigens like viruses, bacteria and so on. To "Activate" a B-cell it needs binding of the antigen to one of it's membrane bound antibodies. So in other words, when let's say a bacteria happens to come on contact with a B-cell and the surface proteins on the bacteria match and bind to the surface receptor on the B-cell it becomes "Activated". Or really that's one step...

B cell's are in turn stimulated by T-cells (or Helper T-cells).

A B cell sort of wanders around looking for things and consumes an antigen (a non-self molecule, virus or bacteria) into it's internal cellular compartments and then processes it or kills it internally, breaks it apart and then spits it out on it's surface on what is known as an MCH complex (Major Histocompatability Complex). There are two MCH complexes (MCH1 and MHC 2). There is a difference between them which I'll get to in a bit.

An "Activated" helper T-cell who's variable portion of their T-Cell Receptor that is specific to this same antigen presented by the B-cell can come along and bind to it. So the T-cell binds to the B-cell and this then "Activates" the B-cell.

Once activated it either becomes a "memory cell" or an "effector cell". Memory cells stick around to make this process faster in the future - and Effector B-cells start making gazillions of antibodies. These antibodies that are released by the Effector B-cells, then go out and start sticking (binding) to the surface of things like bacteria, viruses etc etc. and marks them for destruction by the various other immune cells in our system like macrophages and neutrophils and so on.

AS WELL:

All T-cells have "T-cell receptors" BUT they also have proteins on them as well. Some have what's called CD4 Proteins and some have what's called CD8 proteins. So there are CD4+ and CD8+ T-cells.

Most T-cells are "Helper T-cells". CD4 basically means helper T-cell.

The CD4+T-cells want to bind to MHC2 Complexes whereas CD8+ T-cells are attracted to the MHC1 complex.

Cells infected with viruses and bacteria tend to express MHC2 proteins on their surface. On the other hand Cancer cells etc tend to express MHC1 complexes. Because of this, most CD8+ T-cells are cytotoxic i.e they want to kill cancer cells or damaged cells.

T-cells want to bind not only to an MHC Complex BUT they also need to bind to some antigen. Every nucleated cell in our bodies express MCH complexes. This is how they notify our bodies that they need to be destructed, or something bad is going on inside, or they are infected etc etc.

So it's a two step process. Or like a safety check.

CD8 T-cells Kill Bad Cells

CD4 T- Cells, once activated can also activate “B” cells, AND they also then start releasing Cytokines - so these (cytokines) are the alarm bells. This is the process we're all familiar with with by taking Remicade etc... The drug itself t blocks this alarm bell pathway.

By blocking this pathway, the "bosses" can no longer tell the "workers" where to go to work, so the neutrophils stop showing up! And this is turn brings some relief to our symptoms. As Remade wears off in between infusions, the "Bosses" can start telling the workers where to go again and what to do. SO wee need to keep pin taking it in order to cut off communication between the "Bosses and the Workers"

So the interaction between the T-cells and B cells is what mostly what causes things like "neutrophils" and "Macrophages" to attack. And the process of attacking is what does the damage.

Remicade and other biologics work upstream by blocking the Cytokine signalling pathway. Imuran etc work downstream.

Hope that all made some sense!
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The paper OM posted really is a way in which "Upper Management" can tell the "Bosses" to no longer worry about signalling the "Workers" to go to work on a specific set of self-recative or cells expressing "self reactive" molecules"


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EDIT I should also say when you see (+) as in CD4+ - the Positive means they are "activated".

Post Edited (Canada Mark) : 5/11/2014 7:49:12 AM (GMT-6)

i was gonna say!! you need to be a teacher, mark! i know you've thought about it but you should go for it.

Those are some pretty complicated questions in a way. I'll try to answer as best I can. There are others that are probably a lot more qualified. I'm only year 1 down in school now so...

(Question 2&3) I can't find the link to the actual study so I'm not sure on what cells they are all referring to but if it has to do with cytotoxic T-cells and self-targeting cells then they are talking about CD8 cells. And I believe they are talking about blocking the antibody/antigen binding not the MHC complex. Interrupting one of the two would block/prevent the response anyway. But I'm not 100% sure on that. I'd have to read it again. But I'll keep this going anyway....

1) Yes, in most cases an activated CD4+ T-Cell is required to activate a CD8 T-cell but it's not always required. For the most part yes though. BUT your question of what is causing the issue/inflammation is really "The Big Question" !! It's what everyone is looking for the answer to.

In UC there seems to be more involvement of the Innate Immune System, whereas in Chron's it seems to be more of an Adaptive Response or Humoral Response.

No one knows in IBD diseases what the heck the body is attacking or why. But this might help give you some personal thoughts to think about:

Free floating antibodies are only good for things floating around in extracellular fluids so the body needs a way to figure out how to tell if a cell is infected with something or damaged and how to then deal with it. This is done through MHC1 complex. It's on every cell except for Red Blood Cells I believe.

So MHC1 Complex is "Internal" infection and MHC2 Complex is "External" infection/problem I guess you could say. And both require the binding of this (MHC) plus a highly specific antigen to cause action or say it's OK to attack. So we have two responses - Humoral (Adaptive) and Cell Mediated Immune Response. And this in itself is interesting because in Crohn's it's suggested that we have a massive presence of deep intracellular infecting bacteria present and in UC it's surface bacteria with a few penetrating the first layer of the epithelial cells. In intracellular infections macrophages play a big role, and in surface or mucosal surface protection neutrophils play a big role in dealing with these infections but you'll find in IBD in general both ply a role.

At the same time, let's say something infected and caused damage to our epithelial cells.... maybe a mucosal virus of some sort like Influenza type thing. Our epithelial cells will then recognize internally that they have been infected. So they sort of chew the virus up into little pieces (proteins) and spit the tiny bits out to the surface on MHC1 complex recptors. This marks the epithelial cell for destruction so that it doesn't replicate and create more virally infected cells basically. From here other immune cells respond, bind to the infected cell and inject them with other proteins that force the cell to die, or break holes in it's membrane causing it to explode I guess you could say.... It's thought then when this takes place during the "clean-up" of these infected and killed cells, that certain other immune cells can pick up this debris, which may include parts of our own tissue. It's thought, and has been proven that since its little chains of amino acids that are displayed by infected cells, maybe there's a few viruses or bacteria where their surface coat proteins (what they are surrounded by) are very, very similar to our own tissue. This has been so far proven (I believe) in Narcolepsy and a reaction to self proteins by those who received a specific type of vaccine. In general the antibody process is very, very selective though, right down to specific individual amino acids. If it wasn't then the body might start to mistakenly attack self cells. If it's not an exact match to the antigen/antibody and to the MCH Complex Receptor Protein the attack will not take place.

The body has a few safety checks though to be sure that it's doesn't attack healthy cells and can differentiate between them and non-self. This is done through a process called "selection" in the Thymus. This is where the body decides and "selects" what immune cells are reacting to non-self molecules and what cells are reacting to self molecules. This process basically kills off or forces and "self reacting" immune cells to die (apoptosis) and allows only the ones that are no-self reactive to pass into the body to help us. Actually this whole process is divided into four processes for selection. Complex again, haha. Anyway, it's thought that an error somewhere in all of this is what causes "autoimmune" diseases where the body starts mistakenly attacking normal healthy tissue. The truth is no one actually knows for 100% sure.

Crap, this get's long fast cause there's so many aspects and pathways to the immune system, but in IBD we have inflammation going on. The source or cause of this inflammation is simply unknown. It's thought that because we respond to immune suppressing drugs and because no one has identified an exact pathogen (Bacteria), it may in fact be an "auto-immune disease". If this is the case then blocking the autoimmune reaction as in this paper would fix the issue if they were to be able to determine just what we were reacting to.

Soooo... Hmmm.. I'm trying to think of a better way to answer but at the moment I cannot. So I'll just post this and maybe you can google some things or better yet maybe consider reading about it in an immunology text at the library perhaps if it all interests you.

In IBD you can pretty much pick anything - CD4+ Cells, CD8+ cells, MHC1, MHC2, Bacteria, Viral, Fungus, Cytokines, Neutrophils, Macrophages, MAIT Cells and just about any other immune cell or response you can think of and you'll find something, some paper somewhere in which elevated levels are shown or some study shows they are more prevalent in IBD. It's crazy.

It's as if either our entire Immune System just went totally bonkers one day, or what I like to think about most lately is that something happened to out mucus barrier as Old MIke dug up a long time ago. To me, personally, if we have a problem with our barrier for some reason then all of these crazy immune responses can take place.

At this point I forget what and if I even answered you questions! haha. I'll look at your questions again later tonight. I have a gazillion dishes to do at the moment! Cooked dinner for mom and the family tonight.

I also better re-check what I wrote lol... so don't quote me on anything!

@ Canada Mark - Thank you so much for the review of the immune system! Im really sorry though, I should have mentioned that Im also in third year (well just finished) and have taken a few immunology courses, so I already have a pretty strong background on the general workings of the immune system. I am, however, less familiar about the nature of the immune system in the context of UC (I.e. do we have self-reactive CD8+ T cells that cause damage or is the damage only mediated by the signalling of self-reactive CD4+ T cells).

That being said, the co-stimulatory signals were my first guess as well, but the article OM posted seemed to imply that the "second signal" was a signal that occurred during the "attack" process of the T cell, rather than the activation process. This is why I was confused about whether they are targeting the CD4+ or CD8+ T cells. Though, it could just be that the article was not written as accurately as it could have been.

Regardless, thanks for the reply and Im sorry for making you write out that long review of the immune system (though I do appreciate it); Im sure itll be very useful for many people!

Ps. Judging by your name, Im gonna guess your from Canada. Im curious about what university you attend? Im at McMaster btw : )

Ok It was bugging me so I looked it up just now so I could go to sleep without thinking about it, haha...

I'll just type this word for word from my text:

"Naive CD4 T-cells may become unresponsive (anergic), die (apoptosis) or differentiate into regulatory T cells (T-reg) if they recognize a peptide-MHC complex on and APC (Antigen Presenting Cell) in the absence of further stimuli alone (Signal 1 alone). This can lead to antigen-specfic tolerance. If however the T-cell additionally receives positive signals through CD28, from B7 family members CD80 and/or CD86, it will become fully activated (Signal 1 plus Signal 2). In contrast negative signals delivered by molecules such as CTLA-4 or PD1 can inhibit T-cell activation. Other signals regulate the type of effector response that develops, such as into Th1 versus Th2 or Th17 cells (Signal 3)."

By signal 3 the textbook means Cytokines and various other molecule interactions...

So again I'm sure they (the paper OM posted) are referring to Signal 2 which would be the "Go Ahead and turn into a mega killing machine" signal.

Well here is something on cd8 cells the ratio of cd4:cd8 is also important, check out what is going on in the appendix.

OM

http://faculty.ucmerced.edu/khoyer2/pdf/23871638.pdf

http://www.ncbi.nlm.nih.gov/pubmed/17701017

http://www.ncbi.nlm.nih.gov/pubmed/16097061

then the thymus, thymus involution my old thread\

https://www.healingwell.com/community/default.aspx?f=38&m=2599665

 

Post Edited (Old Mike) : 5/12/2014 4:58:31 AM (GMT-6)

Hmmm, no, Dr. Marshall is my GI up there. Is Reinisch your GI? Dr. Marshall is pretty awesome, and I hear quite a few other doc's up there are equally as awesome. They seem to be on quite the mission there in regards IBD and curing it...

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I think they are in fact targeting CD8+ T cells - as the signal process is exactly the same as CD4+ T cells as in the example I gave but with an extra step per say (also CD8+'s bind to MHC 1 whereas CD4+'s bind to MHC2) - Not only do the CD8+ T-cells need to bind to the MHC1 complex, but they need to have adequate stimulation through CD28 as well which is the same as the process for CD4+ T-cells (but through a different MHC2), BUT an Antigen Presenting Cell (APC) like a dendritic cell can activate them directly without the need for an already activated CD4+ T-cell, but in this case the APC needs to be "licensed". And even then the "license" expires after a short period of time.

So you need either a licensed APC or a combo of three cells - and APC, a CD4+ T-cell and a CD8+ T-cell that all recognize a specific antigen.

Old Mike's first paper on the post above yours is well worth a read.

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But like you say, I don't understand either how they are specific to auto-reactive T-cells, and not others if they are blocking the co-stimulatory side.

So that got me wondering... Do you think that maybe they are talking about the way cells display MHC1 molecules specifically??... From my understanding the way it works is that immune cells can't see "inside" other cells, so they need a way to figure out if they are in fact infected or if something is going wrong inside like cancer etc. So all cells display "Self" class 1 MHC molecules to show that they are in fact healthy and to leave them alone because everything inside is fine and dandy, and since CD8+ are supposed to only recognize "non-self" antigens, they leave normal healthy cells alone. When a cell is infected with a Virus/Bacteria or has something wrong going on inside, it begins to export some of these "Non-Self" or foreign peptides instead of just "Self" peptides. This then signals that it's OK to kill them, haha. So "Self Peptides are Don't Kill Me" - and "Non-self peptides are Kill Me"...

So I wonder if they are messing around interfering with this process specifically or this side, not the general activation. If that makes any sense!


EDIT: now that I think about it it can't be this side because any change would appear "foreign" so without a doubt it's the co-stimulation side they are interfering with... There's just something we're missing.

Post Edited (Canada Mark) : 5/13/2014 12:56:57 PM (GMT-6)

@Maurader93 -Got the answer:

It is in fact the Co-Stimulatory Signal as mentioned... and it is CD8+ T-cells they are targeting.

The trick is there is more than one Co-Stimulatory Receiver and they are different for different cells... They are targeting LFA-1 and ICAM-1

Did you every come across this in any of your studies?

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"One approach for tolerance induction is based on the long- standing concept of second signal blockade. The concept of the two signal requirement for T cell activation was first proposed by Kevin Lafferty and coworkers in 1975, and has been under intensive study since. Engagement of the T cell antigen receptor (TCR) by appropriately presented cognate antigen (signal 1) provides specificity of interaction, activates the T cell and prepares it to respond. Signal 1 also prepares the cell to become anergic or die in the absence of the second signal, which would normally rescue the cell from induced anergy/death. So second signal blockade can lead to inactivation of attacking T cells. The most studied second signal is received by resident CD28, although several additional T cell surface proteins have been classified as receivers for a second signal. This includes both of the T cell surface proteins targeted in the present study, ICAM-1 (intercellular adhesion molecule-1) and LFA-1 (leukocyte function associated antigen-1).

Second signal blockade has been employed in association with diabetes and most studies have used antibody to effect the blockade. Examples include blockade of the T cell costimulatory molecules CD28/B7 or CD40/CD40L to treat T1D or assist in islet graft acceptance in NOD mice. Also, over nearly two decades, antibody or full protein blockade of LFA-1 and ICAM-1 interactions has shown promise for treating T1D by tolerance induction but the promise has not been fully realized. Because second signal blockade has shown such promise in animal models, it seems imperative to continue to explore this approach from different angles to elucidate the factors that might promote success in humans."


"Considered together, data presented here suggest that peptide blockade of LFA-1:ICAM-1 interactions in NOD mice inhibited or somehow reversed infiltration into the pancreas and also inhibited activation of T cells with reactivity to pancreatic antigens. In vitro, the peptides inhibited activation of both murine and human T cells that were under a general mitogenic stimulus. The accumulated data suggest that this combination of LFA-1 and ICAM-1 blocking peptides may help further elucidate the mechanisms of T1D, and could potentially provide a useful therapeutic model for autoimmune disease and organ transplantation."

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This is pretty amazing actually when you really think about it... If it works...