Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS, 2020, Lipkin et al

Specifically, what types of kinase inhibitors do you think might benefit ME/CFS patients (to interrupt signaling)?

 

They don´t seem to have in mind the following findings on Protein kinase RNA-activated (PKR), at least these findings are not listed in their literatur:

Unravelling intracellular immune dysfunction in [CFS]: Interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance
Meeus et al 2008

Confirmed by Sweetman et al 2018 [38]. which is referred to here:

Current Research Provides Insight into the Biological Basis and Diagnostic Potential for [ME/CFS]
Sweetman et al 2019

page 6

Maybe there has an imbalance arisen from to less b cells during infection?? (if I am allowed to speculate)

1. https://www.uniprot.org/uniprot/P19525

1.a Activity Regulation [my paragraphs and bold]

5 publications​

1.b Function [my paragraphs]

24 publications​

(I underlined cytoskeleton because Lipkin et al mentioned actin. NLRP3 might be interesting in a whole context, though difficult to judge at, of course.)

2. a) Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2
N Schrantz et al 1999 May;6(5):445-53. doi: 10.1038/sj.cdd.4400508. https://www.nature.com/articles/4400508

abstract, my pragraphs

The following finding involves dopamine, which Lipkin et al, somehow, do refer to, too (page 2). (->?)

2. b) Manganese-Induced Toxicity in Normal and Human B Lymphocyte Cell Lines Containing a Homozygous Mutation in Parkin
Jerome A. Roth et al 2012, doi: 10.1016/j.tiv.2012.07.005 PMID: 22841634

 

One thing @Jonathan Edwards has been highlighting is that rituximab does not kill all (antibody producing) B-cells i.e. it does not kill long lived (antibody producing) B-cells.

Another thing that Jonathan has highlighted is that symptoms similar to ME would be produced if B-cells, responsible for command & control, were dysfunctional; however, that supposes that this type of (command & control) B-cells exist.

 

I have to be honest, the technicality of this paper is way beyond me, but i have a few questions:
1) does their work warrant further study in this specific topic, what would it be and where would that lead?
2) if the clonal expansion leads to suggestion of autoimmunity, would this be grounds to target it via biologic drugs other that Rituximab, or is it still too early?

 

Does this study tie in with the one by fane mensah
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02421/full

 

I don't think I said that! I have no idea what a command and control B cell would mean.

 

Oops apologies you referred to deranged T-cell rather than B-cells - https://www.s4me.info/threads/me-cf...maintains-status-quo.12949/page-2#post-228586

Thank you very much for the posts - even if I misunderstand them.

 

Answers to questions.

1. Can you please explain the biological significance of the quadratic transformation of the data?

The quadratic transformation of data allows us to understand and interpret the connections between protein analytes and ME/CFS, since these connections are not linear. The data suggest that both high and low levels of a certain protein are associated with an increased risk of ME/CFS in our sample. This is what we call a U shaped association. On the one hand, the people withME/CFS in our sample have higher levels of IGHV3-23 than controls, and on the other hand, subjects with ME/CFS in our sample have low levels of IGHV3-23. However, very few subjects with ME/CFS in our sample had very low levels of IGHV3-23, so we want to be cautious about drawing conclusions.There may be a biological reason for this U-shaped connection, which we don’t yet understand, but may be worth pursuing. Overall, these results suggest that there is a potential role for IGHV3-23, and more work should examine it.

1. To demonstrate B cell clonal expansion, do you need to sequence the antigen binding section of the antibody (CDR or complementarity determining region)?

Yes, in order to demonstrate B cell clonal expansion, we would need to sequence the variable regions of B lymphocytes using one or more techniques, such as next generation sequencing or single cell B-cell receptor sequencing (sc-BCRseq).

3) "We speculate that, at least in a subset of ME/CFS subjects, an increased level of IGHV3- 23 may be due to antigen driven clonal expansion, and that these patients might benefit from identification of the antigen driving B-cell receptor signaling or kinase inhibitors that interrupt signaling." Specifically, what types of kinase inhibitors do you think might benefit ME/CFS patients (to interrupt signaling)?

B-cell malagnancies have been shown to be sensitive to kinase inhibitors that disrupt BCR signaling. The use of the kinase inhibitor Ibrutinb has had promising results in early trials among patients suffering from marginal zone lymphoma and chronic lymphocytic leukemia. If, indeed, a subset of people with ME/CFS suffered from a similar B cell dysfunction, targeting BCR signaling could have apositive potential. However, our results are preliminary,and further work will need to be done in different and larger samples before therapies can be considered.

 

LL37 is the same as CAMP which was up in this Lipkin study. Someone suggested to me that it could be worth exploring in ME/CFS.

It has been tested here: Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial - PubMed (nih.gov)

 

Thanks for asking these questions, very useful.

During the Massachusetts ME/CFS conference Lipkin said their findings were confirmed by a Japanese group. I assume he was referring to this paper by Sato et al. Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Sato et al | Science for ME (s4me.info)

The Japanese group found higher levels of IGHV3-30 using next -generation sequencing, especially in those with an infectious onset. They also report that "B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset".

 

In one of the recent NIH ME/CFS CRC update webinars Ian Lipkin gave a general update for their NIH ME/CFS center and in the Q&A at 27-28mins he described in mid-1990's finding high antibody levels to a wide range of "things" in a swedish cohort while working on a project to look for Borna virus.

https://www.youtube.com/watch?v=Y71Y91Gy0xQ

Here is the video transcript:
"My first engagement in this field was in the mid-1990s when we were asked to look at whether or not a virus called borna might be implicated and in those days we went back we used pcr we used uh antibody tests and we found no evidence for borna virus infection but i was impressed at that point as were my colleagues by the observation that people with mecfs in the swedish cohort had very high levels of antibodies to a wide range of things some of them that you don't even encounter in nature so at the tail end of our paper we said we find no evidence that this particular virus is important in mecfs but we do find evidence of abnormalities in the immune system suggesting that this is a biologically based disorder"

I think this is the 1999 Lipkin CFS paper regarding the work he mentioned in his talk.
Paper : Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome
https://www.jneurovirol.com/pdf/5(5)/495-499.pdf

I thought this text in the discussion section of the 1999 paper key:
"Although serum immunoreactivity to BDV proteins observed in Swedish CFS patients by ELISA may reflect infection with related microbial agents that induce cross-reactivity with conformational determinants on BDV proteins (Kliche et al, 1996) and b-galactosidase, the serologic findings are also con-sistent with nonspecific polyclonal B-cell activa-tion."

 

Worth exploring as in trying to lower the levels?