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Uncontrolled Immune Response/ DD/HR
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Uncontrolled Immune Response/ DD/HR

While not directly related to HCV, I found the following article interesting particularly the parts regarding an "uncontrolled immune response" and related inflammatory issues. In a similar fashion, could treating with interferon be causing some of our post tx symptons, of course a much more benign level.

http://www.medpagetoday.com/InfectiousDisease/URItheFlu/tb/4873

"...he 1918-19 Spanish flu may have killed 50 million persons by unleashing an uncontrolled immune response that fatally damaged lung tissue, researchers here say..."
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15 Comments Post a Comment
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Avatar_n_tn
The Spanish flu was most effective against the healthy with robust immune systems.

The question I have is not related to treatment but the virus itself.

If carriers of HepB,C are getting liver damage NOT from the virus itself but our own immune system killing the infected liver cells (the virus really isn't doing anything bad on its own except for the rare event in Hepb where it MAY integrate into cell DNA and cause copying errors leading to cancer) why isn't there any focus on limiting this immune system response?

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137025_tn?1217768341
My pulmonologist was concerned about a condition or syndrome that he thought i may have developed in my lungs from tx, and I'm so sorry, I cannot remember the name of it.  But his description was something like......"hyperstimulate the immune system long enough and every organ will react in some way."  To make a long story short, I lived with what everyone called pnuemonia (pneumonia) for six months, I did not feel bad, I had no fever, but my lungs were inflamed in the bottom third for at least six months.   All this was after tx, by about a year, it is better now, I can walk every day, but my xrays still s how inflammation in the lungs.  Believe me, my lungs have been looked at about twenty times, no cancer, no nothing.  

Just this stupid inflammatory response, brought on by IFN as far as my pulmonologist is concerned.  So what you write make sense in a really aggravating way.  Shortness of breath upon great exhertion is the only symptom, stairs are the only time it gets me.  So I avoid stairs.  And keep walking.

Willow
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Avatar_m_tn
Good question. I guess it's because the only way we presently know how to kill the virus is by stimulating the immune system with interferon. We do this because if the virus is unchecked it leads to cirrhosis and more of an incidence of HCC in many cases, in the case of HCV at least. I understand you are talking about the virus while I was talking more about interferon, but perhaps future treatments without interferon such as viral "cocktails" similar to how AIDS is managed will kill the virus without thereby moderating any theoretical immune response caused by the virus and by definition preventing any immune stimulation by interferon.

-- Jim
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Avatar_m_tn
should be "by moderating" not "without thereby moderating"
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Avatar_n_tn
All of this is exactly why we should be concerned about the post-tx interferon induced reactions so many of us have experienced.  Just like one of my Johns Hopkins (non-HCV specialty) doctors told me two years ago, the Interferon creates a system-wide response that persists in many people long, long after the interferon is removed.  He claimed that a wide array of systems and organs could be involved, and that cellular structure was often altered for many generations of cells, well after terminating the interferon.  So, in effect, what he really was saying, to paraphrase his description, was that the 'hyper-stimulation' of the immune system could go on for quite awhile after tx, and could cause a wide variety of problems anywhere in the body.  I have experienced just what he was describing, and every week we hear of more treaters who are dealing with these issues.  It boils down to being too much of a good thing....just like the Spanish Flu deaths.  A powerful immune system can save you...or in some cases also kill you!

I like the hyper-stimulation description in the article, because I think it really also describes what interferon does, during and after tx, in many cases.  I think HR has alluded to this post-tx hyper-stimulation, and the potential for finding ways to blunt, or slow this interferon induced hyper-stimulation.  

Maybe all of this is at the root of what we now call the autoimmune diseases.  Probably some sort of viral triggers, or at least pathogen oriented triggers that provoke the immune system, and get it caught up in a repeating cycle which persists, and causes chronic damage and ill health.

We are all learning more as we go along.  I am hoping that the doctors involved in the HCV field are also paying close attention.  I think we are going to need their attention and research.  Some of us may resolve our problems over time, but many others may not be so lucky, without additional treatment of some sort.  Nothing is really available at this point, to deal with the fallout from interferon.

DoubleDose
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Avatar_dr_m_tn
Yes an "uncontrolled" immune response. We see the same fundamental scenario in sepsis, where you die of a "cytokine storm" that way exceeds what the body can tolerate.

The task of the immune system is to either neutralize microorganisms(using antibodies) - that is the so called Th-2 response, or killing intracellular invaders - by killing the host cell - thats a Th-1 respnse.

The task of destroying a lifeform ( bacteria, viruses, fungi) within our own bodies/tissues is an extreme difficult one. In the end it amounts to chemically destroying biological microstructures by "eating" them and placing them in carefully separated digestive chambers ( Macrophages), or inducing an intracellular environment of high oxidative stress using mainly peroxide ( part of an inflammatory response and mainly caused by cytokines like eg TNFalpha, or inducing an infected cell to undergo apoptosis, or simply killing that cell ( necrosis). The cytokines cannot always be restricted to the local area of antigen recognition/ local inflammation, although - the body really tries. So when you have a bladder infection or a hepatic inflammatory infiltrate you feel sick all over.

The intensity of the immune response depends on many variables, mainly on primary signals felt by the innate immune system - the dentritic cells and macrophages- that orchestrate the vigor of the overall response, the recruitment of the adaptive arm and the unspecific elevation of reactivity that starts then to unleash an attack where there was a genetically predetermined propensity, like the lung. The bodywide dissemination of immune complexes, particularly in the skin, also leads to enhanced reactivity to trivial stimuli.
The immune response overall is often way from being perfect.
There was a comment in Nature " If we had no immune system, we would feel great, but would die very quickly." And sometimes we die because we have an immune system, like in systemic autoimmune disorders, diabetes, spanisch flu etc.
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Avatar_m_tn
One of the problems as I see it, is that unitl the medical community -- doctors, researchers, etc -- start acknowledging the problems with interferon therapy, that there will be less motivation to move beyond interferon in treatment protocols. The eye all too often seems to be on a too narrow ball which is SVR as opposed to the totality of the patient's health once they achieve SVR.

--Jim
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Avatar_f_tn
My immune system post treatment developed that skin disorder that I now have T.M.E.P. (short for something I can't pronounce).  It's an increased amount of mast cells in my skin and dilated vessels (determined by a skin biopsy).  The dermatologist had more blood tests ordered, but I would not find out if there was anything significant until a few weeks from now when I go in for follow-up.  I have no rash.  Just a problem with itching and burning (mostly arms and legs), when I get exposed to heat, exercise in an not cool enough environment, have any sun exposure or take too warm of a shower.  If I get stressed out too much, it flares up.  When it comes on it's intense burning itching and it feels like my skin has fire ants biting on it or something.  She said that it may be autoimmune, or systemic, or just a local to the skin reaction.  The weird thing is that I did not have this on treatment.  I asked her if the treatments could have caused this and she did not know.  She had to actually do some research about my path finding because she wasn't all that familiar with it.  The treatment she gave me was Zantac and Allegra.  She said that the research she found suggested that these drugs have properties in them that my help my condition.  I'm thinking about bringing the path report to my liver doctor and showing it to him to see if he's heard of anything like this.  
Susan
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Avatar_n_tn
You are right, the odd thing is that many of these post-interferon problems crop up AFTER ending the interferon therapy.  In ways, it seems that the interferon may have been acting, instead of our own immune systems, so to speak.  Maybe after we finish therapy, our own immune systems kick into high gear and create a different sort of havoc, thus inflicting a range of strange, autoimmune-style disorders upon our own bodies.
I am often amazed at the intensity of some of the post-tx fallout, as compared to the tx itself.  I often felt pretty good on tx, where the post-tx is a different thing altogether.  Maybe not worse than tx, but different.  There seems to be a good bit of overlap, or commonality in post-tx symptoms from person to person.  We really need to understand the mechanism for this response, and how to keep it from doing more ongoing damage.  I am happy that my liver is no longer under full scale assault, but that said, I prefer not to have the rest of my body 'burn out' in some sort of autoimmune 'firestorm'.

The medical community DEFINITELY has not yet come to grips with this interferon fallout issue.  I really believe that many doctors just do not really believe in listening to their patients.  If you took our forum as a cross section or sample, you would find a very high proportion of tx'ers who seem to be affected by post-tx complaints, and longer term interferon related problems, than the current literature would lead one to expect!

DoubleDose
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137025_tn?1217768341
I'm not so sure that the docs are ready to pay attention to the left-overs of IFN yet.  We all already know the numbers, up to 4 million folks infected and the tx is all still INF based.  Call me paranoid, but somewhere, along the way, a trade-off must have been made when IFN tx was approved.  From what I have read, there was a sudden surge of horrific HCC deaths, then a big rush to find a cause, found the cause and started looking for a cure.

I wouldn't feel comfortable saying anyone was wrong, but I'm not gettin a warm fuzzy feeling from any of my health care providers that they understand some of my lingering issues are from IFN.  In fact, I have gone way past the point of even making an issue out of it, when I first started IFN in 2002, my hep doc )long since gone) swore there was no stated research showing that my fatigue had any medical basis.  And that I was being a whimp.  

It was fun firing him.  But now I have one that tells the truth, don't know which is less fun.  Even he acknowledges there is little known about long term IFN, cept most folks are't the same chipper folks they were when they started IFN.

Chipper Willow
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Avatar_n_tn
This may have been discussed before but I have to admit I am way behind reading here.  This brings to mind something I was talking about with someone the other night.

What is the likelihood of less post tx problems if we were tapered off the Peg at the end of tx?  We are told not to quit most AD's and some other drugs cold turkey, why wouldn't the same reasoning apply here?  You all speak/write so intelligently, it's all I can do to read, let alone try to express my own thoughts.  

miss
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Avatar_n_tn
miss u r very right. inf dose shud be halved at the end
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131817_tn?1209532911
I have heard from HR that we should be tapering off inferon at the end. Your immune system is not used to having to fight off the virus and goes into a shock when stopped and it has to start working on it's own. (Please correct me if I am saying this wrong!) To gradually let the immune system take over the job of the antivirals makes much more sense. I guess the meds make our bodies not have to produce it's own interferon and rely on the artifical means.
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Avatar_f_tn
on the other hand, if HCV is actually persisting in spite of negative serum results, then the so called post tx, sides attributed to IFN, are actually caused by our own immune system still trying to deactivate the persistent strands.  I see no way of knowing for sure that it is all IFN/TX related in every case.  Then, we still have the reactive arthritis many suffer while infected, which in theory is supposed to become permanent if the infection is not treated on time.  Symptoms showing up months or years after tx ended, will be extremely difficult to tie to IFn or Riba as the source, even more so.  Reading HR's comment above, it seems that the foundation for autoimmune trouble is laid by HCV presence, seemingly making the body very susceptible to full blown syndromes when tx starts.
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Avatar_n_tn
There was an interesting article in the paper today about Johns Hopkins researchers studying the immune system and cold viruses, discussing how the virus also stimulates a protein in our bodies which eventually 'turns off' the immune system, and allows our symptoms to subside.  They quickly followed up with the comment that anything that stimulates our immune systems, especially over longer periods of time, (think interferon) has the potential to cause permanent problems in the form of autoimmune disease, namely lupus, diabetes, rheumatoid arthritis.  

Think about the problems many are experiencing after tx, and compare the manifestations to the above autoimmune diseases!
Also note how many of us are seeming to be moving toward diabetes, or have developed diabetes, after tx, and think about the immune system stimulation we endured for 6 months, a year, or in many cases, multiple therapies  adding up to several years or more of interferon!  How about the additional blood pressure issues and cholestorol, triglycerides, elevations seen after tx....and you wonder if that might also be tied to autoimmune related causes.

As for the residual HCV causing the problems, my question would be this:  If many of these people had none of the symptoms before tx, and they had massive amounts of very active virus in their bodies, why did the virus not cause these autoimmune problems before tx????  Why then should minute, sub-detectable levels of the virus cause all these exaggerated symptoms seen right after therapy?  I think that the likely culprit is the interferon, which caused the immune system hyper-stimulation for very long periods of time.

Remember, the reason why we do not generally clear the virus on our own, is that the virus EVADES recognition by our immune systems, thus allowing it to become chronic.  That is also why we don't have daily interferon-like symptoms just from having the virus...it is often asymptomatic.  Thus, the likelihood of the minute amounts of residual virus actually being the cause of all the post-tx problems, must be very minimal, as compared to the role of the interferon.

What several doctors I have spoken with in the past few years have told me is that there is a growing recognition of the power and impact that interferon has on those who use it, often for many years after ending its use.  It is a very intense immune system stimulator, and as the doctors in the JHH article stated, any long term-over stimulation of the immune system, can often provoke permanent autoimmune diseases.

DoubleDose
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