Characterisation of B cell Subsets and Receptors in Chronic Fatigue Syndrome Patients

[A.B.]

Characterisation of B cell Subsets and Receptors in Chronic Fatigue Syndrome Patients

Limited immunological changes have been previously reported in B cell phenotype in Chronic Fatigue Syndrome (CFS) patients, so there is no clear established role of B cells in the pathophysiology of CFS patients. The aim of this study was to evaluate B cells subsets including naive, memory naive, memory switched, memory non-switched, double negative, transitional, plasmablasts, HLA-DR+, plasma and regulatory B cells (Breg) in CFS patients compared with non-fatigued controls. B cell activation markers (CD81, CD21) and surface receptors (CD79a/b, IgM, IgD, IgA, IgE) were also examined in CFS patients compared with non-fatigued controls. 46 CFS patients (age=50.00 ± 2.00 years) and 34 non-fatigued controls (age=49.00 ± 2.16 years) participated in the study. The percentage of BCR IgM+ B cells was significantly increased in the CFS group compared with non-fatigued controls(p=0.037). Similarly, there was a significant decrease in the CD1d+ B cells in the CFS group compared with non-fatigued controls (p=0.046). No additional differences in B cell phenotypes, activation markers and surface receptors were found in the CFS patients compared with the non-fatigued control group. The differences observed in the B cell phenotype of CFS patients compared with non-fatigued controls may explain some of the disturbances in the immune homeostasis, however whether this is causal or the consequence of immunological imbalances previously reported in CFS patients requires further investigation.

 

[A.B.]

The part that most readers will probably be interested in (possible link to autoimmunity or viral infection):

Our results indicate a significant increase in the percentage of BCR IgM + B cells (CD19 + CD79a + CD79b + IgM + ) in the CFS group and this may suggest that signaling through the surface IgM may be increased in the CFS patients. Membrane bound IgM is a necessary component of the BCR complex for mature B cell survival [22]. BCR IgM + has been shown to activate signaling pathways involving Btk, Syk, ERK1/2 and p38 phosphorylation. BCR IgM + also activates a negative feedback loop that controls the magnitude and extent of the phosphorylation of these signaling motifs thus fostering optimal B cell signaling [23]. Ligation of IgM has been shown to reduce terminal differentiation of B cells [24]. In the present study, although, the terminally differentiated B cells were lower in the CFS patients, they were not significantly different.

Interestingly, earlier studies have characterized CFS as an IgM + related immune disorder [25]. Another study has also confirmed significantly increased IgM mediated response to acetylcholine in CFS patients compared with controls, categorizing it as an autoimmune response that may be responsible for the dysregulation of certain cellular functions [25]. According to Guo et al. IgM enhances anti-Ig- initiated B cell activation and proliferation. Additionally, B cells are responsible for the increase in the production of IgM in response to infection. It is well known that IgM enhances complement activation and has a critical role in the defense of the host before adaptive immune response [26]. Further studies are required to evaluate B cell activation and function in a larger sample of CFS patients.

B cells are also responsible for presenting lipid antigen to CD1d- restricted invariant Natural Killer T (iNKT) cells in the healthy immune system. A previous study reported decreased CD1d expression on B cells in autoimmune diseases such as SLE leading to a reduction in the frequency of iNKT cells in this population. It has a role in maintaining tolerance in autoimmunity [27,28]. There was a significant decrease in the percentage of CD1d + B cells in the lymphocytes of CFS patients compared with Non-fatigued group. The decrease in the CD1d + B cells presented by the CFS group is suggestive of a possible dysfunction in the iNKT cell in this population. Additionally, CD1d + B cells may be induced to produced IL-10 and this has been shown to regulate Th2 immune responses [29,30]. CD1d is generally expressed on most subsets of B cells and a decrease in this marker may affect the regulatory effects of B cells during inflammatory reactions. CD1d is essential for antiviral immune responses and may be reduced on antigen presenting cells in the presence of pathogens such as viruses [31-35]. In CFS recurring viral infections have been suggested to occur and this may be related to a general decrease CD1d expression on immune cells.

 

[Bob]

@A.B. is this brand new, or have we seen it before? I don't remember it, but that doesn't mean anything.

 

[A.B.]

@A.B. is this brand new, or have we seen it before? I don't remember it, but that doesn't mean anything.

It was published on 26. January 2015. I searched for the title here in the forum and got no results. It was indexed by Google scholar 4 days ago.

 

[Bob]

It was published on 26. January 2015. I searched for the title here in the forum and got no results. It was indexed by Google scholar 4 days ago.

Thank you. Well spotted! I'm surprised we didn't spot it earlier, but I guess we've all been distracted!

 

[drob31]

Does this hint at a TH2 imbalance and also that CFS is an autoimmune condition (in some cases)?

 

[DanME]

Very interesting. Though the study was published one month ago, I haven't heard about it yet.

They found an increase in BCR IgM+ B Cells and a decrease in CD1d+ B Cells.

The sample size wasn't huge, but bigger than in other immune studies (46/34).

IgM is the earliest produced antibody in case of an infection or another antigen and regulates the complement system and IgG production by other B Cells. But what this means for us and CFS is beyond my understanding.

Is IgM regulation a known factor in other autoimmune diseases? Maybe @Jonathan Edwards knows more and is able to give us some insight.

 

[Ema]

On hyper IgM:

http://primaryimmune.org/about-prim...s/specific-disease-types/hyper-igm-syndromes/

It is associated with infections and autoimmunity.

 

[Jonathan Edwards]

Very interesting. Though the study was published one month ago, I haven't heard about it yet.

They found an increase in BCR IgM+ B Cells and a decrease in CD1d+ B Cells.

The sample size wasn't huge, but bigger than in other immune studies (46/34).

IgM is the earliest produced antibody in case of an infection or another antigen and regulates the complement system and IgG production by other B Cells. But what this means for us and CFS is beyond my understanding.

Is IgM regulation a known factor in other autoimmune diseases? Maybe @Jonathan Edwards knows more and is able to give us some insight.

Surface IgM positivity on B cells is just a sign that they are young. I don't think the findings tell us anything about IgM secretion (which is from plasma cells much later). To be honest nobody seems to find the same thing on B cells in ME. Everyone finds something here or there but nobody else does much so it is likely to be by chance, I think. Finding anything significant is going to need more subtle analysis. I cannot make much of the discussion I am afraid because we do not have evidence for any change in IgM secretion as far as I know - that would be measured by the IgM level, not by B cell maturation markers.

 

[DanME]

Surface IgM positivity on B cells is just a sign that they are young. I don't think the findings tell us anything about IgM secretion (which is from plasma cells much later). To be honest nobody seems to find the same thing on B cells in ME. Everyone finds something here or there but nobody else does much so it is likely to be by chance, I think. Finding anything significant is going to need more subtle analysis. I cannot make much of the discussion I am afraid because we do not have evidence for any change in IgM secretion as far as I know - that would be measured by the IgM level, not by B cell maturation markers.

Thank you very much! Always good to have an actual immunologist...

 

[Bob]

To be honest nobody seems to find the same thing on B cells in ME. Everyone finds something here or there but nobody else does much so it is likely to be by chance, I think. Finding anything significant is going to need more subtle analysis.

Perhaps it would be worth looking at <3 years and >3 years?

 

[Jonathan Edwards]

Perhaps it would be worth looking at <3 years and >3 years?

Some people already are!!

 

[greeneagledown]

@Jonathan Edwards -- Can you comment at all on how this work compare to the work Dr. Jo Cambridge is doing right now and how these results compare to Dr. Cambridge's preliminary findings? Is she doing a completely different type of B-cell analysis? (Totally understand if you can't comment since Dr. Cambridge hasn't published any results yet.)

 

[Jonathan Edwards]

The initial set of studies Dr Cambridge did tried to confirm differences in B cell populations in ME found by Dr Bansal. However, taking ME is a whole no significant differences have showed up. As I said, a variety of groups have looked at B cells in ME as a whole and have come up with possible differences as in this Australian paper but there does not seem to be any consistency. Dr Fluge and Dr Mella of course looked at this and found no differences. Dr Cambridge is now involved in more detailed subset studies and I am not in a position to say anything about those as results are still coming in.

 

[WillowJ]

Authors are Ramos S, Brenu E, Nuyen T, Ng J, Staines D and Marshall-Gradisnik S
(That's how I often search for old threads, either because I recall the author or because the title keywords yield too many results)

 

[Snow Leopard]

The initial set of studies Dr Cambridge did tried to confirm differences in B cell populations in ME found by Dr Bansal. However, taking ME is a whole no significant differences have showed up. As I said, a variety of groups have looked at B cells in ME as a whole and have come up with possible differences as in this Australian paper but there does not seem to be any consistency. Dr Fluge and Dr Mella of course looked at this and found no differences. Dr Cambridge is now involved in more detailed subset studies and I am not in a position to say anything about those as results are still coming in.

Previously you also mentioned that autoreactive b-cells don't necessarily have a different phenotype, other than having an autoreactive BCR.

I was wondering what kind of (important/replicated) B-cell phenotype differences have been observed in autoimmune diseases that you know of?

When you mention subtle analysis is needed, what do you mean (and I am not asking about specific details about ongoing research)?

 

[Jonathan Edwards]

Previously you also mentioned that autoreactive b-cells don't necessarily have a different phenotype, other than having an autoreactive BCR.

I was wondering what kind of (important/replicated) B-cell phenotype differences have been observed in autoimmune diseases that you know of?

When you mention subtle analysis is needed, what do you mean (and I am not asking about specific details about ongoing research)?

We don't really expect autoimmune B cells to have a different phenotype in terms of the sorts of markers used in cell sorting of circulating cells. These are not subset markers in the sense that CD4 and CD8 are subset markers for T cells. The markers for B cells just tell us how mature they are (with a few exceptions) and to do anything interesting a B cell has to go through all maturation stages to the plasma cell stage. Class switched cells committed to IgA or IgG subclasses are differentiated in a specific way but people do not tend to look at these in blood.

The number of cells at different stages of differentiation in the blood is unlikely to tell us anything very direct about disease but in conditions like RA and lupus there seem to be shifts in the proportions of cells at different stages of maturation. We do not really know what that means.

What may be more interesting is that in autoimmune disease class switching and usage of heavy chain variable region genes (Vh) can be skewed. In lupus cells using the Vh4-34 gene turn up in lymph nodes in places where they normally do not, for instance. When rheumatoid patients make rheumatoid factors they tend to use different Vh genes to do so from normal people making rheumatoid factors. These are the sorts of fine detail that might give clues when standard cell sorting may show nothing much. One can also measure free light chain production, which is probably a sign of B cells in overdrive.