Wednesday, 24 January 2018

The interpretation of results can depend on the way you look at things.

Look at this picture. What do you see?
Do you see an old woment (you see a nose) or a young women (you see a jaw)?

Now Look at this. What do you see?
Don't know what this is?.
An educational comment for pwMS and researchers
It is interleukin 10.

It maybe doesn't mean much to you, but it may help you understand papers a bit better and questions whether you should accept dogma without thought.

Say this to a T cell immunologist and they see an immunoregulatory cytokine.

"Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatorycytokine"

In humans, IL-10 is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type 2 T helper cells (TH2), mast cells, CD4+CD25+Foxp3+ regulatory T cells, and in a certain subset of activated T cells and B cells

IL-10 is a cytokine with multiple, pleiotropic, effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages.

Now show this to a B cell immunologist and they see something different 

IL-10 is a cytokine that enhances B cell survival, proliferation, and antibody production and could be produced to help make antibody producing cells

How about Interleukin 4.

T cell immunologist says "IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell IL-12."

or a  B cell immunologist says "IL-4 stimulates activated B-cell proliferation, and the differentiation of B cells into plasma cells. It is a key regulator in humoral  immunity. IL-4 induces B-cell class switching and up-regulates MHC class II production to potentially act as an antigen presenting cell.

How about interleukin 6?
It is viewed as being pro-inflammatory?, 
However, It can be anti-Inflammatory but it can also supports the growth of B cells .

So lets looks in MS and see what has been have found

Guerrier T, Labalette M, Launay D, Lee-Chang C, Outteryck O, Lefèvre G, Vermersch P, Dubucquoi S, Zéphir H.Proinflammatory B-cell profile in the early phases of MS predicts an active disease. Neurol Neuroimmunol Neuroinflamm. 2017; 5(2):e431. 

OBJECTIVE:To assess whether any alteration of B-cell subset distribution and/or the cytokine production capacities of B cells could be associated with any stage of MS and could be predictive of MS evolution.
METHODS:We prospectively enrolled radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), naive patients with relapsing remitting MS (RRMS) of any disease modifying drug, and healthy controls (HCs). Peripheral blood B-cell subset distributions and the interleukin (IL)-6/IL-10-producing B-cell ratio were assessed by flow cytometry to evaluate their proinflammatory and anti-inflammatory functional properties.
RESULTS:Twelve RIS, 46 CIS, 31 RRMS patients, and 36 HCs were enrolled. We observed that a high IL-6/IL-10-producing B-cell ratio in patients with RIS/CIS was associated with the evolution of the disease in the short term (6 months). This imbalance in cytokine production was mainly explained by an alteration of the production of IL-10 by B cells, especially for the transitional B-cell subset. In addition, a significant increase in IgD-/CD27- memory B cells was detected in patients with CIS and RRMS compared with Hs (p = 0.01). Apart from this increase in exhausted B cells, no other variation in B-cell subsets was observed.
CONCLUSIONS:The association between a high IL-6(pro-inflammatory)/IL-10(anti-inflammatory) -producing B-cell ratio and the evolution of patients with RIS/CIS suggest a skew of B cells toward pro-inflammatory properties that might be implicated in the early phases of MS disease.

So as you can see the B cell production of IL-6 is viewed as pro-inflammatory and IL-10 is antiinflammatory, but are these simply B cell producing agents? 

I don't have the answer which is which, but use this to illustrate that many things you get told you may have different explanations



    have you seen this?

    1. No I havent but it was published a long time ago

      •14-3-3 adaptor proteins facilitate axon growth
      •Stabilization of 14-3-3 complexes with Fusicoccin-A stimulates axon regeneration
      •Fusicoccin-A targets a complex between 14-3-3 and the stress response regulator GCN1
      •GCN1 acts as an intrinsic brake on neurite outgrowth

      Damaged central nervous system (CNS) neurons have a poor ability to spontaneously regenerate, causing persistent functional deficits after injury. Therapies that stimulate axon growth are needed to repair CNS damage. 14-3-3 adaptors are hub proteins that are attractive targets to manipulate cell signaling. We identify a positive role for 14-3-3s in axon growth and uncover a developmental regulation of the phosphorylation and function of 14-3-3s. We show that fusicoccin-A (FC-A), a small-molecule stabilizer of 14-3-3 protein-protein interactions, stimulates axon growth in vitro and regeneration in vivo. We show that FC-A stabilizes a complex between 14-3-3 and the stress response regulator GCN1, inducing GCN1 turnover and neurite outgrowth. These findings show that 14-3-3 adaptor protein complexes are druggable targets and identify a new class of small molecules that may be further optimized for the repair of CNS damage.

      Interesting but I'' let it advance abit before I comment...

    2. Thanks MD, saw it on MS news today and thought it looked interesting. Guy who made the discovery was only a young PhD student too

  2. Honestly, this blog has become so dry and directionless since last year. What does the blog stand for anymore? It used to be much better.

    Reinvention is great, but this new approach isn't connecting with me.

    1. So what would you suggest we do?

      Go back to the two or more posts a day?
      Maybe get profG posting more often as he has been on a blog holiday:-)?

      Stop posting on science and interpretation of science

      Give up on the B cell story?

      Maybe start posting about how great T cell immunotherapy is

      However, how many times do he have to post about falls, etc.

    2. And yet traffic increases month by month. Go figure ;-)

    3. Re: "And yet traffic increases month by month. Go figure ;-)"

      They're called bots, MD2. Fewer daily posts, more bot activity.

    4. MD1, and all concerned, keep writing posts like this. I continue to get a much better understanding of this disease because of it. Love your work!

  3. Interleukin 6 (IL-6)

    Is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine (cytokines produced and released by muscle cells ). In humans, it is encoded by the IL6 gene.[5]

    L-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells

    L-6 is also considered a myokine, a cytokine produced from muscle, which is elevated in response to muscle contraction.[11] It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery.[12]

    IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage.[15] However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric "nondamaging" muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.[16]

    Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NFκB signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the Ca2+/NFAT and glycogen/p38 MAPK pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally independent of a preceding TNF-response or NFκB activation, and is anti-inflammatory.[17]


    1. Thanks.....the readers now get all of wiki on IL-6 :-)

      Anti-IL6 has become an approved treatment will it be used off-label?
      In my youth I did some staining with anti IL-6 and it was amazing how it picked up gliotic astrocytes. Would it inhibit their function?

  4. It seems that vigourous exercise is anti-inflamatory and neuroprotector in pwms

    High intensity interval exercise decreases IL-8 and enhances
    the immunomodulatory cytokine interleukin-10 in lean
    and overweight–obese individuals

    Aerobic exercise increases hippocampal volume
    and improves memory in multiple sclerosis:
    Preliminary findings

    Aerobic exercise resulted in a 16.5% increase
    in hippocampal volume (baseline = 5958 mm3,
    follow-up = 6942 mm3), a 55.9% increase in
    verbal memory (CVLT Total Learning baseline
    = 31, follow-up = 48; CVLT Long Delay
    Free Recall baseline = 7, follow-up = 11),
    and 51.3% increase in nonverbal memory
    (BVMT Total Learning baseline = 18, followup
    = 23; BVMT Delayed Recall baseline = 4,
    follow-up = 7).

    Good for the heart good for the brain......:)



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