Immunology in five-minute bites: T cells, cytokines and MHC

SDSue

Southeast
Messages
1,066
Likes
3,036
Thanks @MeSci ! Maybe you are Simon, but just use two identities lol!

This practitioner is quite cutting edge an trained in Italy. I'm excited to learn more.
 

Simon

Senior Member
Messages
3,788
Likes
14,822
Location
Monmouth, UK
@Simon Thanks so much for all the work you do getting information to PR members.

I wonder if you could point me to the part of the course, or your writings, that covers cytokines.

I have found a local osteopath who is having success with targeted treatment via cytokine nasal sprays. As you are likely aware, cytokines are currently being tested for use as adjuvants in nasal spray vaccines because of their profound affect on the immune system, and I could sure use a profound effect on my immune system! Because of all this, I'm very interested in learning more and possibly seeing this doctor.

Thanks again for all your work.
Thanks, @SDSue

The article @MeSci pointed to is helpful, and I think illustrates just how damn complex cytokines are and how hard it is to make sense of them. And it's incredibly early days for thinking about therapy.

In one of his talks Ian Lipkin said that if the IL-17 finding in ME/CFS patients held up it might eventually be a therapeutic target eg using anti-IL17 antibodies - but he cautioned that it's too early to start testing, and warned that mucking around with cytokines can cause all kinds of problems. Cytokines are not necessarily your friend.

We have just covered cytokines in the course, but I'm not sure I'm going to write about them because of their complexity. To understand cytokines properly (and I'm not claiming I do) you have to understand the immune system they regulate. It's generally pretty hard to say cytokine X always does Y. cytokine X probably does a bunch of different things and cytokines N, O and P also do Y. I'm afraid I'm not going to be able to say anything that's likely to help from a treatment perspective.

To the best of my knowledge I'm not MeSci, but you know what they say about great minds :)
And fools, of course.
 

SDSue

Southeast
Messages
1,066
Likes
3,036
In one of his talks Ian Lipkin said that if the IL-17 finding in ME/CFS patients held up it might eventually be a therapeutic target eg using anti-IL17 antibodies - but he cautioned that it's too early to start testing, and warned that mucking around with cytokines can cause all kinds of problems. Cytokines are not necessarily your friend.
Thanks for the nice summary. I have a feeling Ian Lipkin has a greater mind than all of us put together, so the warning is duly noted!

I am totally in the dark when it comes to understanding the immune system, so I'm thinking cytokines are wayyyy beyond my grasp!
 

Simon

Senior Member
Messages
3,788
Likes
14,822
Location
Monmouth, UK
Your short(ish) guide to T cells

Most people are familiar with B cells, the antibody-producing celebrities of the immune system. But it turns out that in most cases T cells are more important in protecting us then B cells. T cells, which get their name because they develop in the thymus, a small organ near the throat, are the immune system's major system for tackling viruses and bacteria (that live inside cells) and plays an important role in tackling cancerous cells. Not to mention helping prevent autoimmunity*. And even B cells can't do their work without help from T cells.

Perhaps unsurprisingly, some T cells have been implicated in causing ME/CFS, though that makes them part of a pretty large club of contenders. More on this in a later post.

There are lots of different types of T cells but just two main groups, the cytotoxic T cell 'assassins' and T helper cells, which basically tell other immune cells what to do. This post will look at the cytotoxic T cells.

Cytotoxic T cells

When we get sick we hope to be tended to and fixed (obviously not the case with ME/CFS) but sick and cancerous cells basically just get shot. When cytotoxic T cells find sick cells they lock on and deliver toxic chemicals, as well as a signal to self-destruct for good measure. You could see them as an internal security force that's most definitely licensed to kill.

In this video a small cytotoxic T cells destroy tumour cells. The tumour cells disappear into ‘bubbles’ which are actually tiny capsules of debris left from the dying cell.


We have lots of cytotoxic T cells, making up a large lethal force, so it's important to us that this resources is pretty accurate and doesn't cause collateral damage. T helper cells, amongst others, help keep cytotoxic T cells honest but most of their accuracy comes from the receptor they use to recognise infected and cancerous cells. Helpfully called the T cell receptor, this comes in a zillion different forms, much like antibodies, and recognises very specific molecules on target cells. This leads to very specific targeting of sick cells, leaving healthy cells in peace (though this can go wrong).

’Don't kill me’: all cells are forced to show cytotoxic T cells what they are up to.

We've evolved a clever system where cells are forced to show T cells what they are up to. Proteins don’t live forever, and when they are degraded fragments from a small proportion of them are automatically displayed on the cell surface by a molecule called MHC 1, which cytotoxic T cells check out. This MHC 1 and protein fragment acts a bit like an identity card. If the displayed fragments are bits of normal cell protein then the T cells pause to look, then move on. But if the fragments are part of viral coat or bacterial enzyme, say, revealing the enemy hidden within the cell, then the cytotoxic T cells get mean. Similarly, cancerous cells tend to produce unusual proteins, and again these are recognised by cytotoxic T cells with lethal results.

Immune wars: Us versus Viruses

Normally, this system works well and it keeps us safe. However, in an attempt to avoid the T-cells’ deadly kiss, some viruses can force the cell to stop making the MHC I molecules - and no MHCI means no viral antigens presented to give the game away to cytotoxic T cells. Fortunately, in this case we have evolved a counter-tactic. Natural Killer cells (yes, the ones that are less effective, on average, in ME/CFS patients) are constantly checking that cells are making MHC I and showing it on their cell membrane. Cells that don't have enough MHC I molecules may be infected by sneaky viruses so get wiped out by Natural Killer cells, just to be on the safe side. It's war out there.

* but not autoimmunity caused by autoantibodies

Next: T helper cells​
 
Last edited:

Simon

Senior Member
Messages
3,788
Likes
14,822
Location
Monmouth, UK
Helper T cells: co-ordinating the immune response

While cytotoxic T cells are assassins, taking out infected or cancerous cells, T helper cells mainly tell other immune cells what to do. If T helper cells had egos they’d probably be offended by the ‘helper’ tag: they’ve also been called Conductors or Generals of the immune system, ensuring that we respond appropriately to each danger and don’t waste energy or risk self-harm by excess inflammation.

The critical role of T helper cells is shown by HIV/AIDS: HIV infects T helper cells and as the illness progresses the level of T helper cells falls, leading to AIDS, Acquired Immune Deficiency Syndrome, where patients sucumb to all kinds of opportunistic infecitons - which is primarily caused by a lack of T helper cells.

The two major types of T helper cell are Th1 and Th2, which I’ll feature in this post, more characters to come in a second post.

Th1 helper cells: driving response to acute infections

A Th1 helper cell response targets acute infections, whether viral or intracellular bacteria. Mainly it tackles microbes that have got inside cells, and one of its roles is to activate cytotoxic T cells so they start killing off infected cells. Th1 helper cells also fire up macrophages, making them better at engulfing bacteria, and macrophages are also needed to clear up the debris after cytotoxic T cells have done their job. T helper cells also stimulate B cells, making them produce forms of antibody that mark out viruses and bacteria for further attack.

The primary Th1 cytokine is interferon gamma. The aim of a Th1 response is an aggressive response to wipe out the invader. Inappropriate Th1 activation can lead to autoimmunity.

Th2 helper cells: response to chronic infections, especially worms

A different approach is called for with chronic infections that live outside cells, particularly parasites such as worms that dwarf individual immune cells. I know, most people don’t suffer from worms now but throughout our human history they have been a big threat (just as they are to cats and dogs now, hence the need for 'worming') and our immune system has evolved to defend us from them.

Th2 triggers B cells to produce lots of neutralising antibodies – attempting to ‘gum up’ the offending parasite rather than killd them. These antibodies also attract immune cells called eosinophils and mast cells which attack parasites with toxins and other weapons, swarming over parasites a bit like ants:

Th2 type response: Human Eosinophils Coat a Worm - YouTube

Parasites can be hard to shift, especially worms as they are eucaryotic multicellular organisms like us so much more difficult for the immune system to target these without harming our own cells. So Th2 responses often settle for containing an infection, rather than eradicating it. This can be a better option than expending too many resources on a war it can't win, or causing too much inflammation and self-harm.

The Th2 system also deals with toxins.

When there Th2 response gets out of hand the result can be allergy, such as asthma.

Th1/Th2 balance

What matters here is that the immune system produces an appropriate response to the particular threat, eg Th1 for acute viral infections and Th2 for parasitic worms. Sometimes the immune system gets it wrong (see below) and produces too much of one type of response, and some studies suggest that ME/CFS patients T helper cell response leans too far to Th2. That remains to be confirmed.

Th1 or th2?
The type of t helper response is set when a T helper cells is first activated. A brand new T helper cell that emerges from the Thymus is sometimes called 'naive' or Th0 as it hasn't yet been exposed to an antigen. It's activated when a specialist antigen presenting cell such as a macrophage presents antigen to it's T cell receptor (note that as before, T cell receptors each recognise a specific antigen and only respond to that, much like antibodies). This activation happens in lymph organs such as lymph nodes under the arms, when macrophages and other cells seek out T helper cells in response to an infection (though naive T helper cells also head out into the blood looking for action).

Whether that naive Th0 T helper cell develop down the Th1 route or Th2 route depends on cytokines. T helper cells exposed to the cyotkine IL-12 develop into Th1 cells that will target cellular invaders, while those exposed to IL-4 become Th2 cells targeting extracellular invaders.

th1-th2.jpg



Although this diagram shows things as a nice clear choice, leading to either Th1 or Th2 cells, the reality - as is often the case with the immune system - is more complex. Th1 and Th2 cells represent extremes, but some cells will be a bit of both.

Leprosy: the wrong Th1/Th2 balance

Leprosy is a good example of the need for the right T helper response. It’s a bacterial infection caused by Mycobacterium leprae and most people can fight it off fairly easily: their macrophages (scavenging immune cells) hoover up the bacteria and destroy them. In a minority of cases the some bacteria survive inside the macrophages, and this is where the Th1/Th2 balance comes in. With a more aggressive Th1 response the bacteria are largely contained, though they can spread slowly, resulting in some skin and nerve damage over a long period of time.

But for some reason, some patients mount more of a Th2 response, which isn’t appropriate for an intracellular parasite and allows the bacteria to spread more readily, destroying skin, bone, cartilage and nerves: this is leprosy.


To come: other types of T helper cells with critical roles – aggressive Th17 cells and chillin’ T regs
 
Last edited:
Messages
620
Likes
1,701
Thanks for these superb summaries, Simon. I try to read them when I have the energy, although that seems increasingly rare as Christmas approaches...

Nevertheless, when I read them, I am always impressed by the clarity of thought and expression you bring to this topic. I like your analogies too! keep it up - I hope you are getting a lot out of this course.
 

Simon

Senior Member
Messages
3,788
Likes
14,822
Location
Monmouth, UK
Thanks for these superb summaries, Simon. I try to read them when I have the energy, although that seems increasingly rare as Christmas approaches...

Nevertheless, when I read them, I am always impressed by the clarity of thought and expression you bring to this topic. I like your analogies too! keep it up - I hope you are getting a lot out of this course.
Back to school! That was brilliant - thanks Simon!
Thanks for the encouragment (especially pleased you like the analogies, @Battery Muncher), and thanks for sticking with this. As I'm learning in this course, the immune system is staggeringly complex and not easy to grasp.

Currently revising for the end of course exam, and feeling way too old for such intense studying.
 

Simon

Senior Member
Messages
3,788
Likes
14,822
Location
Monmouth, UK
The Hippie and The Warrior: T regulatory and Th17 T cells
Previous enthralling episodes looked at the two main types of T-cells: Cytotoxic T-cells that kill infected and cancerous cells, and T helper cells that help manage the immune response by telling other immune cells what to do - more now on T helper cell types involved in chronic inflammation and autoimmunnity.

hippieandwarrior.jpg


Th1 and Th2 T helper cells play critical roles in the management of the immune response. The two other main helper cells types are the highly inflammatory warrior-like Th17 cells and the peace-loving, more hippie-ish T regulatory cells that help stop the immune system from over-reacting and causing collateral damage.

If everything goes according to plan, T-regs and Th17 help keep the body protected and reacting just the right amount. Malfunction of both types of cells, however, are implicated in chronic inflammation and autoimmunity (suspects in ME/CFS). And too much T regulatory activity can let tumours go unchecked.

Th17 cell: The Warrior

Th17 cells effectively man the barricades, guarding the body's borders such a lung, skin and gut against invaders. They are highly inflammatory and are particularly important in fighting off extra-cellular bacteria such as V. cholerae that causes cholera, and fungi.

Th17 cells are probably closest in function to Th1 cells in function that also promote a highly inflammatory response, but within the body rather than at its borders.

The signature cytokine of Th17 is IL-17, which is how the cells got their name (Th3 might have been more logical for a T helper cell, after Th1 and Th2). Th17 stimulates the production of other cytokines and other inflammatory factors and recruits neutrophils (bit like the infantry of the immune system) to the site of attack.

Genetic defects that prevent Th17 development can lead to problems starting with acne in new-borns, repeated pneumonia and chronic fungal infections. Th17 have been implicated in several inflammatory and autoimmune diseases including psoriasis and multiple sclerosis with anti-IL17 antibodies used to damp down Th17 activity (remember that IL-17 is the main cytokine of Th17 cells).


T regulatory cell: The Hippie

T regulatory cells (T-regs) are Hippies by comparison with Th17, their "let it be" mantra calming down the immune system so that it doesn't waste energy or cause collateral damage through chronic inflammation or autoimmunity. So if not exactly spreading love, T-regs do send a message of tolerance both of self-antigens (preventing auto-immunity) cells) and other harmless antigens, such as pollen that can trigger allergies and antigens on friendly bacteria.

The body is home to trillions of bacteria, most of them in the gut and most of them doing us no harm. T-regs help the body live peacefully with these friendly bacteria, rather than attempting to fight an unwinnable and futile war. T-regs also help quieten down the immune system after it’s mounted an effective response against a pathogen.

Genetic defects that prevent T-regs development show the importance of these cells. Children born unable to make T-regs have problems including chronic, potentially lethal diarrhoea (inflamed gut), Type 1 diabetes (autoimmune disease) and allergic skin rashes (more over-reaction from the immune system). T-reg problems have also been implicated in Inflammatory bowel disease and other diseases with a suspected autoimmune component.

T-reg activity can unfortunately impede the immune system killing tumour cells and reducing T-reg activity is a potential route to tackling cancer.


War or Peace: Th17 or T regulatory cell?

warpeace.jpg

Even though Th17 and T-regs behave in dramatically different ways they are very close relatives, both developing from the same undeveloped T helper cells (sometimes called Th0). The cytokine TGF-β primes the undeveloped T helper cell to become a Th17 or a T-reg. In the presence of the inflammatory cytokine IL-6 (which will be around when the body is under attack from pathogens) the result is a Th17 cell. But in the absence of IL-6, i.e. in more friendly conditions, the same undeveloped T helper cell will mature into a T-reg:


th17treg.gif


It depends what the body needs: with no threats having more T regulatory cells is ideal, but when the body is under attack a more aggressive response is needed and more Th17 are made. You could see Th17 and T-regs as complementary 'Yin and Yang', both essential parts of the whole. As usual, it's probably not appropriate to simplify the immune system like this (but that doesn’t stop me trying).

A recent review paper suggests that both Th17 and T-regs, and the balance between them, is important in a number of inflammatory diseases.

The ME/CFS connection

Needless to say both Th17 cells and indirectly T-regs have been linked to ME/CFS.

Certainly there is some evidence of elevated IL-17 in ME/CFS patients (see Dr Gordon Broderick's study as well as results submitted for publication mentioned by Drs Ian Lipkin and Mady Hornig).

Also, if Ian Lipkin and Mady Hornig are right about the gut microbiome being a source of inflammation in ME/CFS, it's likely that T-regs are involved. Studies on mice indicate that, surprisingly, gut bacteria are needed for the normal development of T-regs, and mice reared in sterile environments, and so have no gut microbiota, have depleted levels of T-regs and are prone to developing chronic inflammation when they are exposed to pathogens.


Photo credit: Hippie by Witthaya Phonsawat courtesty of freedigitalphotos.net; clipart by Open Clipart and Clikr
 
Last edited:
Messages
5,902
Likes
12,696
Location
South Australia
@Simon and others

I have some questions with regards to the development of autoimmune conditions and I'm hoping this is the most appropriate thread to ask..

Unless I have misunderstood completely, autoimmune conditions arise through feedback loops that allow immune cells to bypass regulatory checks, allowing auto-reactivity. In particular, B-Cells which produce antibodies that in turn promote the survivability of those same B-Cells.

The nature of the disease also reflects the points at which the B-cells may have evaded regulation. For example high levels of ANA suggest B cells have evaded regulation at points (eg Bone Marrow) where specificities towards DNA or RNA containing ligands can remain.

Anyway, I was reading the following article, but I still have some holes in my understanding

"B-cell selection and the development of autoantibodies"
http://arthritis-research.com/content/14/S4/S1

It was suggested that the bone-marrow selection processes are not as specific as say, for T-Cells in the thymus.

The following rates of polyreactivity (auto-reactive to self antigens, though not necessarily with high affinity) have been shown (see above study for references)

75% very immature CD20+CD27- CD38hi CD24hi CD10+ b-cells are polyreactive

25 to 45% of immature blood B cells CD20+ CD10+ CD21lo IgMhi CD27-

After transition to mature B-Cells: CD20+ CD10- CD21-hi IgM-hi CD27- 10 to 20%

It was therefore suggested that the two key checkpoints are in the Bone Marrow and there is an additional checkpoint in periphery as B cells transition from immature to mature.

It was proposed that the Toll-like receptor plays an important role earlier selection steps and later activation and expansion.

How important are the bone-marrow selection processes in avoiding the development of autoreactive B-cells?

However, for B-cells to become activated, there must first be antigen presentation by the B cell to an activated T Helper Cell, which in turn activates the B-Cell. This in turn can initiates germinal centre processes.

In a germinal centre, the B-cell undergoes somatic hypermutation of the immunoglobulin. These cells soon migrate from the dark zone to the light zone of the germinal centre and are subject to selection processes involving antigen presentation to CD4 T-follicular helper cells (with pro-survival signals such as ICOS, CD40L, IL-21).

So for a B-cell to become activated, it must first present to an (autoreactive) T-helper cell before it has a chance to start producing antibodies. What are the chances of this happening, given the tight selection processes of T-cells?

Once that B-Cell is activated however, there is he possibility of autoantibodies interfering with regulatory processes that ultimately lead to greater survivability of autoreactive B-cells.


There is a hypothesis (in the above paper) that there may be another subset of immature/transitional B-cells (red pulp /RP B cell) which have the ability to responding to antigen, particularly in conjunction with a Toll Like Receptor agonist, and can mature into antibody secreting cells and can undergo class switch recombination.

But unless these B-cells underwent somatic hypermutation, then surely their affinity for self-antigens would remain fairly low? If these were the only autoreactive cells, wouldn't this result in a different response pattern over time to Rituximab?


Or perhaps there is a possibility of a slowly increasing feedback loop multiple generations? Starting with B-Cells with 'slightly' autoantibodies contributing to loss of control in the bone marrow and periphery over time?

In mice, it has been shown that delibrerate interference with certain germinal cell processes leads to the development of autoantibodies.

Lastly there was a suggestion that there is an additional selection process for plasma cells vs memory B-Cells, resulting in much lower amounts of autoreactive plasma cells in the bone marrow, I guess this makes sense in terms of Rituximab efficacy (since plasma cells don't express CD20).
 
Last edited:
Messages
5,256
Likes
32,006
@Simon and others

I have some questions with regards to the development of autoimmune conditions and I'm hoping this is the most appropriate thread to ask..

So for a B-cell to become activated, it must first present to an (autoreactive) T-helper cell before it has a chance to start producing antibodies. What are the chances of this happening, given the tight selection processes of T-cells?
A very reasonable set of questions, Snow Leopard, and I do not think anyone knows all the answers.

I would just say, however, that the autoreactive B cell does NOT have to present to an autoreactive T cell. This is the key to understanding why in autoimmunity lots of autoantibodies have been found but nobody has found an increase in autoreactive T cells. The antigens that B and T cells recognise are quite different. One is a surface shape on a whole molecule (it does not matter if it is protein or lipid or carbohydrate). The other is one side of a short peptide held in an MHC groove. There is no requirement for these to come from the same molecule and in many cases they cannot (for antibodies to carbohydrates or DNA for instance). The system is set up so that they are likely to come from the same molecule because the B cell normally presents a peptide chopped up from an antigen it has ingested becuase it bound to surface antibody. But if the surface antibody binds to molecule A and molecule A is stuck to molecule B then the B cell will ingest and present molecule B as well. This has been understood as the most plausible explanation for a lot of autoantibody production since the early 1990s. Note that in coeliac the T cell is anti-non-self (anti-gluten) whereas the B cell is anti-self (tissue tranglutaminase) because gluten sticks to translutaminase.
 
Messages
5,902
Likes
12,696
Location
South Australia
There is no requirement for these to come from the same molecule and in many cases they cannot (for antibodies to carbohydrates or DNA for instance). The system is set up so that they are likely to come from the same molecule because the B cell normally presents a peptide chopped up from an antigen it has ingested becuase it bound to surface antibody. But if the surface antibody binds to molecule A and molecule A is stuck to molecule B then the B cell will ingest and present molecule B as well. This has been understood as the most plausible explanation for a lot of autoantibody production since the early 1990s.
This is interesting, do we have any direct observational evidence that this happens?

The example of the gliadin-transglutaminase is a compelling one. Are there any other key parings like this?
How stable does this binding have to be?

Is it plausible for a B-cell to become active towards say, a kinase which was in the process of phopsphorylating a viral peptide? Or does this process happen too quickly for a B-Cell to ingest them at the same time? (or dephosphorylation or ubiquitination for that matter)
 
Messages
5,256
Likes
32,006
This is interesting, do we have any direct observational evidence that this happens?

The example of the gliadin-transglutaminase is a compelling one. Are there any other key parings like this?
How stable does this binding have to be?

Is it plausible for a B-cell to become active towards say, a kinase which was in the process of phopsphorylating a viral peptide? Or does this process happen too quickly for a B-Cell to ingest them at the same time? (or dephosphorylation or ubiquitination for that matter)
Some time around 1985 a number of people in immunology, including notably Jacob Natvig and Antonio Lanzavecchia, (and in fact myself) while musing on how autoantibodies might be allowed, independently hit on this idea of 'piggy-back' antigen presentation. In 1991 Lanzavecchia published a little experiment with Rooznek, demonstrating it happening in vitro. They showed that B cells that make antibodies to IgG constant region (i.e. 'rheumatoid factor' antibodies) will pick up IgG (antibody) in the medium, attached to any antigen X you like and present the antigen X to T cells that do not recognise IgG itself. This was the mechanism for RA antibodies that Jacob and I had been interested in.

Around the same time people had been wondering how you could get antibodies to DNA that seemed to depend on T cell help when of course T cells cannot recognise DNA. The obvious option was that B cells picked up DNA attached to nucleoprotein and that the T cells recognised nucleoproteins maybe from bacteria. This story got very complicated and it became clear that by binding to a toll-like receptor DNA can stimulate B cells to make antibody probably bypassing normal T cell antigen specific help requirements. And then it became clear that the reverse situation might apply where antibodies to nucleoproteins like Ro and Sm might make use of signals to the B cell from attached DNA. Anne Marshak Rothstein did some interesting experiments on the relation of DNA and rheumatoid factor antibodies, showing how the mechanisms worked in vitro, a bit like Lanzavecchia. In the end it became clear that both TLR9 and TLR7 were probably relevant and people are now thinking of TLR4 as well. The hypothesis has broadened to include a whole range of 'piggy-back' options. This is all well understood by a group of immunologists interested in these things. The problem is that it is too complicated for the mainstream community to get their heads around so it tends not to find its way into textbooks or teaching courses.

Another potentially interesting example is that in PANDAS, which are not quite typical of autoimmunity but may be related, mice showing an aberrant immune response to streptococci developed anti-complement antibodes. Complement binds to bacteria as one of its main functions in promoting phagocytosis.

The review Jo Cambridge and I wrote for Immunology in 1999 (I think freely accessible on my ResearchGate page) goes through some other potential examples.

I think the idea you suggest about producing an antibody to a kinase that binds a virus is very much in line with what seems to happen in this model. The only reservation I would have is that phosphorylation of viral protein is likely to occur inside a cell and unless the kinase-protein complex gets released into tissue fluid where it can interact with B cell surface receptors it would not engage a B cell response.
 
Messages
5,902
Likes
12,696
Location
South Australia
I think the idea you suggest about producing an antibody to a kinase that binds a virus is very much in line with what seems to happen in this model. The only reservation I would have is that phosphorylation of viral protein is likely to occur inside a cell and unless the kinase-protein complex gets released into tissue fluid where it can interact with B cell surface receptors it would not engage a B cell response.
The interesting possibility arises of virus induced autoimmunity though?
For example, there are known viral mechanisms that interfere with apoptotic signalling, particularly for viruses with large genomes such as EBV. For example, BHRF1 has been shown to be a BCL-2 homologue in B cells and kinases such as VRK2 have been shown to phosphorylate BHRF1. JNK also phosphorylates BCL-2 (which inactivates it), so I'm wondering about potential cross-reactivity there too.

This still happens within the cell though, but surely the possibility exists for B-Cell interaction after cell lysis?
Edit - on additional thinking, I realised such antibodies would still be mostly useless, except perhaps as a potential catalyst towards development of a B-Cell lymphoma...

Lastly, there is this interesting theoretical study on the specificity of human kinases for phosphorylating viral proteins:
http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0040694&representation=PDF

Lastly, is your opinion on activated B cells themselves expressing CD40L and thus providing a survival signal during germinal centre processes?
 
Last edited:

Bob

Senior Member
Messages
16,455
Likes
34,051
Location
England (south coast)
Here's a blog that came to my attention on Twitter. It's not new - it's from 2013. I thought readers of this thread might be interested in reading it. The blogger points out that abnormalities in T-cells have been a persistent feature in a number of ME/CFS studies, and discusses the implications of T-cell dysregulation for disease, and the role of T-cells. I'm not well enough or knowledgeable enough to attempt to assess the contents for myself, but I thought it was an interesting observation about the three studies that are cited.


FRIENDS, an old friend is manipulating the immune system
December 27, 2013 by SCIENCE ME
https://moms4science.wordpress.com/...old-friend-is-manipulating-the-immune-system/

Extract....

Summary

All four studies found an increased percentage of Tregs in patients diagnosed with ME/CFS. Regulatory T cells play an important role in maintaining immune homeostasis. Increased levels of Tregs have been found in many cancers and various chronic infectious diseases. Tregs are known to suppress other immune cells. The bystander immune suppression caused by increased percentage of Tregs could lead to reactivation of latent herpes viruses and other opportunistic infections commonly found in immune compromised patients.

Furthermore, these results would suggest that the immune system of patients with ME is unable to clear a chronic infection.
 
Messages
5,256
Likes
32,006
The interesting possibility arises of virus induced autoimmunity though?
For example, there are known viral mechanisms that interfere with apoptotic signalling, particularly for viruses with large genomes such as EBV. For example, BHRF1 has been shown to be a BCL-2 homologue in B cells and kinases such as VRK2 have been shown to phosphorylate BHRF1. JNK also phosphorylates BCL-2 (which inactivates it), so I'm wondering about potential cross-reactivity there too.

This still happens within the cell though, but surely the possibility exists for B-Cell interaction after cell lysis?
Edit - on additional thinking, I realised such antibodies would still be mostly useless, except perhaps as a potential catalyst towards development of a B-Cell lymphoma...

Lastly, there is this interesting theoretical study on the specificity of human kinases for phosphorylating viral proteins:
http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0040694&representation=PDF

Lastly, is your opinion on activated B cells themselves expressing CD40L and thus providing a survival signal during germinal centre processes?
Yes, I think the way viruses tinker with cell death and associated danger signal pathways is a good reason to think that a virus might trigger an autoimmune response. I would ditch the idea of cross reactivity though - there is so little evidence that it is relevant despite the fact that immunologists are obsessed with it. I prefer the sort of model we see in coeliac - the T cell recognises the foreign material and the B cell recognises not something that cross reacts with it but an enzyme that binds to the foreign material (tissue transglutaminase). In lupus the antibody recognises DNA which is bound to nucleic acid binding proteins and the T cell help may well come from T cells recognising microbial DNA binding proteins. No cross reactivity involved but 'cross-talk' all the same.