Th1 and Th2 responses: what are they?

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Th1 and Th2 responses: what are they?

Postby Lyon » Wed May 02, 2007 7:27 pm

This paper makes a few oft heard terms a little more understandable. I'm not certain of the exact date but I THINK it's from August 12, 2000.
Bob

Th1 and Th2 responses: what are they?

Abi Berger, science editor.

BMJ

Cytokines are the hormonal messengers responsible for most of the biological effects in the immune system, such as cell mediated immunity and allergic type responses. Although they are numerous, cytokines can be functionally divided into two groups: those that are proinflammatory and those that are essentially anti-inflammatory but that promote allergic responses.

T lymphocytes are a major source of cytokines. These cells bear antigen specific receptors on their cell surface to allow recognition of foreign pathogens. They can also recognise normal tissue during episodes of autoimmune diseases. There are two main subsets of T lymphocytes, distinguished by the presence of cell surface molecules known as CD4 and CD8. T lymphocytes expressing CD4 are also known as helper T cells, and these are regarded as being the most prolific cytokine producers. This subset can be further subdivided into Th1 and Th2, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines.

Th1-type cytokines tend to produce the proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses. Interferon gamma is the main Th1 cytokine. Excessive proinflammatory responses can lead to uncontrolled tissue damage, so there needs to be a mechanism to counteract this. The Th2-type cytokines include interleukins 4, 5, and 13, which are associated with the promotion of IgE and eosinophilic responses in atopy, and also interleukin-10, which has more of an anti-inflammatory response. In excess, Th2 responses will counteract the Th1 mediated microbicidal action. The optimal scenario would therefore seem to be that humans should produce a well balanced Th1 and Th2 response, suited to the immune challenge.

Many researchers regard allergy as a Th2 weighted imbalance, and recently immunologists have been investigating ways to redirect allergic Th2 responses in favour of Th1 responses to try to reduce the incidence of atopy. Some groups have been looking at using high dose exposure to allergen to drive up the Th1 response in established disease,1 and other groups have been studying the use of mycobacterial vaccines in an attempt to drive a stronger Th1 response in early life.2

An additional strategy is being used to prevent the onset of disease; this involves the study of pregnancy and early postnatal life. Both of these states are chiefly viewed as Th2 phenomena (to reduce the risk of miscarriage, a strong Th2 response is necessary to modify the Th1 cellular response in utero). The fetus can switch on an immune response early in pregnancy, and because pregnancy is chiefly a Th2 situation, babies tend to be born with Th2 biased immune responses. These can be switched off rapidly postnatally under the influence of microbiological exposure or can be enhanced by early exposure to allergens. It is also hypothesised that those who go on to develop full blown allergies may be those who are born with a generally weaker Th1 response, although it is now apparent that babies with allergies produce weak Th1 and Th2 responses.

Some people have suggested that immunisation programmes (and the subsequent reduction in microbiological exposure) are responsible for the increasing incidence of atopy. There is, however, no evidence that immunisation causes atopy. Moreover, this is not an argument that we should be exposing children to potentially fatal diseases again. If experiencing native diseases reduces the incidence of atopy, then the task of immunologists must be to develop vaccines that mimic the positive effects of infection.
Last edited by Lyon on Sun May 06, 2007 8:20 am, edited 1 time in total.
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Trying to understand Th1 and Th2

Postby Smilingface » Sun May 06, 2007 7:43 am

In the pathogenesis of MS, are researchers convinced that there is an imbalance between Th1 and Th2? Is it generally agreed that enhancing the TH2 response is beneficial to those with MS?
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Re: Trying to understand Th1 and Th2

Postby Lyon » Sun May 06, 2007 3:27 pm

Smilingface wrote:In the pathogenesis of MS, are researchers convinced that there is an imbalance between Th1 and Th2? Is it generally agreed that enhancing the TH2 response is beneficial to those with MS?
Hi Smilingface,
Hopefully someone who knows more about it will respond. I was happy to find that page explaining TH1/TH2 because I didn't/don't fully grasp the situation.
Is it generally agreed that enhancing the TH2 response is beneficial to those with MS?
I think most researchers realize that the correct balance between TH1 and TH2 is what is needed, but we don't have the ability to do that so suppressing the TH1 is within our ability...somewhat.
Bob
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Re: Trying to understand Th1 and Th2

Postby Smilingface » Sun May 06, 2007 5:27 pm

[think most researchers realize that the correct balance between TH1 and TH2 is what is needed, but we don't have the ability to do that so suppressing the TH1 is within our ability...somewhat.
Bob[/quote]

Do you folks remember that really comprehensive German article Dignan posted Jan 18, 2007? I read with great interest the section on fumaric acid. It says that fumaric acid, which is the basis of BG-12 acts by increasing the TH2
response. That really was a great article. I keep re-reading it one section at a time.......
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Aha! Th2 and IL-10 are connected

Postby Smilingface » Sun May 06, 2007 7:21 pm

I just read Twisted Helix's post "Naive B cells and IL-10" which connects Th2 and IL-10 nicely. I love it when stuff actually makes sense! Now for my burning question.... Is this Th2--B cell connection a common pathway to nerve degeneration in relapsing/remitting disease and progressive disease?
What do you think? Perhaps the results of the OLYMPUS trial with rituxan will provide the answer. :)
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Postby Lyon » Sun May 06, 2007 7:44 pm

Because the memory cells are among the B cells, actually what I was wondering was whether Rituxan would offer an advantage to someone on the Tovaxin treatment. Remove the myelin reactive T cells with Tovaxin and blank out the memory so that no more are produced? Definately interesting times ahead!
Bob
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Postby TwistedHelix » Mon May 07, 2007 5:30 am

Hi Smilingface,
I posted the "naive B cell" article before I had a proper read of this post, and I hadn't realised how neatly they tie in. In fact, there seem to be quite a few dots here which are beginning to join up: the effects of pregnancy and the Th-2 immune response of the mother; the effect also on the unborn child; immunisation and the Post Natal exposure to environmental pathogens, (which to me sounds spookily like the hygiene hypothesis), and the fact that it is the balance between the Th-1 and Th-2 response which is crucial, just as it's the balance between naive B cells and memory cells that is so important. Much food for thought here,
Dom
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oldie but goodie

Postby notasperfectasyou » Wed May 23, 2007 11:08 am

........... napay climbs back in front of the key board for a moment.

I think this is good. If you want to get a more defined picture of this stuff you might want to read my 101 and 102 posts. The 101 post is in my sig below and the 102 post is: Understanding MS 102: My Doctor is Expressing Cytokines: Code Cipher Training

napay
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Postby Lyon » Wed May 23, 2007 12:56 pm

Thanks napay!

I still haven't gone through and read your information all the way through and I need to find the time one of these days.

Bob
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TH1 and TH2 resposes

Postby Nemotoday » Wed May 23, 2007 1:48 pm

When a cytokine profile converts from a TH-1 to a TH-2 status, it means that it moves from a hyper-stimulated and pro-inflammatory state to a largely anti-inflammatory condition . This would result in the reduction of inflammation-mediated tissue damage in patients with inflammatory conditions.

Hope it helps
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Postby Lyon » Wed May 23, 2007 2:51 pm

That does help. Thanks Nemo. I guess where I'm really lost is in determining how current medications relate to that?
Bob
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Postby Smilingface » Wed May 23, 2007 3:41 pm

[quote="Lyon" I guess where I'm really lost is in determining how current medications relate to that?

Bob[/quote]

My interest in understanding Th1 and Th2 stems from my treatment path of fumaric acid. Fumaric acid from which BG-12 is derived is documented to work by enhancing TH2 response. But what I can't resolve in my head is --I have PPMS, which is known not to have an inflammatory component so why does my neuro think it will work for me.
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Postby Lyon » Wed May 23, 2007 7:17 pm

Smilingface wrote:I have PPMS, which is known not to have an inflammatory component so why does my neuro think it will work for me.
Interesting question. I don't know the answer but I'll investigate to answer my own curiousity. Hopefully someone else on the site knows the answer right now?
Bob

Just to vocalize a long term wild speculation/brain fart of mine. In my world, at some level, everything has to make sense, including MS. I think it's important to keep in mind that there is an abundance of things about MS which aren't understood. The medical profession can't say when the MS process starts because nothing has been identified which can specifically identify MS. Even if there were something specific to identify MS, who would think to look until the patient experiences symptoms to complain about?

When my wife experienced slurred speech which led to her diagnosis there were over 7 lesions on her brain but she had never experienced any problems earlier. If we'd waited another two weeks the slurred speech probably would have resolved itself. How long might she have gone without knowing that she had RRMS? Maybe to the SPMS stage? And what is the difference between SPMS and PPMS? Only that SPMS is preceded by RRMS, right?

My point is, how many people might go through the entire RRMS phase without even an awareness and are later diagnosed with PPMS or PRMS? One of many proofs of the fallability of even modern medical science are all the assumptions which were based on the MRI which are now being thrown akilter by the newer, higher resolution MRIs. I think this PPMS/PRMS situation is only one of many in which MS researchers have taken wrong or incomplete information and used it to come to incorrect conclusions.
Last edited by Lyon on Thu May 24, 2007 1:33 pm, edited 1 time in total.
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Postby daisy » Wed May 23, 2007 8:09 pm

Funny - Several of us are on the same page regarding TH1/ TH2 balance.

Don't know if these will help but here are some excerpts, quotes and my personal notes from the background research that I am currently doing for an opinion paper.

* Th2 activated. In a simplified nutshell, this means you over-respond to toxins, allergens, normal bacteria and parasites, and under-respond to viruses, yeast, cancer and intracellular bacteria (such as Chlamydia/mycoplasma). Allergies, asthma, eczema are examples of Th2 activated diseases. IL 10 tends to be the primary cytokine activated.

* [b]Th1 activated[/b]. Also, in a simplified nutshell - This means you over-respond to virus, yeast, cancer and intracellular bacteria and under-respond to toxins, allergens, normal bacteria and parasites. [b]MS is generally considered to be Th1 activated as are Rheumatoid Arthritis and IBD. [/b] IL 12 tends to be the primary cytokine and there tends to be a perfusion of macrophages and Tlymphs.

* The immune system has two different modes of attack, based on the type of invader. One is Th1 (T Helper 1). It goes after organisms that get inside our cells ‚ intracellular pathogens. It is also known as cell-mediated immunity. The other is Th2 (T Helper 2). It attacks extracellular pathogens ‚ organisms that are found outside the cells in blood and other body fluids. Some call this humoral or antibody-mediated immunity. A healthy immune system is dynamic, able to switch back and forth as needed, quickly eradicating one threat and then resting before responding to the next.

* Viruses, especially herpes viruses like EBV, CMV and HHV6, can make proteins that mimic IL-10. The virus which should be handled by a Th1 immune response tricks the immune system into acting as if the threat needs a Th2 response. So the immune system shifts from an appropriate Th1 mode that attacks viruses to the Th2 mode that is weak and ineffective against viruses. The virus increases its chances of survival by diverting the immune system.

It is now thought that many, if not most, pathogens have this ability. For example, you get a parasite which should be handled by a Th2 response. The parasite however produces as part of its will to live defense an IL-12 like molecule, which fools your immune system into thinking the threat is coming from a virus, yeast or intracellular bacteria. The fake IL-12 causes your immune system to shift from the TH2 response that would go after the parasite, to the TH1 response, which does little if anything to parasites. Points for the helminth's are good for MS'ers theory.

[b]Elevation of cortisol is also known to suppress Th1 cell-mediated immunity and to cause a shift to the Th2 type of immune response. [/b]. Several mechanisms are involved, including suppressing the secretion of IL-1 by macrophages, inhibiting the differentiation of monocytes to macrophages, inhibiting the proliferation of T lymphocytes, and increasing the production of endonucleases, which increases the rate of apoptosis of lymphocytes . Could this be why the folks successfully experimenting with bee venom therapy see their success? Does it shift/attempt to balance the immune system from a Th1 response to a Th2 response?

*The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis.

* Th1/Th2 imbalance is hypothesized to up-regulate some diseases and down-regulate others. Compared to controls, multiple sclerosis (MS) (Th1-mediated) has been linked to a reduced risk of allergy and asthma (Th2-mediated), based on patient questionnaire studies and a review of asthma medication.

*One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and T-helper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1- and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway ("cellular immunity") to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway ("humoral immunity") and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other.

[b]But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro-Th1 or -Th2 patterns. [/b]The non-helper regulatory T cells, or the antigen-presenting cells (APC), likely influence immunity in a manner comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or Th2 dominant fail to meet the set criteria. [b]Experimentally, Th1 polarization is readily transformed to Th2 dominance through depletion of intracellular glutathione, and vice versa.[/b] Mercury depletes glutathione and polarizes toward Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2 balance, including plant sterols/sterolins, melatonin, probiotics, progesterone, and the minerals selenium and zinc. The long-chain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect.

* Also MS patients secreted increased amounts of IL-4 and IL-10 and decreased quantities of TGF-beta. TGF beta controls proliferation, differentiation, and other functions in most cell types. Thus, these studies suggest that there is a dysregulation in the balance between pro-inflammatory Th1 and anti-inflammatory Th2 cytokines in MS. It appears that the presence of Th1 secreting autoreactive T cells in healthy individuals may be counterbalanced by the presence of cells secreting Th2 cytokines and by the augmented production of the immunosuppressive cytokine TGF-beta, whereas in MS there is a decrease in these anti-inflammatory agents.
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Postby Lyon » Thu May 24, 2007 1:18 pm

daisy wrote:It is now thought that many, if not most, pathogens have this ability. For example, you get a parasite which should be handled by a Th2 response. The parasite however produces as part of its will to live defense an IL-12 like molecule, which fools your immune system into thinking the threat is coming from a virus, yeast or intracellular bacteria. The fake IL-12 causes your immune system to shift from the TH2 response that would go after the parasite, to the TH1 response, which does little if anything to parasites. Points for the helminth's are good for MS'ers theory.
I like the way you think Daisy, thanks!

It never ceases to amaze me how smart the people are who haunt the thisisms site.

Not only do I expect to continue to see good things from the Tovaxin clinical trials (wife is enrolled) but "loss of evolutionary normal conditions" in the developed countries creating a population wide primary predisposition to immune dysfunction is my long term obsession.

You sound like you know a thing or three about it also!

Bob
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