B Cells and Lactate Slow Down the Immune Response

Sodium lactate
A simple injection of sodium lactate can influence inflammasome activation.
This week on TIBDI: IL-35-secreting B cells inhibit immune responses; lactate interferes with inflammasome activation; and mucus and microbiota link nature and nurture.

New Inhibitory B Cells

B cells, known more for their antibody producing potential, also have a regulatory function when they secrete the anti-inflammatory cytokine interleukin (IL)-10. In a recent publication of Nature, Ping Shen and Toralf Roch of the German Rheumatology Research Center (DRFZ) in Germany discovered that IL-35-secreting B cells also play a similar role. They found that triggering co-stimulatory receptors on B cells induced IL-35 production and that IL-35-deficient B cells both hindered the recovery from a model of autoimmune disease (multiple sclerosis) and increased the immune response to an intestinal pathogen (Salmonella). Given the widespread influence of IL-35 producing B cells during infection and inflammatory disease, it will be interesting to see if they also are important for inflammatory bowel disease (IBD).

Lactate Slows Down Inflammasomes

Previous literature has indicated that the NLRP3 inflammasome is associated with Crohn’s disease (CD), and may be needed to induce protective immune responses against invading bacteria. Inflammasomes in macrophages are activated, in part, by danger signals. While danger signals mainly induce pro-inflammatory cytokine production, they also stimulate metabolic pathways, and one product that is produced is lactate. According to results produced by Rafaz Hoque of Yale University, lactate can function as a negative regulator of inflammasome activation. The team at Yale found that stimulation of the lactate receptor GPR81 could modify Toll-like receptor 4 signaling and lower subsequent NLRP3 activation. In vivo, lactate was effective at reducing acute organ injury in models with potent inflammasome activation, such as hepatitis and pancreatitis. This could mean that lactate modulates NLRP3 responses in Crohn’s disease as well.

Nature, Nurture and Mucus Production

Intestinal mucus has the important function of preventing bacterial contact with the epithelial surface. In fact, TMF-/- mice lacking a specific Golgi-associated protein (TMF/ARA160), which produce thick mucus, are generally protected from experimental colitis. However, Shai Bel of the Bar Ilan University in Israel has found that the protection is not derived from mucus alone. The intestinal microbiota are also important. The team found that the microbiota of TMF-/- mice is different from that of wild-types, and has larger populations of bacteria from the Firmicutes phylum. Even more importantly, transfer of these populations to normal mice, by co-housing, also transferred the colitis protection. This underscores the potential role of microbiota manipulation in lowering IBD susceptibility despite genetic predisposition.

Q: What’s your opinion about microbiota manipulation for IBD prevention? Feel free to contribute your thoughts here or on the LinkedIn discussion group.

References

4 thoughts on “B Cells and Lactate Slow Down the Immune Response

  1. I have found manipulation of the Gut microbiota to be an effective treatment option for Crohn’s disease. (treated member of immediate family).
    This is my humble understanding and opinion, I am open to correction.
    The Human body is colonized by microbes soon after Birth. Some studies even suggest the presence of beneficial bugs in breast milk for delivery of these bugs to the newborn infant.
    The Human body decides which microbes make a home on and in the body by producing antimicrobial molecules called DEFENSINS. These are secreted by immune system cells called T-Reg calls. (REGULATORY T- CELLS).
    This process is determined by surface molecules present on white blood cells, called The Major histocompatibility complex, also called HLA or Human Leukocyte antigen.
    T-Reg cells are produced from Naive T-cells by cell differentiation via the DNA.
    This process is controlled by environmental factors, among which BUTYRIC ACID , a short chain fatty acid has a role. The process is called Epigenetic switching.
    Butyric acid is a by-product of the Fermentation of indigestible polysaccharides (FOS, INULIN, and RESISTANT STARCH) in the COLON by SOME species of BACTERIA. Eg: CLOSTRIDIUM BUTYRICUM
    Thus, BUTYRIC ACID, produced by SOME bacteria results in the formation of T-Reg Cells in the body. These cells secrete DEFENSINS which ERADICATE undesirable BACTERIA to keep a BALANCE between the DESIRABLE and UNDESIRABLE Bacteria.
    A lack of DEFENSIN production by the body due to a smaller population of T-Reg cells (may be Genetic pre-disposition) will cause DYSBIOSIS—INFECTION by undesirable BACTERIA.
    These BACTERIA may cause disease by producing proteins /enzymes that mimic human proteins. The Human body will produce ANTIBODIES in response to the BACTERIAL proteins or Enzymes that may translocate into the bloodstream (via a LEAKY GUT ?) and these ANTIBODIES may then react with the “similar looking” HUMAN PROTEIN resulting in (AUTOIMMUNE REACTION) INFLAMMATION———-Disease and IBD
    A lack of DESIRABLE BACTERIA such as the CLOSTRIDIA which produce BUTYRIC ACID may lead to a smaller population of T-Reg cells being converted from naive T-cells and as a result a shortage of DEFENSIN molecules————-INFECTION by undesirable BACTERIA.
    A lack of DIETARY FOOD or SUBSTRATE in the form of INDIGESTIBLE fibres for fermentation by the desirable bacteria in the Colon will mean a SHORTAGE of BUTYRIC ACID and other short chain fatty acids , the EPIGENETIC SWITCH for conversion of naive T-cells to T-Reg cells which secrete the DEFENSINS which keep the UNDESIRABLE Bacterial population in check to maintain the COMPOSITION of the MICROFLORA. This SHORTAGE of BUTYRIC ACID will lead to DYSBIOSIS and infection.
    For treatment purposes I have simplified my thinking about Crohn’s Disease and Ulcerative Colitis.
    I believe IBD is caused by an imbalance (or Dysbiosis) in the composition of the Intestinal microflora due to a genetic inability of the patient to produce antimicrobial peptides (Defensins) which would normally eradicate undesirable, potentially pathogenic microbes. This results in a Chronic infection and inflammatory response.
    This idea simplifies treatment.
    1. Treat inflammation and Diarrhoea with GELATIN TANNATE. This agent also appears to mop up “Toxins” from the intestinal lining.
    2. Introduce an agent to mimic the action of the missing antimicrobial peptides to eradicate the causative microbes.
    My choice is the herb NEEM LEAF. It is available as Neem Leaf powder or capsules containing an Extract of the Neem Leaf. This is best taken at night, apart from the Probiotic.
    Neem has antimicrobial properties and is also reported to prevent Bacterial adhesion to the intestinal epithelium/mucus. It is used in India for a host of inflammatory conditions. Perhaps the mechanism of action of Neem herb is by modulation of the intestinal microbiota?

    3. Re-populate the Gastrointestinal tract with suitable Probiotics. Butyrate producing Bacteria appear to help. Butyric acid produced by Clostridium Butyricum may be involved in the conversion of naive T cells to Regulatory T cells which may produce interleukin 10 and Defensins that may modulate the intestinal microbiota further.

    My choice is the probiotic BIFILAC-HP, taken in the morning.

    Introduce Prebiotic foods into the Diet. Resistant Starch in the form of Raw Potato Starch together with Whole Psyllium seeds, Inulin, Fructo-oligosaccharides, Guar gum , Pectin and Gum Arabic are suitable examples.

    1. Hi Ashwin. Thanks for replying to my post and giving your view about how things might work! I have some comments that will hopefully clear up some misunderstandings in your theory.

      1) Defensins are actually produced by cells of the epithelial layer lining the gut wall and not by Tregs.
      2) HLA refers to the MHC class I and class II molecules that are expressed by human antigen presenting cells. Indeed, it is the interaction between these molecules and T cell receptors (TCRs) of T cells along with co-stimulatory and co-inhibitory signals that determine T cell differentiation.
      3) Epigenetic switching is not the process used during T cell differentiation. Epigenetic switching refers to changes in heritable gene expression, not gene expression that is caused by changes in transcription factors.
      4) The primary role of Treg is not to kill bacteria. It is actually to suppress the pro-inflammatory functions of surrounding immune cells.

      Given these points above, you’ll need to rework your theory regarding the role of Tregs. However, the overall view of your theory, which is that changes in the intestinal flora combined with a decreased barrier function lead to unwanted immune reactions (for instance, antibodies against self-antigens) does have merit.

      To add back butyrate and Treg to the theory, you may have to consider additional processes that are going on. For instance, you’ll need to think about what the Treg are actually doing to help lower inflammation. Treg primarily downregulate the activities of other T cells (as you mentioned sometimes with IL-10), but they also are known to interfere with the workings of other immune cells too. In actuality, good bacteria via butyrate support anti-inflammatory responses. This may seem strange, but the real problem with IBD is uncontrolled inflammation.

      You did mention something like this with the concept of leaky gut and antibodies reacting to self-antigens. This concept is called molecular mimicry, and, thus far, hasn’t been proved to be involved in IBD. Instead, many focus more on the abnormal reactions towards bacteria. IBD patients have more T cells directed towards bacterial antigens. This isn’t a good thing because it causes inflammation when there actually shouldn’t be any. This is one area where Tregs would be needed.

      Not being familiar with gelatin tannate, I found this article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358810/. I wouldn’t say that it mops up toxins, it is more that it interferes with TLR4 signaling. TLR4 is expressed on pretty much all immune cells and the gut epithelial layer. When it binds to bacterial LPS, it turns on a pro-inflammatory program. So you would have to imagine that it blocks TLR4 signaling, while neem leaf lowers the bacterial load and the probiotics with prebiotics repopulate the flora.

      The idea of combining an antimicrobial with a probiotic and prebiotic is a familiar one. In many ways, fecal microbiota transplantation does exactly this. FMT is fairly successful for UC but not for CD. Perhaps, what CD is missing is what you suggest, a danger signal blocker.

      My personal feeling says that manipulating the microflora will not always be successful. Simultaneous manipulation of the adaptive immune response will probably be needed as well to re-educate the adaptive immune system.

        1. Just keeping reading and you’ll get the hang of it.

          I took a look at it. Interestingly, I was pretty familiar with the work behind it as the same theories are used for rheumatoid arthritis research. Molecular mimicry was very popular back in the early 00s when I was doing my PhD on RA. Naturally, there’s some truth behind what they’re writing about, but it’s short-sighted to focus on only one pathogen or one mechanism. Genome wide association scans (scans that show associate different gene mutations with disease) have shown that multiple genes (100+) are involved with IBD. I mention this not to say that IBD is 100% genetic, not a chance!, but to stress that IBD is actually a heterogenous disease. This means that multiple mechanisms can break down to lead to its initiation. This might mean that Klebsiella could be a factor in one patient, while in others different infections (Candida or Mycobacterium paratuberculosis for instance) or other, non-infectious, events could be important.

          Additionally, care should be taken when trying to apply a direct antibody specificity to mechanism approach in IBD. The reason is that these patients, like you mentioned, have leaky guts and a stimulated immune response. This means that they will have antibodies specific to many harmless antigens including bacteria and food antigens.

          However, I am positive about the reduction of starch in IBD to control bacteria outgrowths. I also followed the specific carbohydrate diet for two years until I couldn’t stand it anymore. It didn’t cure my Crohn’s disease, but it did seem to keep the condition under control, and I still resort to the chicken soup when I’m under the weather.

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