Author Topic: What type of hypersensitivity-autoimmunity is Sjogren?  (Read 5203 times)

inga

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #15 on: December 14, 2010, 12:25:52 PM »
Thank you Baklava and Nathan....I appreciate some scientific info....BTW....why are they saying that serum anti-fodrin antibodies are irrelevant to diagnosing Sjogrens?

I will make your plight more complex.  I am highly ANA+, (both fine speckled and also totally nucleolar, ranges, 1:640-1:1280) but SSA and SSB negative, but have severe infiltration of minor labial salivary glands with severe occular sicca....mild distal renal tubular acidosis and very bad small fiber neuropathy.)  What the heck do I have??  I am on very few meds, except for the big one....IVIG.

Oh as far as mimicry goes....I was infected with Borrelia?

I gave birth to several sons, so could be microchimerism?

Please continue the molecular dialogue.  I don't get it all, but I learn fast.

Baklavas

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #16 on: December 14, 2010, 01:13:05 PM »
The lymphocyte infiltration is the only sure thing.

If T cells have exerted considerable (f.e. long lasting) action against the glandular tissues, along
genetic susceptibility and environmental factors (f.e. stress, trauma, hormone therapy, infections)
 the upcoming rupture of the tissue leads to liberation of othewise confined self antigens...
Hence the SSA, SSB, anti-fodrin Abs and some other less commonly detected.
What I am tryin 2 figure is this very exact point of whether lymphocytes lead to formation
of Igs according to the above or whether Igs preexist and lead to activation of lymphocytes according
to a type III autoimmune process.

Upon the mimicy issue, the Borrelia infection, I am unaware of..
What I am aware of are the Coxsackie virus B4 +A13, 4 which I can oppine
it is found in ALL  biopsies of glandular tissues.

4 the latter argument see, [Triantafyllopoulou A, Tapinos N, Moutsopoulos HM. Evidence for coxsackievirus infection in primary Sjogren's syndrome. Arthritis Rheum 2004; 50: 2897?902]

I am equally unaware of the microchimerism involvement - only 4 the negative involvement of abortion - not of loss, but abortion.

Again excuse for any vagueness or stilted expressions whatsover.

Nathan

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #17 on: December 14, 2010, 02:18:46 PM »
I was mistaken, I apologize. SJS doesn't fit the classification of Type III Hypersensitivity. It's closer to Type II, but even that I am unsure of.
It is not Type IV, since it is antibody-mediated.

Thank you for the Johns Hopkins article, it has been helpful, even though it is out of date (It says the etiology is unknown, this isn't entirely the case anymore.)

Baklavas: The answer lies in the MHC II-presenting cells. Glandular Epithelial cells are different from most epithelial cells in that they present a MHC II binding site, presenting antigens. Our previously mentioned autoantibodies against alpha-Fodrin bind to the presented antigens on those glandular epithelial cells (These are CD4+ T-Cells mind you, they can also enter the cell), and ultimately cause apoptosis through the Fas-Fas ligand binding complement system.

As for why we have issues of seronegativity, I have no idea why. It may be an error of test sensitivity, or maybe it just takes a while for the body to produce the antibodies we are looking for? I really don't understand the role of SSA/SSB in the disease process, as these are antibodies against Ribonucleoproteins. Also, as far as I understand, the autoantibodies against alpha-Fodrin execute molecular mimicry against the Glandular Epithelial cells. This is why they are targeted (although, I don't understand entirely how a epithelial cell can present the same or similar enough as a cytoskeletal protein??)

I don't think that the formation of autoantigens happens intracellularly. A CD4+ T-Cell wouldn't know to invade a autoantigen-containing cell in this situation either. It needs to have the same surface receptors to bind first. I believe that this whole process forms B-Cells (Memory B-Cells?) which then do all the recruiting of other lymphocytes.

inga

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #18 on: December 14, 2010, 05:28:49 PM »
I don't know if this will help you....I have a high CD4+ count and a high CD4/8 ratio....5.92, I believe.  I can dig out the lab sheet if you need specifics, to support or rule out any premise you may have. 

You are over my head a bit here, and if I wasn't  remodeling my family room right now, I would sit and study this a bit more.....but demo beckons and if I don't supervise, well, let's say it could get ugly.  I can only marginally contribute.

I don't think most people on here have had such specific labs, maybe a few.  They were ruling out lymphoma, and all this got done in that endeavor.

On the epithelial tissue idea....distal renal tubules are epithelial tissue too, and dRTA is found in SjS patients.

It is interesting that many with SjS get a 'non-inflamatory erosive arthritis', which I think relates perhaps to the potassium, calcium loss of dRTA?  Exocrine glands make sense, GI makes sense, urinary makes sense.

Why would so many with SjS get small fiber neuropathy?  Why would the small fibers get attacked too?

I think the Sicca has two mechanisms.  One is denervation, the other inflammation.  To be honest, Sicca is the least of my issues.

Also, if I interpret what you are saying, those lymphocytes so liberally present in my labial salivary glands are 'proof' of autoimmunity, regardless of serum markers?

My +ANA came 6 years after the seriously lymphocytic biopsy.

I am thankful that there are people like you working on this issue.  I don't think sometimes, that lay people comprehend the intelligence of researchers.  It is easy to complain, but, apparently not easy for people to get thru all those science and calculus classes.

Thank you.  I know this is a complex problem, with no easy answers.

BTW, I am not convinced of the efficacy of monoclonal antibody 'drugs' yet.


Nathan

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #19 on: December 14, 2010, 05:53:31 PM »
Inga: If you don't mind looking for it, I am incredibly interested in your lab numbers, especially given your other symptoms.
You're very correct about dRTA.
I am also interested in the general "arthralgia" seen in a vast majority of SJS patients. Is this really an inflammitory process? Why are joints attacked?
I'm not sure about the non-inflammatory erosive arthritis, but I'm interested in this too. Speficially interested in the groups of people this occurs in (and if it's entierly unrelated to osteoarthritis?)

The question of small fiber neuropathy is another big one. It really doesn't make much sense to me (Or why neurologists often run EMGs on people with neuropathy in SjS when it is so unlikely they're going to find any abnormalities).

Lymphocytes seen in the salivary gland biopsies are there because they "found" something in the glands they were attracted to. This is why we can have a positive biopsy proving autoimmunity when our serum levels are inconclusive.


If there's anything else I can find out, I'll definitely add it in here. If you have any more questions, feel free to ask and I'll see what I know :)

As for Monoclonal Antibodies, they absolutely fascinate me. I know they're a bit... different, but they're also new. They've been doing some majorly good work in the cancer world, so who knows, maybe in the future they can help us? (Although, I'd look a little bit harder at applying caspase inhibitors, since they've been proven to drastically inhibit the development of autoimmune lesions in a murine model.

inga

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #20 on: December 14, 2010, 06:58:06 PM »
On monoclonal antibodies, I will be more excited when they define the mechanism of the disease a bit more specifically.  Just cautious I guess. 

OK this is 2 years old.  I was not on any treatment at that time and it had been a while since I had anything.  My ANAs run 1:1280 in general, either speckled, speckled-nucleolar, and purely nucleolar.  The ENA is negative.  I don't have much done now other than BMP, since IVIG messes that up for 4 months due to long half life.

WBC                                            4.6         range 4.0 to 10.0 e3/uL
%lymphocytes                              52      H  range 20-45%
lymphocyte #                               2410       range 1000-3400/uL
CD3+CD4 %T-helper CD4             71      H  range 32-61%
CD3+CD8+ % T suppressor CD8   12      L   range 18-42%
TOT CD3%                                  82          range  53-88%
CD3+CD4+ABS# T-Helper            1711  H  range 467-1085/uL
CD3+CD8+ABS T SUPP                289        range  109-656/uL
Total CD3 ABSOLUTE #               1976    H range 630-1546/uL
CD4+/CD8+ ratio                         5.92    H  range 0.86 - 4.60

I will see what else I can find that relates to this work up.

High CD4/CD8 ratios are more typical of Sarcoidosis.

The arthritis is a more aggressive form of osteoarthritis.  I also have recurrent bursitis and tendonitis.  I have had unexplained fracture, and I think this is due to the dRTA causing an osteomalacia which is confused with osteoporosis, altho my bone density is only recently getting slightly below normal in the femur.  Having been athletic, I always wrote it off to training injury, but it wasn't.  My PN is best described as a 'bone' pain type, with little burning.  I am also globally anhidrotic.  Seems to me, I do sweat, but likely at a higher temp than the box gets to.  I also had an epidermal nerve fiber density, which was quite abnormal below the knee, also present in the biopsy, was a Langerhans cell.  My muscle biopsy shows neurogenic myopathy, but, if I recall, there is something more in it....I have to look it up....something with a blue stain.

I have also had a low alpha one globulin peak, but am negative for the gene that causes hereditary COPD.  This was an incidental finding, so I had the gene tested and it came back normal.

Knock yourselves out!!

anita

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #21 on: December 14, 2010, 10:00:23 PM »
I find this conversation quite interesting even though a bit over my head.  I am also sero-negative yet highly positive on minor labial salivary biopsy.  I share many of the same symptoms as Inga and likewise have wonder what the heck is REALLY going on.  I'll get Inga to translate much of this for me later...LOL

I certainly have no place trying to contribute to this conversation, but have a question based upon a portion of Nathan's last post, which read:  

"Lymphocytes seen in the salivary gland biopsies are there because they "found" something in the glands they were attracted to. This is why we can have a positive biopsy proving autoimmunity when our serum levels are inconclusive."

If this is the case, then why are there so many discrepancies with reading the biopsy?  Mine was read with the Greenspan grading scale, but it doesn't appear there is a common use of any one scale and it's hit or miss with reading these biopsies.  However, criteria for a SjS diagnosis seems to clearly define a positive result ONLY if more then one focus (aggregate of 50 or more lymphocytes, histiocytes and plasma cells) is present, which is a grade 3 or 4 using Greenspan.

Lymphocytes infiltration can be present in smaller numbers or even in heavy concentrations (just not enough to be classified as a focus) and the biopsy is negative.  Certainly these infiltrates "found" something they were attracted to and seemingly autoimmune in nature, but they are still classified as negative.  Any thoughts on this?

Thanks
« Last Edit: December 14, 2010, 10:02:32 PM by anita »
50 yr old SjS, APS w/strokes, Autonomic Neuropathy, PN, Nephrogenic DI, (PID) IgG def., Cushing's, Asthma, Gastroparesis.  Sero-neg w/+ lip biopsy.  Meds: IVIG & pre-meds, Arixtra, Aspirin, Plaquenil, Nitro, Cardizem, Imdur, Toprol XL, Domperidone, Nexium, Midodrine, Symbicort, Oxycontin, Zofran

rnathans

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #22 on: December 14, 2010, 10:38:34 PM »
Anita, not a scientist by any means but my biopsy was originally read as negative. Then my rheumie had it recut and reread. There were foci but not the magic number. She still dx me with Sjogrens saying there was no other plausible reason for the infiltrates given my medical history, age and exam in my case and my symptoms matched a Sjogrens diagnosis.

irish

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #23 on: December 14, 2010, 11:44:50 PM »
I'll throw a little info in here just to stir the pot more. I have been ill for over 40 years and know that I had a bad sjogrens flare during last pregnancy in 1972---now that I know what I have. I had a positive lip biopsy in 2003. I was sent to my awesome doc who is an internist pediatric oncologist with hematology residency also. Extremely intelligent man who sits and thinks about me and hasn't figured it out yet.

I have myasthenia gravis that is anti acetylcholine receptor negative. However, I have an antistriated muscle antibody that runs over 61,000 and is one of the highest he has ever seen. I also have dysgammaglobulinemia with an absolute CD 3 of 449 on diagnosis and went down to 329. Last test was in the 800's but haven't had it checked lately. Normal is 1064-1672.

I have Hashimotos with an antithyroglobulin over 3000 (norm is 0-25) and an antithyroperoxidase antibody of 1019 (norm 0-60). My CRP was 0.7 in 2006 and was 0.50 on September this year. I was in a Sjogrens study in 2005 and had positive SSA and SSB. They were negative in September of this year. I also have Bullous pemphigoid which is a skin autoimmune disease.

I have positive ANA and FANA is positive for speckled and nucleolar. Doc says I act like a lupus but my DNA was negative.

I have had a genetic test done for one disease which was negative (can't remember or find the info) and also negative for the antitrypsin lung issues--think I got that right. I am not all that smart on this stuff. All I know is that the body chooses to try and kill me off but has failed so far.

I had a lot of the arthritis in the earlier years of my illness. I would get up in the morning and couldn't move my hands and they felt as big as a baseball glove. I put them under cold water and that seemed to draw the inflammation out. My feet were the same. I have a lot of tendonitis issues.. soem neuropathy.

Of interest to me is that I had a very high TSH one time and didn't know it at first. I was so stiff and had so much pain I could hardly walk. I was just a mess and thought I would end up with a walker or wh/ch. It just got worse and worse. After my thyroid med was increased and about 3 weeks down the road all these symptoms vanished. I was totally surprised because now I no longer know whether it is my sjogrens or my thyroid that is causing me issues. Darn confusing that is for sure.

My doc thinks that my myasthenia and other autoimmune disease came first and then the low t-cells. I had an aunt who I think had sjogrens and possibly myasthenia plus she had to have had low b or t cells as she would have to get gammaglobulin shots to help her get over infections. Darn interesting as well as confusing. If you find anything please post it as it would be interesting to see what is being researched and found to be true. Irish ;D

Just keep it as simple as possible please!!! :P

Baklavas

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #24 on: December 15, 2010, 06:11:22 AM »
Nathan:
   Is SS Ab-mediated right from the start or it becomes Ab-mediated
after the release of self-antigens into systemic circulation due to lymphocyte
infiltration?
   I conjecture that seronegativity of some, opposes to Ab-mediation  - kindly show the flaw in
the concept.

Inga:   Is Inga' s finding of low a1-globulin peak a universal finding as far as anyone knows?

Irish:   The absence of CRP, anti-DNA and vanishement in 3 wk time (which is the time T4 therapy takes effect) shift
etiology of Hashimoto - as your doc conjectured. A most cold comfort for adequate explanation, I concede.

If anyone finds it appropriate, kindly, ask your doctors about the Coxsackie participation.

inga

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #25 on: December 15, 2010, 07:24:45 AM »
My low alpha one globulin peak, seems to be of no interest to any of the docs.  I sent for the genetic testing kit....U of So. Carolina, to rule out the gene for hereditary COPD, which they did.  I don't know why I have the low alpha one globulin peak and I doubt that any one tests for it routinely.  Again it came out as part of the lymphoma work up.  The low alpha one was considered clinically irrelevant....just an oops?  What would the low alpha one peak mean without the gene present?  If other people with my serological profile have it, well then it would be of interest, I suppose.

I have other labs with some other CD levels, NK levels etc.  I will try to find those too.

We have a huge constellation of people on here.  Some completely seroneg.  Some like myself with +ANA, neg ENA and then those with +SSA and SSB.  I imagine there are those with seronegativity and negative biopsy, with pure sicca symptoms and no findings, some with likely drug related sicca as well, to those with full seropositivity and + lip biopsy.  I wonder, often, if there is more than one disease entity and etiology represented.

I often get into a heap of trouble on here saying, we don't all have the same disease, and I stick by that.  Research is extremely specific.  You have likely already googled 'Autoimmune Epithelitis'?  Which I think is a better name for those with seromarkers or +biopsies.

http://www.ncbi.nlm.nih.gov/pubmed/18068857

Also, I do have the low C4 and PN, but also have the other constellation as well....(My goose is cooked, so to speak.)

Would low alpha one globulin peak, relate to Sjogren's liver damage?  PBC?  Is that possible?

I don't think it is worth your time to weed thru the multitude of symptoms that all of us have, myself included, but if you are interested in CD counts and other labs, perhaps others can post these more sophisticated labs, and you may get some clue that has been missed.  I don't expect to get an accurate diagnosis in my lifetime.  For now, until the kidneys give up, I will stick with IVIG, I guess.....for lack of a better option.

« Last Edit: December 15, 2010, 08:49:01 AM by inga »

puccini914

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #26 on: December 15, 2010, 07:40:30 AM »
Baklavas, Welcome!!!!!!!!! ;D

If you're interested in collecting some raw data from us here on the site, I'm sure many people here would give you all the lab values they know and complete lists of symptoms and probably medication lists as well.  f you could post a questin asking for exactly what you need so that you don't get swamped with stuff you don't need, I'm sure many will respond. 

We pray everday for more research, we want to be  understood and to understand, we want better treatments.  If this is your field of research, the n God Bless you.

By the way, I love Baklava,  I make it home when I've got enough energy to stand he hour it takes to set it up, make the honey syrup, an hour baking etc
I also make Tabouli Salad (sp?) and stuffed grape leaves.  I live way up in the Georgia mountains so getting the supplies I need has been tough.  Some days I find myself wishing for a Gyro more then anything in the whole world.  I don't miss Florida, but I sure miss the Greek food in Clearwater Beach.

My symptoms are very Lupus like.  Major non-erosive arthritis, swelling and redness in hands and feet.  Dry eyes, mouth and genital areas. Hives, Mylar rash on face, fatigue, fatigue, fatigue, migraine headaches,possible gastroparesis, hair loss, neuropathy, brain fog,several bouts of costochondritis, and just a constant feeling of ill health.

My Ana was positive 1:1280, my F was 65, my SSA was 8 and my SSB was 16.  I've never had a high sed rate and all my other labs are within normal range.
I think I read somewhere on here that those with positive SSB often have the sunsensitivity.  I am so sun sensitive that 20 minutes in direct sun, will cause a major flare up within 2 days.

Feel free to ask anything else.  Always glad to help research in this field.

Peace Be With You and many prayers for you Mother.

Jennifer

echofuzz

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #27 on: December 15, 2010, 08:27:18 AM »
i have to say, reading this thread made my day. my week, actually. i don't understand all of it -i have a science background but it's not so biology heavy- but it's all information that's right up my alley. i plan to do some digging of my own to learn more of what y'all are talking about.

 ;D

thanks for lifting my mood!
echo
Dx: UCTD/possible SJS (no dry eyes or mouth; joint/muscle pain, muscle weakness/spasms, headaches, fatigue, brain fog)
AID meds/supplements: Plaquenil, methotrexate, folic acid, vitamin D3, CoQ10
-------
"The greatest oak was once a little nut who held its ground." - Unknown

anita

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #28 on: December 15, 2010, 08:40:25 AM »
I have no idea of the significance, but old labs done a couple years ago and even further back at Mayo showed the following:

Borderline high Alpha 1 globulin %
High Alpha 2 globulin %
Beta globulin -normal %

Then after seeing Inga's comment about looking for CD & NK labs it reminded me of a letter written from Mayo to my local doctor about these same labs.

From the immunologist at Mayo--...Other than a known mild IgG3 deficiency, she had an undetectable NK cell activity.  However, lymphocyte blastogenesis for both mitogens and antigens was normal. A flow cytometric study showed some NK cells in circulation as shown by positive CD16 and CD56 cells.  They didn't know the significance of the markedly diminished NK cell activity and wanted it explored for the specific NK lytic defect (never done---not found to be important by local doctor).  On another lab:  There is an increased CD4:CD8 ratio, but no morphologic features of lymphoma.  

Again, I don't understand much of this, and have no idea if any of this is helpful or related to patients with a SjS or other autoimmune process.  I am more than open to search for specific labs that may be useful...just let me know which might be helpful.



50 yr old SjS, APS w/strokes, Autonomic Neuropathy, PN, Nephrogenic DI, (PID) IgG def., Cushing's, Asthma, Gastroparesis.  Sero-neg w/+ lip biopsy.  Meds: IVIG & pre-meds, Arixtra, Aspirin, Plaquenil, Nitro, Cardizem, Imdur, Toprol XL, Domperidone, Nexium, Midodrine, Symbicort, Oxycontin, Zofran

inga

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Re: What type of hypersensitivity-autoimmunity is Sjogren?
« Reply #29 on: December 15, 2010, 08:59:48 AM »
Another lab drawn 2 months after showed,

CD4/8 ratio of 5.94
 
I can barely read this, I think it is as follows

%CD19 B Cells          12   range 5-25
%CD16 & 56 NK        5    range 5-30
%CD4 helper cells     70   range 30-62
%CD8 suppressor cells  12   range 12-24
CD3    1803  it appears blurred it could be CD8  just says T cells  range is 582-1992
CD19 B cells    272
CD16 & 56 NK 112
CD4 Helper cells  1548   range 401-1532
CD8 suppressor cells  261