B cells, T cells, and Rituxan

Hal9000 wrote:
. . .
In your readings you may have read about B cells and T cells. Note that T cells mature/ripen in the Thymus over an extended period of time, several weeks as I recall. If one has a T cell ITP problem (row 3 & 4), Rituxan killing off B cells isn't going to resolve the issue. On the other hand, if one has a B cell ITP problem (row 1), Rituxan can be effective.

If one studies the various ITP drugs, I think you will find that MMF, Cyclosporine A, and Danazol are the only ones that can affect T cells. Nplate and Promacta are known to help B cell regulation/balance - but only on the margin (very little). Hence a reason why these drugs can sometimes help in row 1 when the dis-regulation is only slight.

On a different but related front, Celiac and I think Rheumatoid Arthritis and MS are T cell mediated disease. It would be interesting to see a list of how the various diseases divide between T and B cell mediated.

[hr]

poseymint wrote:
Hal- New information for me that goes along with your question about B and T cells. I'm thought now to have Primary Sjogrens syndrome which is known to be a B-cell attack on the salivary glands and also systemic, can affect major organs etc. It comes with a higher rate (up to 40x higher than normal) of B-cell non Hodgkins lymphoma possibly because of the overly-activated B-cells. Oddly immune suppressants like Cell cept don't work to alleviate the dry mouth symptoms, and can make things worse as they increase the risk of lymphoma. Rituxin and IVig are used. Rituxin didn't work for my ITP so I've always thought that maybe it was a T cell issue.

I spent some time trying to gain traction on this B cell or T cell mediated disease issue. Didn't get anywhere. Too complex for me.

About Rituxan though Posey. First, when one reads the various studies on Rituxan it is often commented that there appears to be a relation between treatment success and how long one has been diagnosed. The shorter the ITP duration the higher the success rate of Rituxan. Second, I recognize that not everyone with good steroid and IVIG response (row 1) achieves remission with the drug. A high percentage, yes, but not everyone.

I wonder how to account for these two characteristics. The first could be explained by the complication of a second antibody coming into play. But that seems to change one's steroid and IVIG responses and that isn't seen in the second characteristic.
How about this. How about either because 1) T cells got in on the act, as you mention? Or, 2) Breg cells have become more out of balanced (more convicted in destroying platelets) over time? Doesn't seem to be a way to determine which is the case here with a simple deduction or observation.

I think I see a potential way if T cells (#1) is it. Find someone with a row 1 response that has failed Rituxan and then gone on to achieve remission from some other drug or drugs. Ah, a search through my PDSA notes is in order. One such person looks like they sort of fit the bill: 'seema09'. She(?) achieved remission with the combination Rituxan, Azathioprine (aka Azoran), and then appears to have added Cellcept and Dapsone for a week. Read through her posts and see what you think. My guess would be that Dapsone did not contribute to the remission. Don't recall seeing a study saying it affects Breg or Treg cells.

I have to wonder if the one week of Cellcept was the kicker to the remission. Counts did not go up until it was added. Don't know. From my earlier statements on B and T cell treatments, Azathioprine would be expected to act on B cells and Cellcept would be expected to act on T cells. My guess would be that these two drugs could be enough to induce remission. Also that Danazol might be a good substitute for Cellcept.

In all honesty though, I have to wonder if your situation is different. Whether both row 1 and row 2b antibodies are in play. I guess what makes me think that is the higher Nplate dose of 5. I guess what would eliminate that possibility would be to ask you if you've ever taken a moderate to high dose of steroids along with Nplate/Promacta for a period of time. Most folks seem to have a significantly reduced required dose of Nplate/Promacta afterwards.

Also interesting, my rheumatologist explained that there is a Lupus driven form of ITP. It is an attack on the bone marrow. And in that case all of the numbers will be off- low red cells, low whites and low plates. And when they find the right drug to suppress the attack, in theory all of the numbers should normalize. In my case its only the platelets that are low so it is thought that my ITP is just going along with Sjogrens and whatever else I may have, so fixing one does not necessarily fix the other.

Hal:

I achieved remission from Rituxan seven years after diagnosis. Rituxan wasn't used for ITP when I was first diagnosed. The main trend that I've noticed is that if a person responds well to Prednisone, they are likely to respond to Rituxan, although that is not always the case. I've also noticed that if a person does not respond well to anything, splenectomy is not likely to be successful.

I respond very well to prednisone but had no response to rituxan. Thank goodness for Promacta! Have not been on Any medication for some time but i think promacta is the reason for now being drug free. My husband thinks i never should have been on anything and just would have gone away its own but i beleive it was the promacta! Have no idea of where my platelets are but so long as i am symptom free i am very satisfied.
Love to all

Hi Emily! Nice to see that you're doing well!

That is interesting Hal, thanks for giving it some thought. I have never taken a high or moderately high dose of pred along with Nplate/Promacta. I've taken 10-20mg for angioedema or Lupus/Sjogrens symptoms but for only a day. Strangely though, recently I took 10mg for Lupus one day, then 7.5mg the next day- it was the day I got a CBC and Nplate. My platelets which had been around 30K shot up to 95K. On my usual Nplate plus 7.5mg prednisone?! That is unheard of for me. I have only had counts of 95+ about 5 times in 9years! So it was the combination of Nplate and prednisone. The following week with only Nplate and no prednisone counts were back down to 30.

Anyway, it would be interesting to try to do a high dose prednisone taper along with Nplate. I wouldn't tolerate it for very long though. I seem to be more sensitive to the side effects of prednisone now. I've taken so much of it! Plus I have bone loss from it, so probably on second thought, I wouldn't risk going into osteoporosis just to lower my Nplate dose.

First year I was on Nplate I only needed 3mcg and was getting counts around 50K. Then we upped the dose because I was having wisdom tooth extraction and counts had to be 80+. So the dose was increased to 5mcg and got counts up to 83 but they wouldn't stay up. Even on 5mcg counts were falling back to 33, 39, 49. After that I wanted to get back to my original dose of 3mcg but I could never get the dose back down. My counts then on 3mcg were 9,18,6,13. So I think boosting the dose of Nplate caused some kind of retaliation of my immune system. Now I always like to keep the dose exactly the same so not to trigger my immune system. I have wondered if I slowly taper Nplate, would my Immune system back off also and allow my plates to stay at around 30? Doubt my doc would ever go along with that.

Once my counts shot up to 395 due to a virus. I had no Nplate for a week, then started back of a lower dose (408 instead of 454) and was able to stay on that lower dose. So as you know, some people will have remission or partial remission after their counts shoot up. But there is a risk of stroke in that.

Along the lines of unraveling the mystery-- It was found that my thyroid numbers are low. I don't have a thyroid so it means my med dosage is too low. Doc has increased the meds and I feel so much better. Also my platelets have gone up into the 40s, not a huge jump but they had been in the 20s and 30s. Caused me to wonder if lower platelets were connected to low thyroid somehow? I will be watching to see if plates go up with the increased thyroid drugs. Interesting case study, they increased thyroid and ITP remitted. www.ncbi.nlm.nih.gov/pmc/articles/PMC4855218/

Posey I don't have a thyroid either - recently my TSH shot up to 11.96 thanks to anther medical issue so my Synthroid had to be increased to 150mcg to bring it down into normal range [03.-3.0] - I've never noticed a difference in platelet count when Synthroid dose decreased or increased. I have Graves. Which of your thyroid numbers is low - a low TSH means hyperthyroid and too much hormone, a high TSH means hypothyroid and not enough hormone. Good luck to you!

MelA- I am hypothyroid. I have been on the same dose of Natur-throid (can't take Synthroid) for 17 years so hadn't been checking regularly. My TSH is way high at 31.3 (normal .45-4.5). T4, T3. and Free Thyroxine are all low. I was having so many minor symptoms that are now relieved. After reading more about how people with ITP are more prone to thyroid issues I wonder if the ITP fatigue that people report is not low thyroid. I was not aware of the connection between ITP and thyroid, hematologists have never mentioned it (?!) so its another piece to the puzzle for me.

www.ncbi.nlm.nih.gov/pubmed/17887931
CONCLUSIONS: The prevalence of hypothyroidism in patients with ITP is higher than in the general population. Based on this observation, routine assessment of thyroid function should be done in patients with ITP.
www.ncbi.nlm.nih.gov/pubmed/19932432

Bless your heart - a TSH of 31.3 would do me in!! The almost 12.0 was bad enough! I was going by the American Association of Clinical Endocrinologists recommendation when mentioned range 0.3-3.0 - and I am most comfortable at 1.something. I was well into ITP when the Graves [hyperT] hit, that taken care of put me in hypoT. I have to have the brand Synthroid. As with any treatment for any disorder, what works for some doesn't for others There was a man on here a number of years ago, well it was his wife, and he had Graves and ITP - cant' recall which came first. Everyone should have thyroid blood work yearly even if the results from the year before were perfect! Just had a platelet count done today - the tech said her daughter was diagnosed ITP shortly before giving birth not lot ago - gather her thyroid is off.

I've read that even having anti-thyroid antibodies with a normal TSH can cause symptoms. I know a few people who have that going on. My TSH has been getting lower and lower; the last one was 1.21. Still in normal range, but I've been having symptoms. I have a script to test the T3 and T4 and to test for antibodies, not that a doctor would do anything about it anyway until the TSH was abnormal. They never think out of the box.

Interesting reading about the thyroid stuff. I've been on the brand Synthroid (generic did funky things to me) for a few months and it has helped my TSH numbers to come down. They were always subclinical (got up to 3.5 or something like that, but normal doctors don't flag it until it gets quite a bit higher, like 10+ or so depending on the reference range for the lab) but had been creeping up in my yearly blood work, so I saw an endocrinologist.

Sandi, that's interesting that you are drifting towards hyperthyroidism with the decreasing TSH numbers. I think they say that the ideal for many people is close to the bottom of the range (0.9 or lower maybe?), but I've heard stories about people having different set points that work best for their symptoms, and you only figure out what thyroid levels work best for you by trial-and-error.

You read all kinds of stories of people trying to fix thyroid issues with doctors who won't look beyond the TSH lab range, so good luck figuring out your issues!

My thyroid has been enlarged for a few years and my daughter has Graves, so I try to stay on top of it. My Rheumatologist will only test the TSH but my GP agreed to test the rest.

You are right on the trial and error mom - really that is all you can do with it. I am so fortunate to have a fantastic endocrinologist who does go with the AACE TSH range of 0.3-3.0, the lab has to top range at 5.something - I remember my PCP looked at the blood results for a physical and said all was fine, well my TSH was almost 6.0 so I went home & emailed my endo and we changed my synthroid dose. It took us a couple years to figure out I have to have synthroid. I do envy my friend who has been on the same dose for many years, so far has never had to change it - she was hypoT where I started out hyperT.

poseymint wrote:
...
Once my counts shot up to 395 due to a virus. I had no Nplate for a week, then started back of a lower dose (408 instead of 454) and was able to stay on that lower dose. So as you know, some people will have remission or partial remission after their counts shoot up. But there is a risk of stroke in that.

454 to 408 (about 10%) permanent reduction in Nplate dose is pretty significant at the cost of a week or two of higher counts.
I dunno. Maybe Nplate and Azathioprine together would act the same as Nplate and Prednisone together.

I have been reading up on immunology and whatever I have read Auto immune diseases are primarily a T Cell problem.

Am I not right?

I thought T cells have 4 types of cells Thelper, Tkiller, Tregulatory, Tmemory.

Do you have this kind of mechanism in B cells.

Also to kill organ cells MHC1 needs to be comprised and that is done by T Cells.

Ultimately regulation happens (Partial remission happens) with only TRegulatory cells up-regulate.

jayinchicago wrote: I have been reading up on immunology and whatever I have read Auto immune diseases are primarily a T Cell problem.

Am I not right?

I thought T cells have 4 types of cells Thelper, Tkiller, Tregulatory, Tmemory.

Do you have this kind of mechanism in B cells.

Also to kill organ cells MHC1 needs to be comprised and that is done by T Cells.

Ultimately regulation happens (Partial remission happens) with only TRegulatory cells up-regulate.

Jay, that's a good start to questions and subjects that need addressing. I think it would take a course or two on 'immunology' to get up to speed and begin to talk intelligently about these subjects.

On the other hand. If one just leverages 'evidence based medicine' that can be a very powerful tool to finding useful answers without having to know the details of what is going on 'under the hood' in immunology. This is what I tried to do when I created my ITP treatments table. Enumerate what does and what doesn't work in a clinical setting.

Ok, stumbled on this info.
www.fmshk.org/database/articles/897.pdf
"An Update on Immunosuppressive Medications in Transplantation", 2001

This document talks about immunosuppressants and how they act on T cells in the context of organ transplant (eg kidney). Although several suppressants are mentioned, steroids, Azathioprine, Cyclosporine A, and Mycophenolate Mofetil (MMF) are the ones used for ITP treatments. Figure 2 is a good diagram giving one an clue/idea about what is going on and where.

Cyclosporine A is described as inhibiting T cell signalling (signal 3). Azathioprine and MMF are described as blocking B and T cell cloning / proliferation. Steroids are described as blocking much earlier in the signalling - at the cytokine / inflammation stage (signal 1 and 2). Steroids are also identified as blocking signal 3 but I would bet this effect is very weak - where large doses of steroids required.

Does any of this help to explain my ITP treatments table? Maybe. LOL, warning, here is where the crazy speculation comes out.
Figure 2 suggest that Azathioprine and MMF are interchangeable - both block B and T cell proliferation.
A row 1 steroid response seems to be more rooted on an 'inflammation' response (cytokines from APC) and less so by T cell activity / signalling. Steroids alone are effective.
For row 3 and 4, T and B cell proliferation / cloning seems to be all that is needed to drive the process. That is, steroids cannot block the cell proliferation / cloning.
Why Cyclosporin A would be most effective for row 4 is unclear. The fact that it affects the Calcineurin pathway within T cells may play some part. Clearly, blocking this pathway blocks signal 3 events as well.

All this stuff is completely foreign to me. High school biology is all I know. Can others speak up and set me straight on what I've got wrong or am misunderstanding? Don't be shy!

poseymint wrote:
MelA- I am hypothyroid. I have been on the same dose of Natur-throid (can't take Synthroid) for 17 years so hadn't been checking regularly. My TSH is way high at 31.3 (normal .45-4.5). T4, T3. and Free Thyroxine are all low. I was having so many minor symptoms that are now relieved. After reading more about how people with ITP are more prone to thyroid issues I wonder if the ITP fatigue that people report is not low thyroid. I was not aware of the connection between ITP and thyroid, hematologists have never mentioned it (?!) so its another piece to the puzzle for me.

Posey, I was talking to my niece. She's been diagnosed with Hashimoto's thyroiditis (low thyroid) for awhile. Now she has Fibromyalgia as well.
In my studies on (Alzheimer's, Herpes, and) Lysine, I came across this blog web page on Epstein Barr Virus:
stopthethyroidmadness.com/2010/06/27/be-aware-of-the-epstein-barr-virus/

What do you think of this blog post?

Further down in the comments section they talk about Lysine. I'm getting the impression, from this blog and elsewhere, that EBV symptom outbreaks might be triggered by Herpes, and of course, Herpes outbreaks can be controlled with Lysine supplementation.

So with that, Lysine can then control a whole cascade of problems, as pointed out on the blog page: dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, and multiple sclerosis

Or, have I made a logical error?

Hal, you could probably cure everyone with that logic. I only wish it were that easy to follow down the line! What about the people who don't have herpes but have the other problems? I think just about everyone has EBV and it lies dormant until it manifests as some autoimmune or idiopathic disorder. That is my opinion for what it's worth.

Sandi wrote: Hal, you could probably cure everyone with that logic. I only wish it were that easy to follow down the line! What about the people who don't have herpes but have the other problems? I think just about everyone has EBV and it lies dormant until it manifests as some autoimmune or idiopathic disorder. That is my opinion for what it's worth.

It sounds like I'm preaching to the choir if that is your thinking on EBV.

Take a look at this table on Wiki describing the known strains of Herpes. EBV is strain 4 and hides in 'B cells'.
en.wikipedia.org/wiki/Herpesviridae#Human_herpesvirus_types

This past summer it was discovered the strain for Alzheimer's folks is not Simplex strain 1 as earlier assumed. It is strains 6A, 6B, and 7. The common name for these is 'Roseola'. Per the table, these strains hide in 'T cells'.
www.statnews.com/2018/06/21/herpes-viruses-alzheimers-disease-role/

There are several strains of Herpes in most everyone. As I recall, Chickenpox infects 90% of the population. Same percentage with EBV and same with Roseola. Having all three would be likely. Simplex strain 1 affects some 2/3 of the population so that is likely too. As the earlier blog describes, EBV outbreaks are driven by 'stress'. The stress aspect seems to be true with all strains. Likewise, all of these strains feed on Arginine and the absence of Lysine. Without Arginine, Herpes cannot activate and remains dormant - even with the stimulant of stress.
flipper.diff.org/app/items/5357

The mechanism for how Herpes becomes activated is not clear, but there are theories. A recent finding was 'hyperthermic stress' (high temperatures) can induce activation.
www.virology.ws/2009/04/03/how-herpes-simplex-virus-exits-latency/

Ok, that's my rant on Herpes. But what about the blog? Is it a common understanding what the author describes? That EBV triggers Fibromyalgia and Hypothyroid problem flairs. That it could also cause flairs of things like SLE? Should I lead my niece into investigating her EBV status and thus the possibility of Lysine? This subject is new to me.

I really don't know enough about it, Hal. I don't know that Lysine is the answer for health maintenance. All I know is that it is supposed to help shingles outbreaks.

Hal9000 wrote: ... The stress aspect seems to be true with all strains. Likewise, all of these strains feed on Arginine and the absence of Lysine. Without Arginine, Herpes cannot activate and remains dormant - even with the stimulant of stress...

Sandi wrote: I really don't know enough about it, Hal. I don't know that Lysine is the answer for health maintenance. All I know is that it is supposed to help shingles outbreaks.

Went too far in my rant. Arginine as an energy source is really just linked to the 'alpha' subclass of Herpes, that is HHV1, HHV2, & HHV3. See the sub classes here. The other sub classes are 'beta' (HHV5 / CMV, HHV6 & HHV7 / Roseolo virus) and 'gamma' (HHV4 / EBV / Mononucleosis).

Gamma subclass, HHV4. Note that gamma subclass hides in immune system B cells. There are studies which link suppression of Epstein Barr virus (EBV) with the dietary supplement NAC (N-acetylcysteine).
"N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation"
www.researchgate.net/publication/321735025_N-acetylcysteine_NAC_ameliorates_Epstein-Barr_virus_latent_membrane_protein_1_induced_chronic_inflammation
As you may already know, there are studies linking EBV with several diseases eg: cancer, SLE, hypo Thyroid. I would wonder if EBV is responsible for some cases of ITP, that is, the row 1 B cell group in my table.

Beta subclass, HHV5-7. Note that beta subclass hides in T cells. There are studies which link suppression of T cells with the reduced dietary consumption of, strangely or not, Arginine.
"Arginine and Immunity"
academic.oup.com/jn/article/137/6/1681S/4664953
Whey protein and Yogurt are good sources of low Arginine foods.

So, a high Lysine and low Arginine diet is good for control of both alpha and beta Herpes sub classes. NAC supplement is good for gamma sub class.

On a related subject, the subject of 'stress'. Researchers have found Alzheimer's patients have both HHV1 and HHV6/7 in brain matter. It takes both. But, don't know what is going on, the interplay between the two - yet.
"Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology"
www.ncbi.nlm.nih.gov/pmc/articles/PMC5879884/

I would wonder if HHV1 is reactivated by stress, and HHV6/7 is reactivated by HHV1. A chain of events occurs: stress -> HHV1 -> HHV6/7 -> T cell immune attack -> brain plaques.
Similarly. Recall that SLE is activated by sun exposure and that ultraviolet light activates HHV1. Thus suggesting an event chain of: UV -> HHV1 -> HHV4 -> B cell immune attack -> SLE