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This article will repeat some of the earlier material, but you can still go back and reread them from past CLL Society Tribune editions, Introduction of Immunity Part 1 and Part 2. Let us put together all the factoids from the first two articles and see if we can make any sense out of them.
It is not required that the immune system responds to every single antigen. Sometimes the antigen is simply not antigenic enough or is not in a great enough number or is not recognized by the inflammatory process. This is one issue that may play a part in malignancies. If a cell has a hidden chromosomal defect that simply doesn’t show to the immune system, it can keep on living and multiplying without a response.
Other antigens may be minimally immunogenic such that the response is muted. For example, response to superficial fungi. Other antigens can stimulate an ample reaction, but the antibodies made are not defensive. These non-protective antibodies can show that you have been exposed to a specific antigen but do not interfere with the effectiveness of the antigen. For example, a lot of parasites will cause this type of antibody. This is not the same as being immunocompromised. This is the way the functional immune system works.
We all want the immune system to respond with an immediate and high-powered response to an antigen. First, it would be utterly exhausting to spend your entire life feeling as if you were coming down with a cold. Second, the immune system would be so busy responding to unimportant antigens that it could very well miss the ones it needs to fight.
The immune system doesn’t work that way. It usually misses very low numbers of antigens. In the case of another coronavirus, that of the common cold, you have the virus present in your nasopharyngeal tract for approximately 2-3 days before you have sufficient numbers of viruses needed for immune stimulation. Once you have enough viruses to cause sufficient inflammatory response, the macrophages phagocytize the combination of dead/damaged cells and viruses. When the virus is phagocytized, the various antigenic components are isolated by these cells, they are “presented” to the T lymphocytes. The T lymphocytes then interact with B cells to cause the B cells to make antibodies. It takes about 6-8 days for this to happen.
When you think back to your last cold, you can remember that the first 3-4 days of “having” the cold show the signs and symptoms getting worse each day as the number of viruses increase and the cell damages occurs. Then, days 4-8 are just miserable, not getting better not getting worse. Somewhere around day 6, the first antibodies are functional but in insufficient numbers to make a noticeable turn for the better. But you might notice increased fatigue, swollen glands, and perhaps a sore throat. Somewhere around day 8 or so, there is a turn. You have made enough IgM that you are removing more and more antigens. The tide has turned. Around day 12-14, the IgM has done its work and is decreasing in number while the memory IgG is increasing in number. By the end of 14 days or so, the viruses are gone, and recovery is near to complete. The IgG then cleans up and the B cells making the IgG will remember that virus for a faster response the next time. This example timeline is reasonably close to reality for an immunocompetent body to defeat the typical virus. Unfortunately, not all B cells will remember all viruses to the same extent. You will never get measles again if you had it, but you are capable of getting the coronaviruses that cause the common cold about 3-6 month after the last exposure.
Now, the immunocompromised system can act in its own variations. If you think back to the normal function of the non-specific defense, imagine what could happen if you did not have enough monocytes/macrophages or if they and the granulocytes cannot move as fast as they should. Having your macrophages busy with some type of chronic infection is one way to keep them away from target cells while decreased numbers/functionality of white cells (a hallmark of traditional cancer chemotherapy agents) allows the infective agent to remain alive longer. In medical speak, this combination of fewer and less capable action results in poor wound healing. The longer it takes to heal, the more likely it will be more severe. People with decreased complement also have a lower nonspecific response.
B cell alteration can cause a number of things to not happen. For example, it might take one person’s immune system two weeks to recognize the foreign antigen. When that happens, there is a larger number of viruses and the damage to cells is greater, both in number and in severity, so you start out behind. This will also allow the viruses to move to other sites, cause additional complications. Another possible scenario is that the immunocompromised system can make antibodies in a timely manner, but they are of lesser quality. Maybe they do not last as long as they should or maybe they cannot bind to the antigen as tightly as they should. In the final example, the system might not be capable of making any antibodies at all. B cell diseases such as rheumatoid arthritis, Lupus, or multiple myeloma can have misshapen and non-functional antibodies.
T cell damage is harder to ascertain, again because they are harder to test. T cells are divided into subsets depending on their function. Probably one of the more well-known is the T4 cell. Think of this cell as a foreman, directing cells to perform additional functions. You can think of them as the “on/off” cells. If there are insufficient numbers of T4 cells (this happens with HIV infections) or if they have been suppressed by medication or genetics, then the immune system may not turn on in an efficient or effective manner. Not because the other cells don’t function, but because they have not been directed to turn on. At its most noticeable, the T4 cells will not direct the B cells to make any antibodies. T cells can also become “exhausted” from trying to get the B cells to function over time. For example, suppose you were that patient with lifelong allergies. It could happen that your T cells are so busy trying to control the immune system against the allergen that they are simply overwhelmed and cannot respond to the next antigen.
Traditional cancer chemotherapy cannot distinguish between cells and so everyone using this medication will have a lowered immune response, starting with the T cells which cannot respond correctly. In patients with CLL or other lymphoid disorders, the T cells can be drained of functionality by medications, lack of B cell response and/or collateral damage.
All these functions and dysfunctions occur throughout our lifetimes. Sometimes we win, sometimes not. Sometimes the offending agent is eliminated; sometimes it remains and causes consequences. Sometimes the reaction is noticeable, sometimes low grade. The final article will concentrate on testing as an aid to diagnosis, treatment and monitoring.
Susan Leclair, PhD, CLS (NCA) is Chancellor Professor Emerita at the University of Massachusetts Dartmouth; Senior Scientist, at Forensic DNA Associates; and Moderator and Speaker, PatientPower.info – an electronic resource for patients and health care providers.