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CLL Support Association
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Question - how many different varieties of antibodies can B-cells make? Hint - it's hypermutation (IGHV mutation) that makes it possible

Answer, 1 quintillion or 1,000,000,000,000,000,000 or 10^18 according to a team led by Drs. Bryan Briney and Dennis R. Burton at Scripps Research examined antibody-producing B cells isolated from blood samples of 10 people between the ages of 18 and 30. ... Additional studies are needed to more accurately determine the full scope of the human antibody repertoire

:

The body’s immune system helps prevent or limit infection. One way the body fights foreign invaders, like bacteria and viruses, is by making antibodies against them. An antibody is a Y-shaped protein that’s produced by white blood cells (B-lymphocytes). It’s made of two identical “arms,” each of which has a heavy chain and a light chain. Together, these create specificity for an antigen (the substance that’s causing an immune response).

If our germinal B-cells, the newly minted ones made in our bond marrow, didn't go through this hypermutation process, we wouldn't be able to make all these different antibodies. As we learn when we have a diagnosis of CLL, having 'mutated' CLL cells correlates with a longer time to treatment and longer remission times. That fits in with the general observation that B-lymphocyte cancers vary from acute through to chronic, depending on when in the B-cell lifecycle the cancer develops. The IGHV mutation status test measures to what degree the CLL cells vary from the germinal cell line. With FCR, quite a few patients go on to have very long remission times of well over 10 years if they are 'mutated', i.e. the cancerous clonal cells developed after the B-cell went through the hypermutation stage.

from Decoding the variety of human antibodies - NIH

nih.gov/news-events/nih-res...

Illustration of antibodies, with heavy chains in blue and light chains in white. Imae courtesy of Svisio / iStock /Thinkstock

Neil

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Excellent stuff.

Helping to demystify CLL.

Thank you Neil

Jig

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Thanks Neil!😍.

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Does anyone know if there is any correlation between the % of mutation and average time to treatment? In other words, is 9% mutated better than 4% mutated? I've read that once you are over 3% it makes no difference but intuitively that doesn't make sense to me.

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Percentage of what ...CD38 surrogate?

With regards to IGHV deviation from germ line... 2% is the cut off... greater than 2% is mutated, less than 2% unmutated, and generally unmutated have a shorter TTFT, but there are many, many other factors as well as FISH markers, subclones age and so on...brought into the treatment decision...

~chris 🇨🇦

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Not sure. Experts say that for IGHV anything over 2% is considered borderline and anything over 3% is considered mutated. I am just wondering if the degree of IGHV mutation matters once you are over 3%

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Here is the recent paper on this... TTFT is a prognostic indictor... and from my experience they aren't very good.. I have never seen a predictive indication in this area...

ncbi.nlm.nih.gov/pmc/articl...

Ultimately its a work in progress and they play around with the numbers, but 2% is the current tipping point, perhaps next week it will be 3% or 1.8% ... just the way it goes...

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Thanks Chris, exactly what I was looking for. Very interesting findings here. Seems pretty clear from this that there is a direct correlation between % deviatation of IGHV and treatment outcomes, there really isn't a go / no go tipping point.

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It is really beyond the human reference to comprehend 10^18 . It is mind boggling in its size.....for example, quarks, the part that make up the nucleus of an atom are only around 10 ^ -16...tiny beyond imagination.....and this number is huge beyond imagination......

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Indeed the number is huge beyond comprehension. Counting at the rare of one a second would take about 32 billion years or roughly twice as long as the universe is thought to have existed. Someone has calculated how many grains of sand there are in all the world's beaches and deserts and that number comes out about 8 times larger. Suffice to say, no matter what unique three dimensional shape a pathogen has, the hypermutation process in B-cells should be able to change the IGHV DNA region to generate a matching key in the B-cell receptor and later free floating antibody/immunoglobulin.

That our immune system goes through this process and then starts up a factory pouring out billions of identical immunoglobulins to flag the invaders for destruction in about a week is mind boggling. Effectively our immune system does the equivalent of combing through all the grains of sand on one continent to find another grain of sand that matches closely enough to lock together. No wonder our nodes/glands swell in response to an infection with all that activity!

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Thanks - very simple explanation for a very complex subject

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