The Rogue Immune-System Hall of Shame
Science is discovering that defective innate immune system agents which protected us when we were young, are joining the enemy (disease) in old age. Instead of destroying and clearing out old/ineffective cells, these primitive immune cells go mental or become nearsighted, sometimes killing off effective cells as collateral damage. Meanwhile, the highly-evolved adaptive immune system (T-Cells who are trained to kill invaders identified by the innate immune system, plus “memory” B-Cells who remember what T-Cells used to do) get old and pathetically weak. Such rogue immune system agents are thought to be the culprits in Cancer, Alzheimer’s, M.S., and a host of other old-age diseases. What are we to do?
We are learning that in old age, the innate immune system (made up of macrophages and cytokines) may have stopped being our friends. In fact, they often perform acts of treason and join the other side, or at least become the “boy who cried wolf” and give false signals. Meanwhile, the adaptive immune system (T and B cells, elegantly designed by evolution to specifically attack the bad guys) are too weak to control these “bad” immune agents. The best protection against rogue macrophages and cytokines is to essentially slow the aging process, by eating healthier foods, exercising, and judicious use of some anti-inflammatory agents (such as NSAIDs, corticosteroids, and possibly Metformin, Statins, Rapamycin and other mTOR inhibitors). It also helps to get your gut flora to early-train the immune system via mother’s milk, vaginal birth, and early exposure to germs (preschool?). And now a quick rundown of these bad-acting immune system agents:
Tumor Necrosis Factor Alpha (TNFa)-Perhaps the most famous of the rogue cytokine family, Tumor Necrosis Factor Alpha is a small protein used in cell signaling, which in your younger days helped identify dangerous viruses and bacteria while inducing fever to kill said invaders. In later life, rogue TNF has been implicated in Alzheimer’s disease, cancer, major depression, psoriasis, rheumatoid arthritis, and inflammatory bowel disease (IBD). It is one of the cytokines known to be hijacked by cancer cells to do its evil bidding (fooling the T-Cells into thinking the cancer cells are friendly). It is currently controlled by drugs such as Humira, which more or less shut the damn things off (but not too much so that your body can still fight some invaders). (fda.gov,2021)
Interleukin Family (Especially IL-1 and IL-6)-Though there are many Interleukin cytokines, IL-1 and IL-6 are the ones involved in the infamous “cytokine storm” that has been known to overwhelm the lungs of Covid-19 patients (along with other unfortunate victims of secondary infections). Interleukins are dispatched by TNFa (sort of the quarterback of the primitive immune system) through TNF1 and TNF2, and the Interleukins further the process of inducing the death of harmful viruses, bacteria, and fungi. But under the wrong circumstances, the “cytokine storm” not only kills the invaders but much of the good parts of your body (sort of like a bomb that’s so good it kills the bomb maker too). Anakinra (an IL-1 inhibitor) and Tocilizumab (an IL-6 inhibitor)have been used to help quiet this cytokine storm for Covid patients, with some success.(Calvalli,Larcher,Tomelleri,Campchiaro,Della-Torre,et al,2021)
Neutrophils-These are not protein cytokines but macrophages (a sort of critter that is a first responder to the site of the wound/invasion, causing inflammation and/or “eating” the offending agent). These are the most common elements of the primitive immune system, and without them we would literally be in a “world of hurt”, perhaps not surviving our wounds or infections. Neutrophils also build extracellular “traps” which further defeat bacteria, viruses, and fungi. However, later in life, these neutrophil traps can be implicated in cardiovascular disease and cancer metastasis, as they can constrict blood flow and provide a cancer cell “raft” that breaks loose to colonize other parts of the body. They are also implicated in immune-suppression which abets cancer (by muting the effect of T-cells), which in total is called a “metastatic-cascade”. Statins are thought to inhibit neutrophilic “clogging” of arteries by making epithelial cells (the cells that line the arteries) less fatty. Inhibition of CXCR-1 and CXCR-2 (proteins that bind to cytokines) are being explored as a means of suppressing a neutrophil’s ability to abet cancer. Nitric oxide is another agent thought to decrease neutrophil’s ability to suppress T-cells critical in fighting cancer. As usual, one does not want to completely “turn off” neutrophils, as they play a large role in protecting us from other diseases. (Khanam,Trehanpati,Riese,Rastogi,Guzman,et al,2017)
Complement Component 3 (part of the Complement System of cytokines)-The complement system is a complex system of adaptive immunity proteins that regulate things like blood coagulation, organ development, innate immunity, and brain function (by pruning synapses). Ordinarily, the complement system clears a healthy brain of pathogens, dying cells, and misfolded proteins. Though there are many components of the complement system, scientists are looking at one in particular, Complement Component 3 (CC3), as a possible contributor to Alzheimer’s disease (and possibly Schizophrenia, ALS, M.S., and other neural diseases). Apparently, in a normal brain, synaptic pruning takes place, which improves our ability to learn (by trimming neurons with obsolete information). It seems that CC3 (and its downstream relative C5a), which helps trigger this synaptic pruning, may be overexpressed in some people. Tau-tangles and Amyloid Plaques (once thought to be the cause of Alzheimer’s and other neural diseases) are now thought to be the result of this CC3 being over present (perhaps triggered to “clear” the brain of invaders by a false signal). In any case, CC3 inhibitors called PMX53 and PMX205 are now being tried in clinical trial in hopes of slowing-down this neural degeneration process. A major challenge is administering drugs in such a way that they can cross the Blood Brain Barrier (BBB), which is designed to block all but the smallest agents. (Kumar,Lee,Clark,Noakes,Taylor,et al,2020)
T-Cells (that are ineffective in old age)-As we age, T-Cells become less effective in recognizing and killing pathogens. Lately, there have been inventions such as CAR-T Cell Therapy, which re-engineers your body’s T-Cells so that they can better recognize (and kill) the bad guys (especially cancer). In addition, since cancer uses ligands to “hide” from T-Cells, there are agents such as “checkpoint inhibitors” that strip cancer’s masquerading ability. Collectively, CAR-T Cell Therapy and Checkpoint Inhibitors have been quite effective in combatting soft-tissue cancers and melanoma, not as effective in hard tumors (which are apparently harder to target). (Alard,Butnariu,Grillo,Kirkham,Newnham,et al,2020)
TGF-Beta Cytokines-There is recent evidence that “leakage” in the BBB (Blood Brain Barrier) in old age or due to genetic defects, increases the likelihood of an overabundance of TGF Beta signaling cytokines in the brain. Though like CC3, TGF beta (and no, this is not a merger between “Thank God its Friday” restaurants and Alpha-Beta Grocery) helps decrease amyloid plaques, it has also been shown in mouse models that blocking TGF-beta greatly reduces Alzheimer’s symptoms. Like CC3, TGF-beta may be overdoing its job of neuronal-pruning, in compromised patients. Clinical trials of TGF-beta blockers are under way, for both Alzheimer’s and cancer patients. (Liu,Xie,Meng,Kang,2019)
Conclusion: It would appear that collectively, these rogue primitive immune system cytokines and macrophages were intended for the young and healthy, as they start making mistakes as we get older. Perhaps since old-age among humans is a relatively recent thing, these primitive agents have not “selected” for improved reliability. In any case, if one exercises and eats right (particularly reducing caloric intake) going into old-age, one can “fool” the immune system into acting “normal” for a long time (perhaps pushing the inevitabilities of Alzheimer’s or Cancer into one’s 80s or later). Alternatively, there seems to be a growing number of anti-inflammatory agents that “slow” aging, and drugs that counteract the deleterious effects of an overactive innate immune system, or a feeble adaptive immune system.
