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A Primitive Form of Memory Exhibited by the Innate Immune System may Contribute to the Overall State of Immune Aging

The innate immune system evolved long before the adaptive immune system arose as a more sophisticated layer atop it. It is generally considered that only jawed vertebrates have an adaptive immune system, but there are interesting examples of stranger, adaptive-like innate immune systems in some of the more ancient jawless vertebrate lineages, such as lampreys. An overly simplistic view of the difference between innate and adaptive immunity is that the innate immune response is always the same, that for a given stimulus it will respond in the same way tomorrow as it does today. The adaptive immune system, on the other hand, maintains a memory. It will respond far more quickly and efficiently to any future incidence of a stimulus that it has encountered in the past.

Nothing in biology is simple, however. Researchers have become aware that the innate immune response in mammals can in fact change over time in response to stimuli, a phenomenon termed trained immunity. This appears to be an epigenetic process, and thus may or may not be truly lasting for any given individual - it may fade over time, if the stimulus is removed. Nonetheless, in the open access commentary noted below, researchers suggest that trained immunity may contribute to the age-related decline of the immune system into chronic inflammation and incapacity.

The impact of persistent infection or overall lifetime burden of infection on immune aging is more usually considered in terms of its effects on the adaptive immune system. Since the supply of new T cells declines with age as the thymus atrophies, the adaptive immune system behaves ever more like a resource-limited system. Only so many T cells that can become devoted to memory or to specific threats before there are too few naive T cells remaining to effectively tackle new pathogens. Prevalent and persistent herpesviruses such as cytomegalovirus are considered to be the most important burden in this sense, and the immune system uselessly devotes ever more resources to futile attempts to remove these viruses. It is interesting to consider that an analogous harmful reaction to persistent infection may be taking place in the innate immune system as well.

Be aware, innate immune cells remember

Aging is one of the most powerful independent risk factors for the development of atherosclerosis. Among many other explanations, this could be driven by age-related changes in the immune system. Systemic inflammation contributes to atherogenesis and an increased low-level inflammation during the aging process ("inflammaging") has been proposed as a culprit for many age-related diseases. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques, and are key to the formation, growth, and rupture of these lesions. Monocyte production capacity for several pro-atherogenic inflammatory cytokines was higher with increasing age.

In the past few years, three novel mechanisms have been proposed to contribute to this age-related activation of the innate immune system. First, cellular senescence, a permanent arrest of cell growth, is associated with an enhanced secretion of pro-inflammatory mediators, e.g. cytokines. Secondly, due to an accumulation of acquired mutations in hematopoietic stem cells that confer a competitive advantage, more than 10% of subjects aged over 70 years have significant amounts of mutant clones in peripheral leukocytes, which is called clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with an increased risk for cardiovascular disease because these clonal leukocytes have an increased NLRP3 inflammasome-mediated interleukin-1β secretion. Thirdly, we and others have described that innate immune cells can effectively build a non-specific immunological memory that results in an increased proinflammatory phenotype, a process which is termed trained immunity.

Recent studies have shown that circulating monocytes and myeloid progenitor cells in the bone marrow have the intriguing capacity to reprogram towards a long-term non-specific pro-inflammatory phenotype following initial exposure to microorganisms or microbial products. Although beneficial in the context of resistance against reinfections, this mechanism might be detrimental in non-infectious chronic inflammatory conditions in which myeloid cells contribute to disease progression, such as atherosclerosis. We have recently proposed this mechanism to contribute to the well-known association between acute and chronic infections and atherosclerosis. Interestingly, trained immunity is not only induced by microbial products, but also by endogenous sterile atherogenic stimuli such as oxidized low-density lipoprotein (oxLDL) or lipoprotein(a).

Comments

It looks more and more as though bone marrow transplant - probably allogeneic - is a major part of the way forward.

Posted by: John at September 19th, 2018 3:03 PM

I am nitpicking here
>... It is generally considered that only jawed vertebrates have an adaptive immune system, ...
The jawed genera(Gnathostomata) have V(D)J recombination adaptive immune system. While other vertebrates have other forms of adaptive immune system like Variable lymphocyte receptor. For those we don't know much, though. It is not pure innate immunity.

Posted by: cuberat at September 19th, 2018 5:56 PM

@John
It seems so. But probably will be done with artificially cultured stem cells and introduced gradually. Then after the transplant acquires some immunity the pre-existing one can be ablated. Probably can be done bone by bone and lymph node by node. Many visits, but no risk of immunodeficient periods .

Posted by: cuberat at September 19th, 2018 6:00 PM

@John

Irv Weissman at Stanford has been developing method of using antibody-mediated ablation of the immune system whereby the hematopoietic stem cells (HSCs) as well as the differentiated immune cells are targeted for ablation. This is followed up by either allogeneic or autologous transplant of HSCs to repopulate the immune system.
from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061494/

"These approaches to eradication of stem cells, malignant or otherwise, using functionally active mAbs in combination with immunodepleting mAb therapies, will enable minimally-toxic stem cell replacement with material from multiple potential sources, including gene-modified autologous cells, allogeneic stem cells, and potentially embryonic stem cells and induced pluripotent stem cells.

Posted by: aaron at September 21st, 2018 10:28 PM

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