Understanding MS 102: My Doctor is Expressing Cytokines

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Understanding MS 102: My Doctor is Expressing Cytokines

Postby notasperfectasyou » Tue Oct 03, 2006 8:34 am

Understanding MS 102: My Doctor is Expressing Cytokines: Code Cipher Training

This is part of my continuing effort to understand Multiple Sclerosis as best as I can. I’m documenting my efforts as I go because I figure there are a few more others like me who would like to try and understand this stuff the way I’m trying to. I’ve made hyperlinks in blue in hopes that this narrative may be more like a beginning than an end since most any website I’ve linked has a lot more to know than the linked info – explore!. As in my prior posts, I’m not a medical professional, I’m an MS Fiancé and these are my thoughts, and you should see your doctor about medical decisions, yada, yada, yada………………

I want to thank everyone for the supportive comments, thoughts and messages. If you have not read my Understanding MS 101 post, I recommend reading it before this one.

Starting Point: As if it Wasn’t Bad Enough Worrying About Your Brain

So you’re concerned and you know you have this brain thing going on and you worry every time you forget something or don’t understand something, “am I getting worse”? Communication is the issue. It’s a 4 part problem in MS. I’ll cover the first two immediately.



You can click on that to go to the article and read more if you want. But just how well can you understand the quote or even the article? As I see it, medical research folks have a very technical, abbreviated and assumptive way to writing. This is part 1 of the problem. On the flipside, us laypeople don’t do a very good job of learning “doctor speak”. This is part 2 of the problem. This is of course why I’m writing all this stuff out as I’ve started doing; I’ve figured out that no one is going to provide me with a doctor speak cipher training manual. The rest of this post will be dedicated to problems 3 and 4. One of the key problems in MS is that cells are doing a good job of communicating stuff we’d rather they not be communicating. Normally cells are communicating very important stuff that helps us to get and stay healthy. In MS, some cells are sometimes communicating stuff that causes harm. Us lay folks might want to read the rest of this post to learn about how our cells are communicating with each other, our researchers might want to read the rest of this post to see an example of how to communicate to our laypeople audience; an audience that hungers to understand and appreciate their hardwork.
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When You Come Upstairs, Can you Bring Up the Phone

Postby notasperfectasyou » Tue Oct 03, 2006 8:37 am

Second Point: When You Come Upstairs, Can you Bring Up the Phone?

If you have a cordless phone and you live in a place that has a stairway, you know how this goes. You might have even heard it in your head as you read it. There are three things going on here. First of all someone is expressing themselves by calling out. Secondly, a different person is going to be stimulated when they receive this communication that is being expressed to them. When I say stimulated, I don’t just mean that they hear a voice from upstairs, I further mean that this communication causes them to think new thoughts they might not have otherwise had, like “I wonder where the phone is?” or they might feel an unrelated sense of urgency because they are reminded of a friend they forgot to call. Thirdly, the receiver of the communication might decide to move into action and engage in a new behavior that is different than what was happening before. Maybe they were watching TV and now they are looking for the phone. If not for the communication, they would still be watching TV.

The scientist folks use some similar words to describe a similar process that involve molecules called cytokines. Cytokines are molecules that are secreted by cells. This process of secreting is called “expression”. Certain other kinds of cells have the ability to receive the expression, which often stimulates them. Stimulated cells then behave differently than they otherwise would have. Here’s a more official description from emedicine.

“They are secreted and produced by many different types of cells and have different functions, depending on the cell of origin, the quantity in the circulation system, and the presence or absence of other cytokines. Cytokines induce growth of the immune system, support differentiation, cause activation, and induce receptor expression, depending on the precise combination and amount of cytokines in the milieu. They enhance receptor-mediated functions. Cytokines have a molecular weight of 10-30 kd and typically a short half-life.”


There are 4 kinds of cytokines: Interferons, Colony Stimulating Factors, Tumor Necrosis Factors and Interleukins. There are a lot of different kinds of cytokines that fit within the 4 groups. For now I’m going to just give a brief explanation and list some of the members of each group.

Interferons

Interferon alpha (IFNa)
Interferon beta (IFNb)
Interferon gamma (IFNg)

Interferons prevent virus multiplication in cells.

Colony Stimulating Factors

Granulocyte Colony Stimulating factor (G-CSF)
Macrophage Colony Stimulating factor (M-CSF)
Granulocyte-Macrophage Colony Stimulating factor (GM-CSF)
C-Kit Ligand

Colony Stimulating Factors are a growth factor that stimulates production of infection-fighting white blood cells.

Tumor Necrosis Factors

Tumor Necrosis Factor alpha (TNFa)
Tumor Necrosis Factor beta (THFb)

Tumor Necrosis Factors induce necrosis (death) of tumor cells and possess a wide range of proinflammatory actions.

Interleukins

Interleukin – 1 (IL-1)
Interleukin – 2 (IL-2)
Interleukin – 3 (IL-3)
Interleukin – 4 (IL-4)
Interleukin – 5 (IL-5)
Interleukin – 6 (IL-6)
Interleukin – 7 (IL-7)
Interleukin – 8 (IL-8 )
Interleukin – 9 (IL-9)
Interleukin – 10 (IL-10)
Interleukin – 11 (IL-11)
Interleukin – 12 (IL-12)
Interleukin – 13 (IL-13)

They are secreted regulatory proteins produced by lymphocytes, monocytes and various other cell types and are released by cells in response to antigenic and non-antigenic stimuli.

That’s just 22 types of cytokines. The emedicine article that is linked above mentions that there are over 50 kinds of cytokines. Here is an article that provides more information about the 4 groups of cytokines.
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Hey Look, Someone Sent Me a Cytokine

Postby notasperfectasyou » Tue Oct 03, 2006 8:43 am

Third Point: Hey Look, Someone Sent Me a Cytokine

Imagine needing 50 different ways to communicate. You’d think there must be a lot of different kinds of cells that are using cytokines to try and communicate with each other. Actually, there are just a few kinds of cells that send and receive cytokines and most of them are what we commonly call “White Blood Cells”, or WBC’s. There are several kinds of WBC’s (also called leukocytes). This means that “white blood cell” is not a specific term, it refers to a general group of blood cells. In high school biology we learn that they ward off disease. From there it gets more complicated. Here’s a list of the kinds of white blood cells, with subset types and AKA’s:

Polymorphonuclear Granulocytes
….. Neutrophils
….. Eosinophils
….. Basophils
Mononuclear Agranulocytes
….. Lymphocytes
…..…... T Lymphocytes (NKT and Alpha Beta TCR Cells)
…………… CD4+ T Cells (Inflammatory T Cells)
……………….. T Helper 0 Cells
……………….. T Helper 1 Cells
……………….. T Helper 2 Cells
……………….. T Helper 3 Cells
……………….. Tr Cells
……………….. Tr1 Cells
…………… CD8+ T Cells (Cytotoxic T Cells, CTL)
………. B Lymphocytes
…………… Plasma B Cells
…………… Memory B Cells
………. Natural Killer Cells (NK Cells, Null Lymphocyte Cells)
….. Monocytes
………. Dendritic Cells
………. Macrophages

Neutrophils
Neutrophils are produced in bone marrow and work their way around the bloodstream and eventually exit the bloodstream and into infected tissue. They are a primary defense against bacterial infection. The body produces more neutrophils when there is a bacterial infection. Here’s another website that discusses neutrophils from an MS perspective. Neutrophils are rarely implicated in MS except for in Marburg Disease, which is very rare.

Eosinophils
The functions of eosinophils are not fully understood. When an antigen enters the body lymphocytes and neutrophils attract eosinophils to the site where they kill the invading antigen. Their primary function is to immobilize parasites by attaching to them. Eosinophils are rarely implicated in MS except for in Devic Disease.

Basophils
Basophils make up only a small portion of the number of white blood cells, representing only 0.5% of the leukocyte population. They release histamine and other chemicals that act on the blood vessels to mediate inflammation and allergic responses. Histamine attracts other white blood cells to the inflamed site. Although basophils are rarely implicated in MS, here is one theory of the cause of MS that involves basophils cells.

Together the three kinds of cells; Neutrophils, Eosinophils and Basophils make up the group of WBC’s called Polymorphonuclear Granulocytes. Here is a link to a page that has more information about these cells.


T Helper 0 Cells
While it is widely thought that these cells are simply precursors of Th1 and Th2 cells, it has been shown that in the right environment Th0 cells can be become a prevalent population of cells. General understanding is that these cells are derived from naïve Th cells (also called ThP) and then differentiate to become either type Th1 or Th2 cells. Differentiate is used to describe the process that a cell goes through in acquiring a type. Here’s a simplified diagram and here’s a more complicated diagram and narrative about this.

T Helper 1 and T Helper 2 Cells
I’ve tried to describe these separately, but it’s complicated. Most everything on the internet discusses Th1 and Th2 cells together in a compare and contrast sort of way. First of all Th1 cells participate in something called Cell Mediated Immunity. Cell Mediated Immunity is a process whereby Th1 cells recognize an antigen and then begin to divide, thereby making more Th1 cells. The Th1 cells have the ability to activate other cells like macrophages that act directly with the antigen to kill it. Humoral Immunity is a process whereby a B cell recognizes an antigen and then divides to produce plasma cells. The plasma cells produce antibodies that destroy the antigen. The Th2 cell participates in the Humoral Immunity response by activating the B cells to divide and secrete antibodies. While there is still uncertainly about the exact cause and process of MS, it is a widely accepted hypothesis that Th1 cells are part of the disease process and that Th2 cells help to slow the disease process. More simply, Th1 is thought to be bad and Th2 is thought to be good. More on this later. Here’s one more link on the topic of T Helper cells.

Tr Cells, Tr1 Cells and T Helper 3 Cells

There is very little information on the internet about these cells. The role of these cells is thought to be immune response suppression. T-regulatory cells (Tr) appear to play a role of inhibiting Th1 and Th2 cells. T-regulatory 1 cells (Tr1) appear to be similar to Tr cells. Th3 cells are prevalent in the intestines. Here is another link to an abstract that briefly discusses these cells. These cells do not appear to have a significant known role in MS at this time.

CD8+ T Cells

CD8 T cells are sometimes called cytotoxic cells because they recognize infected target cells and kill them. CD8 T cells recognize bits of protein on the surfaces of other cells. If a CD8 T cell recognizes foreign proteins on another cell surface, it generally kills the other cell, since the foreign proteins mean that the cell has been infected with a virus, an intracellular bacterium, or some such invader. The CD8+ cell does this with proteins it makes called perforin and granzymes. The CD8 T cell stores the proteins in bubbles, and when it's time to kill a target cell, the CD8 cell forms a tight connection with the target and blows the bubble out at it. Perforin forms holes in the target cell's membrane, which lets the granzymes in. The granzymes then start a self-destruct cascade in the target cell and force it to kill itself in a process called apoptosis.

B Lymphocytes

There are two kinds of B Lymphocytes, Plasma B Cells and memory B Cells. Plasma B Cells secrete antibodies (Ab) which affect the destruction of antigens (Ag) by binding to them and making them easier targets for phagocytes. Memory B Cells are formed specific to the Ag(s) encountered during the primary immune response. Memory B Cells can live for decades and quickly respond to a second exposure to the Ag. B Cells can multiply via signaling from CD4+ T Lymphocytes. Ab’s are also called immunoglobulins (Ig). There are 5 kinds of Ig’s; IgG, IgM, IgA, IgD and IgE. One important distinction of B Cells is that they don’t attack Ag’s directly as T Cells do rather, they produce Ig’s that do the attacking. This process is called Humoral Immunity.

Natural Killer Cells

There's another type of lymphocyte called an NK cell, which is short for natural killer cell. They are also called Null Lumphocyte Cells. They are not NKT cells, which sounds similar. They are not T cells. NK cells function in a similar way as CD8+ T cells, except that they do not need activation time before they can kill as is required of CD8+ T cells. Meaning, there is no "lag" phase of clonal expansion for NK cells to be active as effectors, as there is with antigen-specific T and B lymphocytes. Thus NK cells may be effective early in the course of viral infection, and may limit the spread of infection during this early stage, while antigen-specific lymphocytes are being recruited and clonally expanded. NK cells recognize their targets in a slightly different way, they see families of receptors and proteins and generally recognize cells that are showing signs of stress or that display signs of pathogens. While, by contrast, T cells recognize very specific pieces of proteins on cell surfaces. The nature of the NK cell receptor (or receptors) that confer this selectivity of target recognition has not been clearly defined, but it has been shown recently that the expression of "self" MHC I molecules inhibits NK lysis of target cells.

Dendritic Cells

Much has been learned about Dendritic cells since their discovery in 1973. It has been recently discovered that there are two different kinds of Dendritic cells. They are often referred to as DC1 and DC2 cells. Unlike many other WBC’s, DC1’s and DC2’s do not have an immediately common lineage, wherein DC1 and DC2 cells result from differentiation in the maturing of a common blood cell. The lineage of DC1’s is said to be Myeloid which are a type of cell that can also mature to be a Polymorphonuclear Granulocyte or a Monocyte type WBC. The lineage of DC2’s are said to be Lymphoid which is the type of WBC that can mature to be a T cell or a B cell. It is important to note that the classification of a Dendritic cell as Myeloid or Lymphoid is not related to whether it is a mature or immature cell.

Immature Dendritic cells are derived from bone marrow, enter the blood and generally find their way to the skin or other tissues where they come into contact with antigens which they consume and present to other WBC’s like T and B cells. When a Dendritic cell matures, it starts presenting the antigens to other white blood cells which “programs” them with a “picture” of what the foreign invader is like so that when the white blood cell finds another like cell it will know to kill it. Researchers are trying to figure out how to use this functionality to create a cancer vaccine.

As Dendritic cells mature they appear to have a T-helper cell bias. Myeloid DC1’s tend to have a Th1 bias, meaning they tend to communicate signals that cause Th0 cells to differentiate towards Th1. Similarly they tend to facilitate cellular mediated immunity. Similarly, Lymphoid DC2’s tend to have a Th2 bias and they tend to facilitate antibody production (humoral immunity).

In case you hadn’t noticed I got very interested in Dendritic cells. Science is fascinated with them. Here’s a few more links that include stuff about DC’s.

Dendritic Cell Maturation
Glatiramer Acetate and Dendritic Cells
Glatiramer Acetate Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells
Immunoregulation of Dendritic Cells
Dendritic Cells Under Investigation in Autoimmune Disease

Macrophages

Everything you read about Macrophages will talk about “Phagocytosis”. So lets deal with “Phagocytosis” first. Phagocytosis is the process of consuming and digesting debris like damaged or dead cells and microrganisims that don’t belong in the body for one reason or another. Macrophages phagocytize (meaning engulf or eat) antigens. This is one of the key roles of the Macrophage. The life of the Macrophage begins in the bone marrow and they enter the blood as Monocytes. When they mature and migrate to tissue they become Macrophages. They can live in tissue for years. Macrophages have unique names depending on the tissue in which they reside:

Ordinarily Macrophages are inactive, which is referred to as Resident Macrophages. There is a two stage process for a Macrophage to get activated. It is first “Primed” by a cytokine then in a follow up action it is activated by an agent, such as bacteria. Recently this process has been described as Classic Activation, which is contrasted with Alternative Activation. Classicly activated Macrophages are thought to exhibit Th1-like tendencies and Alternatively activated Macrophages are thought to exhibit TH2-like tendencies.
Finally, Macrophages are Antigen Presenting Cells (APC’s). Dendritic Cells and B Cells are also APC’s. I realize after looking over my pile of printed up webpages on Antigen Presentation that I ought to take a small divergence from my original path (I was planning to start working on how the WBC’s use cytokines to communicate next) and present a more structured format for the WBC’s that is based on what they do. So first I’ll do a quick summary and then I’ll start on a second perspective on WBC’s based on what their roles are in the immune system.
Recap of White Blood Cells (WBC’s)

I’m just going to include some links here that I came across that I thought would be function as a nice summary:

Overview of the Human Immune System
The Immune System
The Immune System – An Overview
Explanation for Anybody
A VERY COOL Powerpoint!
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Assignments, Assignments; Does Everybody Know What to do?

Postby notasperfectasyou » Tue Oct 03, 2006 8:46 am

Point Three and a Half: Assignments, Assignments; Does Everybody Know What They’re Supposed To Do?

There are four functional groups of white blood cells. Some have multiple roles. The concept here is that there are 4 basic things that WBC’s do. They are:

ANTIGEN PRESENTING CELLS: Macrophages, Dendritic Cells and B Cells

EFFECTOR CELLS: B Cells differentiating into plasma cells, Cytotoxic CD8+ Cells, Inflammatory Effector CD4+ Cells, Neutrophils, Eosinophils, Basophils, Mast Cells, NK Cells and Macrophages

REGULATORY CELLS: Native Regulatory T Cells, Inducer T Cells, Th1 Cells, Th2 Cells, Th3 Cells and Tr1 Cells

MEMORY CELLS: Memory CD4+ Cells, Memory CD8+ Cells, Long Lived Plasma Cells and Memory B cells.

Antigen Presenting Cells
If you start Googling Antigen Presenting Cells, it’s easy to quickly get bogged down in new words and concepts. The overall concept is that an APC gets ahold of an antigen and breaks it down into tiny pieces that are then displayed on the APC’s surface for other cells to see and read. Once your CD4+ cells read the info about the antigen, they become activated and go about seeking more of the same antigen so as to kill it. Three kinds of cells do this; Macrophages, Dendritic Cells and B Cells. Phagocytosis was explained as a process whereby Macrophages consume antigens; Dendritic Cells do the same thing as well. B cells do something similar called Endocytosis. Both of these seem similar however it seems that Phagocytosis means engulfment of a whole particle and Endocytosis means internalization of the outside membrane along with whatever might be stuck to it. When thinking about how APC’s consume antigens, it’s clear that the antigen is something that is not within a cell already. The antigens that APC’s consume are things that are inhaled, ingested or injected into the body. These antigens are called Exogenous Antigens because they are things that do not exist inside a cell. This is contrasted against something like a virus that has invaded one of your cells, exists inside your cell and causes your cell to behave abnormally. In such a case a virus would be called an Endogenous Antigen; more on these later. Examples of Exogenous Antigens include: a splinter in your finger or a protein molecule on a cat hair or peanut that causes an allergy. After the Exogenous Antigen is taken into the cell it’s ripped apart and used to make a Class II MHC molecule that is displayed on the surface of the APC for the purpose of activating CD4+ T Cells against more of the original antigen.

Here’s a quote from another college course webpage that I thought had an easy to understand explanation and picture:



Effector Cells

Effector cells are the cells that respond to the signals of other cells; in this case, an activation signal to seek antigen. There are a variety of effector cells and they include CD4+ cells as described above. CD8+ cells are also effector cells and I’ll explain them first because they use a different system for figuring out good stuff from bad stuff. I explained exogenous above, cells/molecules that are foreign stuff. A cell that was your’s but got infected/takenover is a different thing and the antigens that take over your cells from the inside are called “Endogenous”. This includes stuff like cancer or a virus. So now you have a renegade cell that don’t behave right, the CD8+ cell checks with the cell to see if it’s got your personal MHC I signature on it. If it doesn’t, the CD8+ cell kills the cell using cytotoxins.

There are 2 kinds of CD4+ cells, Th1 and Th2. Th1 cells are activated by Macrophages (APC’s noted above) and Th2 cells can be activated by any of the three APC’s that are noted above. Following activation it is generally the role of the Th1 cells to activate Macrophages. Similarly, the role of Th2 cells is to activate B cells against the antigen. The Th1 and Th2 cells carry out their effector functions via the secretion of cytokines. Here is one more website that has readable information about T-helper cells.

Regulatory Cells

Regulatory cells are also called suppressor cells. The big picture is that these are a subset of cells that are designed to suppress the activation of the immune system. They are T cells just like effector cells, meaning they are CD4+ cells. However, somewhere along the way, some of the CD4+ cells don’t become effector cells, they become regulatory cells instead. When you start to read about these cells, one quickly gets the impression that regulatory cells are probably very important in trying to figure out MS.



When you read between the lines you quickly get the idea that there is an alternative hypothesis about the cause of MS that’s wrapped up in these regulatory cells. The classic theory which is spelled out in my understanding MS 101 post implies that there are renegade white blood cells. This idea is not completely incompatible, but it is different. The implication is that it’s normal to have a certain amount of renegade cells, BUT it’s also normal to have a strong set of regulatory cells to chase them down.

The science folks have figured out some stuff about these regulatory cells and they have a special shorthand for describing them. The most common name I see in literature about these is CD4+CD25+ T cells. This is because researchers have determined that all the regulatory cells have the CD4 and CD25 surface molecules in common. These cells are also called Treg and FoxP3 (Forkhead Box P3) cells. There is atleast one company that is testing an MS therapy based on the idea of increasing the amount of Forkhead Transcription Factor as a means of better regulating the immune system by producing more Treg cells.

Among other things, researchers have found that these cells can effect the process of Dendritic Cell maturation, which can make the DC a poor APC. I was very interested in an article that found that FoxP3 promotes the generation of Treg Cells and represses NF-KB. This sparked a little divergence for me, here it is. Because NF-KB does a lot of proinflamatory things which are, likewise, not good for MS repression of NF-KB would seem to be good for MS. I know I’m jumping ahead here, but if you already got a handle on cytokines, good v/s bad ones, then the following links will help with this idea.

NF-KB promotes activation of IL-2, IL-3 and GM-CSF
c-rel deficiency increases IL-10 and decreases IL-2, IL-3, GM-CSF and TFN alpha
Th2 produced cytokines, IL-4, IL-11, IL-13 and IL-10 suppress NF-KB activation

If you agree that NF-KB suppression is a good thing for MS, then here’s an interesting article about NF-KB suppression and here is a different message board about the topic.

Memory Cells

Timeout. It has been about 2 months since I’ve had time to work on this. It’s unlike me to post something that’s not complete. But, I can see that I’ve taken a break and I need to relieve the burden that I need to get this posted. About two months ago we started planning a family vacation and we had a great time in Boston. Folks, don’t ever go to Boston with a road map, there are NO street sign in the city, seriously. Then we came back and started Novantrone. Now we are planning our wedding.

I will be back. But I might need to be a little less ambitious next time. Between all this reading and seeing how the Novantrone works, I’m convinced that this is no simple disease and it really doesn’t do it justice to try to simplify it. I also believe that a cure is within reach and I’ll never give that up. In the meantime, we are trying our best to learn a two-step in time for our wedding.

I hope that you might take this information and use it as a launch pad to gain more information. Be careful about where you get your information. I’ve been careful to put in links so you can assess the accuracy of the information yourself. Sites that hype supplements or that provide testimonials are not very authoritative, they might be attractively persuasive, and they might even have a quote from a doctor, but please learn to discern the examined information from hype. Drop me a message, or post a reply and tell me what you think. napay

Other similar posts on my road to understanding MS:

Understanding MS 101: Doctor Talk and People Talk
A Layman’s Review of Glyconutrients – not good
Turmeric, Curcumin and IL-12 - good
C is for Controversy – good
Last edited by notasperfectasyou on Wed Jan 10, 2007 7:18 am, edited 1 time in total.
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Re: Understanding MS 102

Postby NHE » Wed Oct 04, 2006 3:42 am

All I can say is...

    Thank You!
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thanks

Postby gwa » Wed Oct 04, 2006 6:43 am

napay,

What a load of references and details! Thanks so much for the time you have spent getting this ready to post.

It will take time to digest all the info, but it is handy having a reference point, especially for newbies.

Have a great wedding day!

gwa
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Thank you

Postby notasperfectasyou » Sat Oct 07, 2006 10:26 am

I was torn about posting it without having completed my original intention. I will one day get to the next part. Please reply and let me know what you think and maybe we cna open up some discussion here ( also to keep it bumped :D )

I think one needs to read the 101 post first and that they work together. Thank You! napay
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great job!

Postby jimmylegs » Sat Oct 14, 2006 8:03 pm

lookin fan-tastic napay!
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