Im wondering if anyone knows....do CLL cells, more or less function like regular WBC, with the exception that they just keep dividing, disrupting the blood composition balance (like, red-to-white blood cells), and by extension, "gunking up" the lymphatic system?
Theoretically, if the CLL cells *did not* proliferate uncontrollably, would they otherwise be...functional WBCs? do they still "do the duties" or regular white blood cells, but there's just too many of them?
Or are they also NOT doing regular WBC duties, just taking up space?
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Glasscheetah
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There a variety of WBCs. We see some classes of them on our differential blood test - neutrophils, monocytes, basophils, eosiniphils, and lymphoctes. There are several types of lymphocytes - B-cells, T-cells, and NK cells. There are many subclasses of each of these cell types, and testing and counting them is harder and more expensive to count so most of us don't get a report that lists them. Researchers count them, though.
CLL cells are B-cell lymphocytesthat get frozen at a stage of development, and resist dying. That's why they build up in numbers, and it's a defining feature of all cancers - resisting normal death. Cells have mechanisms within to detect if they are damaged, and those mechanisms trigger cell repair or death. Cancer mutations break some of these detection or repair mechanisms.
B-cells have many functions at various stages of development. They emit chemical messengers called cytokines that affect other cells to try to stimulate or suppress some kinds of reactions or functions. There are dozens of different cytokines. CLL cells may emit signals that end up changing the balance of other cells, particularly T-cells. This can leave us more vulnerable to infection.
B-cells also make B-cell receptors, which are antibodies permanently attached to the outside of each B-cell. Each B-cell makes a unique antibody that matches a part of invading substances, like bacteria or viruses. The B-cell receptor has to match something, or internal mechanisms force it to die. The B-cell automatically mutates it's B-cell receptor by repeatedly dropping out chunks of DNA to try to make a receptor that matches something. If it ends up matching a part of the body's own cells, the B-cell is supposed to die. Sometimes it gets away with not dying even without being cancerous, and then we get an auto-immune disease. If it runs out of chunks to drop, it's supposed to die.
You may have seen dicussion of IGHV mutation tests in this forum. IGHV is part of the B-cell receptor. A B-cell might start down the path of mutating the B-cell receptor, and then a different part of it mutates, preventing it's automatic dying, thus causing it to be cancerous. The B-cell receptor may match some antigen from a microbe or the body, but a whole chain of other things have to then also still happen. The part that breaks the cell not death mechanisms often breaks other functions, too. So generally, CLL cells do not perform their antigen matching function properly.
Some B-cells go on to become plasma B-cells, which let go of their B-cell receptors to make the serum immunoglobulin antibodies we hear so much about in diseases and medicines. Some plasma B-cells can live a long time, even years. Others die more quickly. If the CLL cell emits chemical signals to tell other B-cells to relax and not develop further, then over time fewer plasma B-cells will result, and total number of our serum immunoglobulins will slowly drop. The lack of serum immunoglobulin antibodies leaves us more vulnerable to infections.
thank you for the detailed reply. that actually changes my understanding of IGHV status.
I thought had to do with the "patient 0" cell that "messed up" its replication process somehow, creating the first cancerous cell, that in turn, kept dividing
I know bone marrow has stem cells, so I was thinking that "unmutated" was essentially that the "patient 0" cell was...."younger" and more stem-cell like and all the "superpowers" that come with that. but now, all the power of a healthy, youthful stem cell are part of the cancer cell too – which would be a bad thing. but from what you're describing here, I was wrong about that.
So if the core, mechanism of a healthy cell replicating into a cancerous cell has to do with b-cell receptor mutation process itself, what defines whether it is mutated or not? that the "patient 0" cell had some partial matches and was on its way to building an antibody? Vs one that hadn't "caught" anything yet, and was a "blank slate?"
I think "Patient 0" is an infectious diseases term for the first patient infected. I think with CLL they call it the "cell of origin." But your analogy is apt.
The IGHV unmutated clone is indeed younger and earlier in development, but not as far back as a stem cell. CLL cells are mature enough to have B-cell receptors.
Most text books have B-cells start in the bone marrow, but recent research has shown that they can also begin from stem cells in the gut. I imagine other sources of hematopoietic stem cells are in other tissues, as well. But it's thought most of them do begin in the marrow. A lot of immunology is based on studies of the mouse immune system, which does have differences in some places. I've found that over the years, dogmatic statements from textbooks as to where and things happen have exceptions.
Acute leukemias and lymphomas start even younger and replicate much faster.
IGHV mutated status for CLL is defined as >=2% difference from the original (germline) DNA That's a fairly arbitrary cutoff, and papers have been written about borderline case outcomes. Note that the B-cell receptor is made from multiple genes, and we only test the IGHV as a quick way to determine mutations status. There are also Light Chain genes, and their story is complex because the cell develops either a Kappa Light Chain by using the IGK gene, or a Lambda Light Chain by using the IGLgene. There are B-cell receptor gene selection and mutation events that happen before the IGHV mutates.
I'm not sure what you mean about superpowers of stem cells. There are perhaps super-potentials to become other kinds of cells. The hematopoietic stem cells are not pluripotent stem cells - there are differences.
A cell can mutate at any stage of development. The vast majority of mutations get repaired. or the cell mechanisms force it to die. The cancerous mutations that survive at that stage define which kind of cancer and its characteristics. So CLL is the cancer that results when a B-cell gets a cancerous mutation sometime during early maturity when the B-cell receptor is also mutating. In the BiteSized Immunology paper I cite below, CLL would happen at the IgM+ B cell to T2 or T3 (Transitional) B cell stage. Other papers may call it Naive B-cell or B1 B-cell. Flow cytometry can measure the markers that are displayed at each developmental stage, with CD23+ being a classic CLL cell stage marker.
Circling back to one of your original questions about bone marrow, the B-cells are a wandering tribe that camp out in some places if conditions are right. Each person has unique combinations of conditions based on infections, their aftermath, inflammation, the developmental timing of the CLL mutation, and probably more. These conditions create niches where CLL cells prefer to live. So some people have more CLL in their blood, some in lymph nodes or spleen, and some in bone marrow. CLL cells replicate in the lymph organs, and some travel outside those organs to blood. The organs get full, and have trouble performing their normal functions. So we get symptoms. The marrow is a unique protective niche, and since all other blood cells start there (with exceptions), when it gets crowded, other cells can't grow, probably due to overwhelming signalling and competition for nutrients.
I certainly don't know all this by heart. I've saved papers that I've found, I've got a few old textbooks - mostly unreadable - and found that research marches on with occasional surprises. I've had undergraduate classes in genetics and immunology. They were harder than the computer courses I've had over the years.
That is so understandable to read and digest thank you! Sometimes things are explained and it goes over my head frustratingly but I will save this post!!
The Rai and Binet staging systems for CLL measure the impact of CLL on our body systems in how they accumulate in our lymphatic system (nodes and spleen), our bone marrow, blood and sometimes other organs. It's both the effects of accumulation and how the confusing CLL cytokine signalling impacts our immunity that threatens our health and is thought to cause symptoms like night sweats and fatigue. healthunlocked.com/cllsuppo... There's also a higher incidence of auto-immune complications with red blood cells, platelets and sometimes neutrophils.
Enlarged spleens filter out red blood cells before their time, causing anaemia. Bone marrow infiltration reduces our ability to make sufficient blood cells, but there's considerable capacity so that while typically at diagnosis, bone marrow infiltration is typically around 25%, it can increase to above 90% by the time treatment is needed due to falling platelet or haemoglobin counts.
CLL cells are active and growing within nodes, spleen (a specialised node) and bone marrow, but in their dormant phase in the blood. They are also small, just slightly larger than a red blood cell, so they don't sludge up the blood as can happen in other leukaemias/lymphomas. That's why it's possible to have lymphocyte counts over a 100 times normal and still be in watch and wait healthunlocked.com/cllsuppo... Development wise, they are stuck in a development state that's closest to that of a memory B cell. (Memory B cells can circulate in our blood for decades, triggered by exposure to a B cell receptor matching protein on a pathogen to propagate and mature into plasma cell producing antibody/immunoglobulin factories and better matching memory B cells ready for the next exposure.)
The process by which B cells mature into plasma cells involves rearrangement of the DNA in the IGHV gene, in a process termed somatic hypermutation. It's this 'mutation' which is meant when we talk about whether we have CLL IGHV which is mutated or unmutated (i.e. our inherited germline DNA).
I was looking at some anatomy charts as I was interested in lymphatic drainage massages. and it kinda seems the cisterna chyli is probably the epicenter in a lot of cases? The reason my dad found out about his cll was because while hes always had back pain, he had said leading up to it that the nature of the pain had changed. that it felt "deeper."
It seems like a direct, physical intersection between the lymphatic system and the spine, where bone marrow is made.
if for example, there was build up from years and years of whatever biotoxic sludge the lymph system had been trying to dispose of, but couldn't because of blockages, might not be a great environment for cell division? kind of like how smoking cigarettes cakes your lungs with tar and other toxins until eventually, lung cancer comes on?
also might explain why lung issues are common secondary issues, right? (pneumonia, lung cancer, and so on.) Also, the spleen is the first stop out of the cisterna chyli. There's also the common sympton of abdominal tenderness.
the way lymphatic massage would drain the cisterna chyli would be to press two fingers down right above the belly button and drag them upwards toward the chest in the direction of the thoratic duct.
If there's blockages or even just build up in the cisterna chyli, couldn't it be creating an uneven flow, and then cause spurts of biotoxic goo whenever an opening happens (up the thoratic duct)? or worse, seeping into the vertebre its attached to, where bone marrow is made?
I was surprised there isnt more research on this. The only thing I found I saw was a single case study report form last year that when the doctor did a scan of it, for unrelated reasons (as they said in the report, it was "mega sized: ncbi.nlm.nih.gov/pmc/articl...
Im sorry if this is an infantile understanding of it. I just thought that as one of the biggest lymphnodes, it would appear more in the studies I was looking at.
The question I've always had about lymphatic massage is where would cells drain to? If the cells are not in a problematic lymph organ, do they end up in another lymph organ, the marrow, and cause more or less trouble there, or to the intercellular tissues, where they cause swelling? Do they end up in the liver?
My calves used to be really swollen. I wore support hose. Since finishing treatment, the swelling has gone down considerably. I didn't do lymphatic massage. My spleen was 17.5cm at its largest extent, and I had a few 5cm nodes. I've read about people with much larger spleens and nodes.
Also, if massage moves cells out of a lymph organ, how long does it take for them to re-home?
I think painful spleen is an indication for treatment in itself.
thats a question I have too...overall, in general, with or without cancer. how does that work? ultimately, btk inhibitors are somehow dislodging the white blood cells that have caked up in the lymph nodes system, then flushing them, which is why the WBC counts first go up (dislodging), then go down. but how? what was preventing that process from happening earlier?
the other thing Ive been wondering is that for any type of malaise, colds, covid, the flu, lymph nodes swell up as the white blood cells drag the pathogen/toxic particles there. Then what happens? how does the body dispose of it from there?
because CLL patients often have swollen lymph nodes, I have wondered if the healthy white blood cells are still doing this with the cancerous ones. That is, are they still "sorting" the cancer cells in the lymph nodes. is the build up in the lymph nodes mostly cancerous ones, as opposed to a similar "blend" or composition/ratio of CLL cells vs regular one as is anywhere else in the body?
It seems to me that they are sorting the cancer cells out, considering that the btk inhibitors "dislodge" whatever's in the lymph nodes, putting them into the blood stream, causing the WBC spikes before going down. if the system just didn't recognize it, then the lymph node content would be the same ratio of cll cells to healthy ones, and we wouldnt see the wbc spike, since thats really measuring the ratio of cell types. if a concentrate is emptied into the regular stream, then yes, we'd see the spike. which we do.
I love the ideas behind the btk inhibitors....the "degunking/flushing," instead of "killing" the cancer cells. its....so smart. its really hard to kill cells that look just like our own cells without killing our own cells. its just so much more gentle and in harmony with how our system usually works. seems to have identified, or getting very close to it, the missing "link" in the chain of our natural processes and trying to fill the gap with the missing chemicals. really smart stuff. someone really stepped out of the box, and i bet they faced a lot of backlash for it. until it worked.
I think the spleen is somehow connected to the flushing system. i believe it might be where the white cells get sorted from the pathogen. the pathogens/toxins get sent through the kidneys and liver, and the white cells go back to the bone marrow production site to start over. I dont know if thats true, but the spleen seems to be the point of connectivity between the GI, the bone marrow production, and the home base, or final destination of the lymphatic system. i can see how that might be an indication for treatment as if thats backed up, nothing is getting flushed....including whatever the regular white blood cells are trying to get rid of, let alone the cancer cells.
this makes me wonder about hot/cold flash baths during the flushing process on calquence. I have been telling my dad to do hot/cold flashes in the shower, since cold causes contraction, and heat causes expansion. back and forthing that simulates a pumping actions, since the lymphatic system doesn't have its own pump, like the heart.
Glasscheetah, The main issue with CLL lymphocytes is that they are clonal. They all have the same B-cell receptor, and as such can only respond to a single specific antigen. They are worthless in responding to a virus, fungus, bacteria, or any other foreign antigen. It is estimated that there are at least 10 million B-cells in a healthy human, each with a different B-cell receptor, just hanging around until activated by some very specific antigen. The clonal CLL B-cells crowd out the healthy B-cells, resulting in susceptibility to infection.
this is probably going to sound dumb, but....if the b cell is a memory cell, in that it had some little contact with the antigen, but not enough to go full plasma, what if we....if they were to encounter whatever that antigen they were starting to build antibodies for again....could they go plasma still?
I don't know, you seem to be asking, "but if exposed would they regain ability...? (that's how I'm reading it, I'm probably wrong).
I think by analogy, imagine a photocopier that has its scanner bed disconnected from the printing mechanism, no matter what one puts on the platen (glass) it will still produce a blank sheet.
The learning connection in our B cells is disconnected so no matter what invader passes by, it cannot duplicate a response, it is as if it didn't happen.
I know that this is a rather crude and simplistic analogue, but that's the way I can explain it to others. If I'm way off or someone can improve on it please do.
It is hard to explain to our friends and family why "it just doesn't work". 🙂
Excellent question! I think that the CLL B-cell might be called a memory-like B-cell, and there are many examples of these cells secreting monoclonal IgGs or Ig light chains. My CLL cells secrete a monoclonal kappa light chain cryoglobulin that causes Raynaud's symptoms. Other secreted IgG have been associated with kidney damage as well as other problems. As far as I know their maturation to plasma cells is extremely rare if it even happens at all. There have been a few reports of cases of CLL and multiple myeloma possibly being clonally related, but the evidence is not strong, despite the fact that a Google search result headlined with AI Overview…
"Yes, under certain conditions, CLL (Chronic Lymphocytic Leukemia) cells, which are a type of abnormal B-cell, can transform into plasma cells"
When I read the article that this quote cited, the paper concluded that the CLL cells had NOT transformed to plasma secreting multiple myeloma cells. "i) the clear presence of two distinct malignant populations;"
More on the BCR:
For CLL cells to proliferate and avoid apoptosis the BCR needs to be stimulated by an antigen or by a mechanism called antigen-independent tonic activity.
I have always wondered why there hasn't been more research on identifying the specific antigens that activate the BCR on CLL cells in the cases without tonic activation. I guess since each case of CLL is probably activated by a different antigen it just isn't considered worth the effort. I did find the following paragraph, which in a way confirmed my thoughts about it.
“For therapeutic purposes, BCR signaling could be abrogated on different levels, for instance by antigen deprivation, by interference with antigen binding, or by disruption of BCR downstream signaling. The promiscuity of U-CLL BCRs for binding to different antigens, and the ubiquitous presence of many of the BCR ligands in the CLL microenvironment complicate the first two approaches, which at this time are not being pursued. In contrast, targeting of BCR signaling has become a field of major interest and explosive drug development.” (my emphasis)
B cell receptor signaling in chronic lymphocytic leukemia
CLL cells are not normal. They’re dysfunctional and don’t protect you like normal cells do. However usually don’t have to treat until they crowd out your bone marrow and you become anemic or have low platelets or some other major problems.
Thank you for asking this question? With all the treatments I’ve had I never thought about many of the specifics shared in these responses. Very educational!
You had many more knowledgeable replies to your question - that level of scientific detail is beyond me. For layperson's purposes - I was told the CLL/SLL B cells are like "junk food" - they take up space and add nothing to your body's health. I kinda liked that analogy.☺️😚
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