Hi Antonio,

looking at your topics (antiphospholip syndrome, SLE,...) one possibility is that those antibodies are directed to T-cell-independent (TI) antigens and that is what you are detecting in some patients. Some of those TI antigens acts as mitogens and you get policlonal B-cell proliferation with no isotype switching; others such as polysaccharides have repeating antigenic epitopes that induce BCR crosslinking and activation but no class switching.

Hope this helps.

Hi Antonio

From what I remember IgM antibodies are common in autoimmune disorders because they are not AS dependent on T cell help in production. Autoimmune disease results from dysregulation of the immune response to allow a response to self tissue. And T cell development in the Thymus theoretically eliminates self reactive clones. So without extensive T cell interaction the switching does not occur?

Looking forward to seeing responses from others on this.

Ray

Usually IgM is continuesly produced in autoimmune disease such as RA , but does not mean that IgG is not detected,

A very good question Antonio and one that has fascinated myself and Dr Jo Cambridge at UCL for some years now. It seems to mean that an autoimmune reaction is not just a reaction to the wrong antigen, it is a dysregulated reaction - perhaps you would agree. The response pattern must be following rules driven by signals not working the normal way. The idea that we put up in a review article in Immunology in 1999 with Vicky Abrahams was that the abnormal signals are in fact the autoantibodies themselves. Thus, autoantibodies to immune signalling molecules, which are common in autoimmune disease may generate abnormal signals by subverting the signalling function of the antigen. Examples of immune signalling antigens are IgG (in rheumatoid), C1q (in lupus), DNA (in lupus - linked to TLR), AChR (in myasthenia, AChr on myoid cells mediate changes in thymic environment), TRIM21 (in Sjogren's, TRIM21 seems to be a sort of intracellular C1q that confers a danger signal to antigens). Stick an antibody on any of these and you get something that might do very strange things.

I guess that one of the reasons for persistent IgM production might simply be the impossibility of clearing many self antigens - it is a sign of ongoing functional antigen excess in certain compartments. But it looks more complicated than that. Something we have been interested in is the usage of the Vh gene marked by the '9G4 idiotype'. Cells destined to make antibodies with 9G4 seem to have different rules for class switching and the crop up a lot in autoimmunity but produce very little Ig in the normal way.

There must be a precise and interesting answer to this question but so far we just seem to have some clues!

Continued IgM, likely due to epitope spreading. So new antibodies made to different epitopes of same antigen or new antigens released during autoimmune damage.

As a patient with SLE (and Hughes, the antiphospholipid antibody Syndrome), I am also very interested in this topic.

I was under an excellent team at St Thomas' Hospital Lupus Unit when they decided to perform the immunoglobulin test as a result of high levels of inflammatory markers (ESR). Unfortunately, this first test seemed to indicate possible multiple myeloma, and a concerned consultant telephoned me to see a haemotologist. However subsequent tests, elsewhere, showed the levels were not this high!

I was sent to a haematologist who confirmed that this was associated with SLE.

In pure layman's terms, I have "normal" ie within the range: IgA levels: high IgM levels; and low IgG. I have met other lupus patients who also similarly report these findings.

Understanding what is happening in my body is important to me. Unfortunately, my understanding of bio-chemistry is very basic, so I appreciate everyone's input here and to thank all of you who are engaged in this area of research.

speaking as non-physician immunologist- your pts have an absence of strong T-dependant antigenic stimuli, Why? is only speculation. T cells are not being activated to drive isotype switching and affinity maturation of the IgG B cell clones in the germinal centres. is there any sign your pts have defect in their gerninal centres? Persistent IgM is from long-lived u chain producing plasma cells likely due to an expansion of the B cell clones of natural IgM autoAbs. it's logical to speculate that you have a subset of pts with defect in Transcription factor for switching. On the other hand your pts are in an "autoimmune dilemma". Inhibitory T cell commands are instructing IR genes not to class switch because of danger for more destructive IgG. i.e. high affinity IgG autoAbs are usually more pathogenic but persistent high levels of circulating IgM of lupus or APS pts, can accumulate immune complexes that block kidneys and fine vascular tissues - more than just a nuisance but real troublesome.

Most of the interactions between B and T cells in autoimmune prone individuals can be low affinity interactions but due to the lower activation threshold of autoimmune B cells they could lead to B-cell activation. Activated B cells (plasmablasts) can also be IgM high and secrete copious amounts of IgM. So constant stimulation by self antigens can induce chronic B cell stimulation. Additionally, any T independent antigens can enhance the IgM specific responses (Bacterial infections).

Interestingly, IgM+ plasma cells in bone marrow can also be the source of consistent

circulating IgM. All these factors may result in high IgM levels in autoimmune prone individuals.

In autoimmune conditions, the causative 'autoantigens' are largely unknown. B cells may be chronically activated to produce IgM without having to switch isotypes that requires additional elements such as T cell help. My view is that the B cells, regardless of whether they are dependent or independent of T helper cells, are epigenetically altered in autoimmune prone individuals. Comparison of the epigenomes of B cells from normal and autoimmune individuals may shed light on this issue.

Hello, Antonio,

IgM autoantibodies against self antigens consitute a major subset of naturally occuring autoantibodies present even in normal healthy individuals without any

evidence of autoimmunity. These natural autoantibodies have important house keeping functions, this is specially true of natural occuring IgM autoantibodies recognizing oxidization specific epitopes. It has been conclusively shown earlier that these IgM autoantibodies in fact prevent autoimmunity. e.g IgM anti oxidized LDL protects where as IgG anti oxidized LDL promotes atherosclerosis. Similarly IgM anti ds DNA protects and IgG anti ds DNA promotes the development of nephritis in Lupus. The pathogeneic antibody are almost always class-switched IgG antibodies which are high-affinity being derived from B cells which have undergone affininty maturation due to somatic hypermutation and are usually present in high titres. I hope that answers your query partly

Just another commuen, maybe not addressing directly th eissue. My fellow fisicians here have reported me that sometimes patients with chronic bacterials infections remain IgM positive for years, before switching to IgG. Thus, since IgM are frequently cross-reactive, the possibility should be admitted that we're seeing the immune response to an unknown non-self antigen that cross-reacts with a known self-antigen. As said by other, usually self-specific IgM are not deemed pathogenic, and often disappear without giving rise to a disease.

I agree with Randall. Another point may be that the IgM memory persists longer than IgG1 memory. In combination with long-lasting nature of IgM responses and epitope spreading IgM responses are persistent findings in Autoimmune disorders.

We observe IgM autoantibodies in various autoimmune diseases during different events/courses (exacerbation vs. remission) of the disease in an antigen dependent manner. As the nature is chronic or acute-on-chronic, we see the fluctuations of IgM autoantibodies during the course. It mainly depends on multiple immune factors, B cell signaling when they see the antigen via BCR and T cell effectors, either by cognate interaction or by cytokine (IL-4, IL-10, IL-2, IL-15) production. Interestingly, pathogenic autoantibody can mimic infectious agents and cause apoptosis. More you see them in immune compartment, you would likely to see more of IgM responses as well as epitope (s) spreading. Thus it becomes unpredictable to judge when the right T cell will take over IgG responses via germinal maturation. Long-lived plasma cells will certainly generate IgG, however, their strength depends on ultimate fate decision of B cell regulatory mechanisms.

Persistent IgM autoantibody mainly belongs to the natural repertoire and is based on germ-line genes. Such autoantibodies are characterized by polyreactivity which is easily picked up by immunoassays. In only few cases, patient samples are available before the onset of clinical symptoms to prove this phenomenon. In general, clinicians are not aware of this fact.

Thank you all for your comments. Our motivation for the question: we checked blood samples of leprosy patients from Amazonia for anticardiolipin and anti-b2 auto-antibodies and we found that these autoantibodies are more frequent in these patients than the controls. Moreover, these autoantibodies are found more frequently than other auto-antibodies and tend to persist even after the end of treatment, sometimes years after. At the last case, no evidence of infection was observed and the auto-antibodies are mainly IgM. The role of these antibodies in leprosy immunopathology is not understood but they appear in patients with severe forms and clinical complications. Thus, the tissue damage driven by the antibodies is a plausible hypotheses in this case. Although polyreactivity is possible for IgM, we couldn't find no other auto-antibodies. I believe that some of your comments are important such tissue damage by the pathogen and epitope spread, T-independent antigens and etc. In my opinion, CD8+ cells starts the self antigen exposure by inducing apoptosis of host infect cells by intracellular pathogens - this is the moment for autoimmunity reactivity in prone individuals. The persistence of anticardiolipin and anti-b2 auto-antibodies is probably an established autoimmune phenomena after intracellular bacterial infection. However, the persistent IgM antibodies, as you can see by all comments, remains to be clarified.

Two types of antibodies i.e. IgG and IgM are involved in the cell mediated immunity, allergy or hypersensitivity against any foreign particle or cells due to mutation behave like autoantigens. Getting IgM more than IgG or persistant getting of IgM might be due to the types antigens/epitopes against which B-cells are getting activated to synthesize Ig are of embryonic or nascent type that might have originated due to microbial infections or some other means. Experimental proof must required to support this hypothesis but the way B-cells mature support this assumption.

Dr Boechat raised an interesting topic indeed with regard to the detection of antiphospholipid antibodies (aPLAb). I presume you detected these aPLAb by ELISA. In my experience, ELISAs have difficulties with unspecific interactions in particular for IgM due to the hydrophobicity of phospholipids such as cardiolipin. We have developed a new technique overcoming these shortcomings by employing a different solid phase. Please let me know whether you are interested in evaluating this new method with your samples.

Are these Mycoplasma pneumoniae specific IgM and IgG antibodies?  Mycoplasma coinfections have been commonly associated with autoimmune disease and cancer progressions.  They are immunomodulating, difficult to culture, and can often be persistent.

Yes, you would be able to see such anticardiolipin and anti-b2 auto-antibodies possibly due to infections. I have detected them in normal individuals including children (20-30%). IgM isotope is common and has been considered to be "Natural antibodies" that may help protect us from recent infections. Some of them may be neutralizing and can activate complement components for phagocytosis. If we know the behavior of neutrophils and subsequent activation of macrophages and/or dendritic cells after infection, we could have understood the mechanisms as well as their functions in vivo. The selection of B cell repertoire as well as affinity maturation in the spleen may help to understand their precise role in humans.

IgM autoantibodies are a part of the repertoire of natural autoantibodies which play a critical role in immune regulation and homeostasis. IgM autoantibodies have an affinity for binding dead, dying and apoptotic self cells. They can also recruit component components such MBL and C1q. They thus serve the important function of clearance of dead and apoptotic self cells which may harbour potentially autoreactive self antigens. IgM autoantibodies have been found in patients in autoimmune who have low disease activity and they have been shown to protect patients of autoimmune disease from severe disease or organ damage. Is your patient cohort one which is comprised or selected for low disease activity and not particularly severe disease? IgM autoantibodies are found in both healthy and patients with autoimmune diseases. These autoantibodies are of low affinity, present in low titres and may persist in patients with autoimmune disease while the high affinity class switched pathogenic IgG antibodies decline with treatment or remission. I am not sure whether these autoantibodies increase in patients with autoimmune disease as a compensatory mechanism.

Based on my experience with polyreactive natural autoantibodies and autoantibodies found in patients with autoimmune diseases, this phenomenon might be due to the high sensitivity of immunoassays employed for IgM autoantibody detection. I think that the persistent IgM existed even before the onset of the particular autoimmune disease. This, however, is hard to proof in practice. In summary, these IgM autoantibodies may even not be involved in the pathogenesis of the existing autoimmune disease.  

I have been providing serum  panels derived from patients with systemic autoimmune diseases, including APS, Sjorgens Disease and SLE. Interestingly,  IgM interference testing is required by  manufacturers of  industrial analyzers for acute viral IgM  and the regulatory agencies  that oversee IgM TORCH diagnostics emphasize the  importance of using serum from autoimmune patients for  submission of the data in compliance dossiers.  It is a pity this data is not prospective and not easily accessible.  I agree with Dirk that persistent IgM of some patients may have  existed  prior to  the onset of autoimmunity.   As indicated by previous  comments, it  remains to be proven if the NATURAL IgM autoantibodies, products of   un-switched  B cell clones and   long lived plasma cells,  are initiated  by  cross-reactive  IgM immune responses to acute bacterial, protozoan or  viral infections encountered earlier in life and then amplified  by  ensuing autoimmunity.

Dear Dirk and Simon, I'm agreeing with you about the persistence of IgM antibodies. Actually, It appears that is T-independent response or sensitivity to IgM detection. We  just finish the analysis and we are seeing that there is no statistical relation with tissue-damage, but we found that the positivity of IgM antibodies against cardiolipin is associated with M. leprae load in clinical followup tests, suggesting that they persists sometimes stimulating T-independet response as Simon describes. Unfortunately, as my collegue Dr. Sandra Euzébio told me, there are no enough samples for further analysis. However, answering Dr. Dirk, I will check this and give you a feedback. Thank you for your support and discussion.