Autoimmune Disorders - Science topic

Autoimmune disorders can have a significant impact on fertility by causing dysfunction in the reproductive system. Immunological interventions may address these issues such as

Autoimmune Attack on Reproductive Tissues: In autoimmune disorders, the immune system mistakenly attacks the body's tissues. In the context of fertility, this can lead to inflammation and damage to reproductive organs such as the ovaries, uterus, or testes. For example, autoimmune conditions like autoimmune oophoritis (inflammation of the ovaries) or autoimmune orchitis (inflammation of the testes) can impair the production and quality of eggs and sperm. and autoimmune disorders can significantly affect fertility through various mechanisms, including inflammation, and hormonal imbalances. Immunological interventions aim to modulate the immune response and alleviate the impact of autoimmune disorders on reproductive health, ultimately improving fertility outcomes for affected individuals.

Is there an autoimmune process not fulfilling, initially, a scavenging function?

Aren't the often long-drawn-out autoimmune processes released by infarction or traumatic brain injuries chronically testifying to this fact?

Which medical expert might tell a depression brought on by a latent infection and a (possibly overshooting auto-) immune reaction apart?

The following RG link is also very useful:

Thank you for your answers!

I don't have experience with a case like this, but it seems plausible that they could be related with this manifestation. I suggest the following literature:

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- https://www.thelancet.com/action/showPdf?pii=S2352-3964%2820%2930558-2

Best regards

Dear Dr Manal Hadi Kanaan, there is a relationship between diet and autoimmune disease. For example elevated levels of immune cells specific to a particular protein in cow’s milk have been seen in individuals with type 1 diabetes. In addition high sodium diets also play a role. Salt increases levels of immune cells involved in inflammation and autoimmunity. Highly processed foods contains large amount of salt, hence it is better to avoid them. Proinflammatory foods such as meat diary, processed vegetable oil adds additional stress to the immune system and may worsen autoimmune diseases. High fibre foods, probiotics, plant diet, foods rich in vitamin D and omega 3 (fish-Salmon, mackerel) may help to reduce the risk of autoimmune disease.

Have a look at the following RG link.

Techniques to study DNA supercoiling include agarose gel electrophoresis and psoralen-based molecular probes. Using these approaches, unrestrained DNA supercoiling has been identified and mapped in eukaryotic genomes.

Good luck

Please also see the following RG links.

Thank you.

Thanks for your answer

Consider this paper:

Arthritis Care Res (Hoboken). 2016 Oct;68(10):1497-504. doi: 10.1002/acr.22857. Epub 2016 Aug 19.

Does Renin-Angiotensin System Blockade Protect Lupus Nephritis Patients From Atherosclerotic Cardiovascular Events? A Case-Control Study.

Tselios K1, Gladman DD1, Su J1, Urowitz MB2.

Tks.

Dear Prof. Edwards,

Thank you. What I meant from Th1 or Th17 is the cytokine responses. For example disbiosis in the gut microbiome would favour Type-2 (Th2) responses in the intestines instead of Type-3 (Th17) responses, which are more optimal for barrier integrity than the Type-2 responses, due to the decrease in the ROR-gt+ Tregs. In contrast, increased Type-3 (Th17) responses promotes colitis and neonatal pathology due to increased ILC-3-mediated Type-3 responses. Like wise, as you know, a decrease in Treg cell numbers would increase Type-1 responses at islet beta-cells. Of course, antibodies also contribute to the progression of tissue pathology. However, their production is also regulated by the cytokines secreted by Th subsets.

My knowledge on this autoimmunity topic is limited and I hope other experienced Immunologists will come up with better views to answer your questions.

Protein arrays might also be an option

I believe we need more data in a sequential fashion in this patient, as above-stated. Apparently he had culture-proven TB, and a positive ANCA test, ? pattern and specificity. A diagnosis of true idiopathic vasculitis would require a tissue diagnosis regardless of the ANCA test. There are several questions to be answered, as raised by the other authors,

if Presumed immunemediated is suspected you should start GCs + AZA (if mild/moderate) or CYC (if severe) or RTX (if refractory) , but if Presumed thrombotic Process is suspected (aPL abs) then you should go with full anticoagulation with IV or SC heparin followed by oral warfarin ± aspirin daily for life

I think because of heterogenity of causative agents and different pathophysiology in different types of pneumonia, there could not be any net suggestion to give steroids even in severe pneumonia. We need to know more about concerete panthophysiology of given patient - e.g. some biomarkers - to have information about how does the immune system work in concrete patient. Without this data I do not give steroids because for me infection=no steroids unless I find some contribution of some autoimmunity or autodestructive process.

Hi. I'll send you some articles. Its a very interesting topic you have. The two angles are autonomic dysfunction and blocking/stimulating antibodies.

Dear

This link could help

Thank you so much. In New Zealand they completely ignore the T3 levels, although I think this is in err. I will follow up on the articles you suggested. Thank you.

I think this young lady should be treated with immunosuppresants since the basis for her current problem is an ongoing  immmune-mediated process.

Good evening Dr Awer,

My experience is that of adult rheumatology.

I am very impressed with the cases in your clientele.  Those patients always raise important unsolved problems.  As usual, there is no answer here but let me try to help.

Basically, an ectopic calcification is the end result of an underlying inflammatory process.  Calcinosis can be localized or diffuse.  The simplified natural history is first, a tissue injury that can be ischemic (tendon in diabetic shoulder), traumatic (extensive car accident with neurological deficit) or inflammatory (post-hip surgery and heterotopic periarticular calcification  or like here, in JDMS). Second, during the healing process, some people (not everyone, which one?, why?) will deposit calcium on their connective tissue components.  Third, that is associated with inflammatory symptoms until, fourth, the deposit stabilize and become inert and indolent.

In this fourth phase, treatment of calcinosis is frustrating and maybe altogether futile.  A potentially useful approach would be chelation.  The nephrologists use a perfusion of sodium thiosulfate (STS) in chronic dialysis to chelate calcium deposits in the vessels or skin.  The benefits are limited but it may be worth a trial.  One of the drugs you are using has a small chelating effect : aluminium hydroxide.  Etidronate was used in the past but I don't know if it is still available.  I don't know about the usefulness of alendronate for that purpose. The other drugs mentioned by Dr Subramanian are there, but I would not build too much hope on those.  Trial and error....Colchicine may act as prophylaxis but that is not the actual attack pattern here.

There has been a significantly impact on the occurrence of post-traumatic and post-surgical heterotopic calcifications using early preventive NSAIDs like indomethacin.  That is an example of acting at phase 2 of the process.  That could be considered.

In DMS, I beleive like Dr Tambic Bukovac, that the most logical and efficient approach is to go AGGRESSIVELY after the underlying disease.  The basic inflammatory process in JDMS is that of a vasculitis. In an adult I would go also with Steroids + RTX + immunosuppression.  If in children MTX and MMF may be more acceptable, I have successfully used in adults cyclophosphamide and AZT to stop the new deposits.  The old ones did not go away.... 

How to monitor treatment?  In adult DMS, there are several myositis-associated autoAbs (MAA) and  in a case like yours, there may be other CTD associated autoAbs that could be used as biomarkers and followed Q 4-6months.  I would thus suggest that you do what I call some auto-antibody-omics.

I would also monitor outcome using imaging of the calcinosis process using a quantitative or semi-quantitative pancorporeal nuclear medicine scan using a bone seeking agent .  That would give you a good idea of the activity of the calcinosis process and indirectly of the underlying vasculitic process. It could be repeated also Q 4-6 months

I apologize for the length of this communication.  Last year I had a similar adult case and that approach worked to stop the process but not to revert it.  Her quality of life was much improved.

Hope that helped.  Good luck with your patient.  Best.

HM

Contact a company called Hooke Laboratories. They make the adjuvant with the MOG peptide and depending on the incidence and severity of disease in your particular mice they will make stronger does of the peptide in adjuvant already made up.

Good luck!

 Dear Ghada Abdallah,

There are 2 components to your question. Let me tackle the easy part first. 

1. Evidence for efficacy for Hydroxychloroquin in ANA positive ITP: It was always known that almost 5% of SLE might start with isolated thrombocytopenia alone. Mechanisms of immune thrombocytopenia in SLE differs from those observed in primary ITP and is probably multifactorial, including antiplatelet glycoprotein antibodies such as in ITP but also immune complexes, antiphospholipid antibodies, autoantibodies to the c-MpL receptor and megakaryocytes.

Since Hydroxychloroquin works so well in treatment of multiple domains in SLE, it was but natural to study it in SLE associated throbocytopenia too where it was found useful. Next, about 20% of all ITP patients are ANA positive without meeting the criteria of SLE and this was the natural target to be studied for the effect of hydroxychloroquin. Interestingly, ANA positivity in ITP has been shown to a risk factor of chronic ITP and resistance to classical second-line treatment for ITP.

In the 2014 study by Khellaf et al, they looked at both SLE with thrombocytopenia and ANA positive ITP who had failed multiple drugs and tried hydroxychloroquin on them. As expected the SLE group indeed did very well with 83% response but even the other group showed a robust 50% response. Considering the excellent safety profile of hydroxychloroquin, these numbers are very encouraging. If these findings are replicated, hydroxychloroquin will very likely make its way into ITP treatment guidelines soon.

2. Why does it not work in ANA negative ITP? 

Where is the evidence that hydroxychlororquin "does not" act in ANA negative ITP as stated by you. Evidence is just emerging that it might be useful to some extent in the ANA positive variety. It requires another study to prove its inefficacy" in ANA negative ITP.

It was a natural step to use a time tested drug like hydroxychloroquin with proven efficacy in SLE to the subgroup of ANA positive ITP (who do not fulfil criteria for SLE). The next logical step seems to be to compare role of hydroxychloroquin in ANA positive Vs ANA negative ITP. I am not aware of any study that has specifically looked at this aspect. Maybe you can plan one such study.

If we are able to show in future that hydroxychloroquin "DOES NOT" act in ANA negative ITP, then we need new studies to study molecular mechanisms to understand the "why". 

hope this helps

hi, good morning, like gabriele casirati, the main concern looks the haemophagocitic syndrome, which not always presents with all the classical picture ( and evolves over time - fever is more common than splenomegaly), and either primary or secondary may be rather serious and rapidly evolving to a fatal condition - the hlh04 protocol is easily acessible on net and the sweden group has been very helpful, in clinical and lab advice - thr mail contacts are in the last pages of the protocol

Bon courage

How I treat hemophagocytic lymphohistiocytosis - Blood ...

Probably, you are aware of this review. It might help.

Thank you very much, Dr.Isho! 

These references are helpful!

Best regards,

Wisit

retinal involvement should prompt treatment with a. cyclosporine- works quickly but relapses more, b. TNF alpha inhibitors- but costly and c. interferon alfa - quick action and longer remission. i have assumed that it is resistant to azathioprine which acts after almost 3 months.

Hi. I agree with Raouf Hajji. 

There are several possible treatments listed, but none really effective. Even with the disease controlled, new calcinosis can appear. 

Some patiets respond to diltiazem or pamidronate, but If it causes symptoms you should consider surgery

You can read free this review from Mayo Clinic: 

Take a look at this article

Regulatory NK-Cell Functions in Inflammation and Autoimmunity

Anna Lünemann, Jan D Lünemann, and Christian Münz

Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zürich, Switzerland

Natural killer (NK) cells were viewed traditionally as cytotoxic effector cells whose rapid killing of infected and transformed cells without preactivation provides a first line of defense prior to the initiation of an adaptive immune response against infection and tumor development. However, it has become clear that NK cells interact with various components of the immune system, and therefore have the potential to function as regulatory cells. While NK cells can assist in dendritic cell (DC) maturation and T-cell polarization, increasing evidence indicates that NK cells can also prevent and limit adaptive (auto) immune responses via killing of autologous myeloid and lymphoid cells. Investigating immunoregulatory NK-cell functions might generate exciting insights into the reciprocal regulation between NK-cell–mediated innate immunity and adaptive immune responses, improve our capacity to monitor these cells as surrogate markers for disease activity and treatment responses in autoimmune diseases, and, perhaps, provide new prospects for NK cell-directed therapies.

© 2009 The Feinstein Institute for Medical Research, www.feinsteininstitute.org

Why not ? Autoantibodies are comonly an epiphenomenon not only in autoimmune diseases, but sometimes temporarily in imunopathological conditions as a sign of increased autoimmune activity of immune response, which could be physiological. 

systemic lupus erythematosus (SLE) with Antiphospholipid syndrome (APS) can show anticardiolipin antibody (aCL), lupus anticoagulant (LA) and anti-beta-2-glycoprotein 1 (B2GP1) antibodies. Other than these alomost 30 different sort of antibodies have seen (in differnt APS and or SLE patients) in SLE associated APS. I hope you can have more information from related articles.

Thank you. I also think that autoantibodies are the main goal for research in Kinsbourne cases. In my experience, symptoms improvement with immunoglobulins is remarkable

The critical issue is to identify potential etiologies. A careful screening for known immune-associated disorders(e.g., ANA, aDNA, ANCA), infection or granulomatous disorders is essential . In the region where I practice, neurosarcoidosis is on top of the list. Some infectious disorders may have tendency for affecting hypothalamic or pituitary structures particularly some fungal infections or bacteria associated with disorders such as Whipple's disease.

autoimmune tiroidities can be associated with hashimoto's enchepahlitis or SREAD ( Encefl, steroids responsive)  that can cause status epilepticus. Useful check  tyroid hormones and Antibody TPO and TBG, and try a course of steroids or Ig ev ( if steroids not allowed  for Diabete).

add phenitoine if VPA  doesn't work , or levetiracetam ev .

Is possibile to do do MRI to the patients? In SREAD could be normal or with stroke like lesions.

thats the point, they are seen in RA for the MOST part. However, we have seen quite a few patients with ccp antibodies consistent with RA (according to the ACR criteria) who developed another autoimmune disease (per classification) later. the interesting thing here is to 1. explain the underlying mechanisms of two autoimmune diseases in one patient 2. maybe further define the role of ccp ab (are they really specific for RA or specific for erosive arthritis?. This is in an interesting topic which in my view warrants more research in these "overlap" patients. 

thans to everybody for your effort and your answersm they have been very thoughprovoking and helpful! 

This is a good question not often enough asked, Zeeshan.

The first point is that lupus manifestations involve a wide range of effector mechanisms, each relating to a different type of autoantibody, of which there are often many in lupus. Anti-phospholipid syndrome is perhaps the easiest to understand. Antibodies to phospholipid disturb the coagulation cascade. Antibodies to cellular elements in blood are also probably important in aspects like thrombocytopenia, lymphopenia and neutropenia, although these may also arise from interactions with immune complexes.

Apart from these cases the focus is on immune complex-mediated disease. What is important to note here is that there are several quite different ways immune complexes can cause disease. In glomerulonephritis large complexes deposit in the basement membrane region of the glomerular filter. They probably deposit in vessel walls in many other tissues but the glomerulus being a specialised filter is likely to suffer most. It is highly likely that there is enough nuclear material being released into the circulation from mechanically damaged senescent white cells or from other sources to provide antigen. In normal people such complexes should be cleared by complement. Remember that within the circulation complement is anti-inflammatory - a clearance mechanism. It is only pro-inflammatory outside the circulation. Deposition of large complexes in lupus therefore probably has a lot to do with complement malfunction - which is very common in lupus. Not only are there complexes but they are not being cleared.

The second major role of immune complexes is in activating macrophages to produce cytokines in response to ligation of Fc receptor - perhaps mostly FcR3. This is likely to be the basis of arthritis and pericarditis. Exactly what the source of nuclear material would be is uncertain. However, note that years ago both rheumatoid and lupus were said to show 'fibrinoid necrosis'. The difference between the two diseases was that the 'fibrinoid' in RA was red (eosinophilic or proteinaceous) whereas the fibrinoid in lupus was blue-purple (haematoxyphilic or full of DNA). Free DNA is not unusual in sections of damaged tissue of all sorts. Most of it may get mopped up very quickly in the normal situation but I see no reason to think that there is not enough to form complexes if the antibodies are there. Remember that in normal people about 10gm of DNA is being chucked out during red and white cell turnover every day. Just lose a few micrograms and you can have complexes.

Then there are the antibodies to nuclear proteins. It is known that some of these can penetrate cells and many are associated with very characteristic signs of 'cell poisoning'. Cell penetration by autoantibodies has had too little attention although Alarcon Segovia showed clearly that it occurs many years ago and you can demonstrate it on living cells if you antibody treat them and then wash, permeabilise and stain with anti-Ig. Thus anti-topoisomerase in scleroderma is associated with progressive exhaustion of vascular cell replication and so to ischaemia. Anti-synthetase antibodies produce a syndrome that looks quite like ricin poisoning (myonecrosis and pulmonary oedema) which targets ribosomes. And so on.

Risk factor genes for lupus are well known. The complement genes are best understood with C1q deficiency most closely associated with lupus - and a more complex link with the other preMAC components, especially C4 alleles. The onset of autoantibody production in people without homozygous complement deficiencies is apparently stochastic, except in drug induced cases, but that would be consistent with a self generating feedback loop within B cell survival, as suggested in the paper with Cambridge and Abrahams on my RG page.

Just need to look at literature- you will find them

Well, you are asking very important, but very difficult question. it has been documented that blood vessels in chronic inflammatory tissues are somehow resembled to high endothelial cells (HEV) in lymph node where lymphocytes enter into lymph nodes. Blood vessels within inflamed synovial membrane would express adhesion molecule , similar to that expressed by HEV, thus, circulating lymphocytes bind to vessels of synovial membrane, then transmigrate into synovial tissues. Some of them might further migrated into tissues by cleaving ECM and finally reach to epithelium of synovial membrane, then leak to synovial fluid. It was shown that lymphocytes within inflamed synovial membrane express MMP, thus cleaving ECM and epithelium of synovial membrane. What you can do is to check the type of adhesion molecules and MMP expressed by normal synovial, inflamed synovial membranes, and/or lymphocytes isolated from inflamed synovial membrane.