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Immunology lends itself to metaphors. In fact, they dominate the field. Detect and defend are indeed the dominant metaphors used to define the immune system. However, each human is not an individual but rather a co-evolved ecosystem comprising mammalian and microbial elements that function together as a whole. Recent technological advances just made this fact more unambiguous.

In this changed landscape, the detect and defend metaphors become inadequate and destitute, even flawed. After all, in this brave new world, friend and foe are garbed alike, having the same or similar triggers, for e.g., pathogen recognition receptor (PRR) ligands. Detect could be detect and deter in one instance, and detect and nurture in another. Defend may well be defend in one case, tolerate in another and even encourage in yet another. Unifying feature? No longer absolute, the initiation, continuation and termination of immune responses become contextual. Who are the contextual players? That’s the stuff of the newer conceptualizations.

Yet the detect and defend metaphors continue to dominate immunology. Not for long though. We’re just living through a transitional period between paradigms. Two complementary ideas could better explain immune system function within the body-as-ecosystem human.

The first concept? Microbiota management. Immune system envisioned as not to detect and deter invaders who may seek to do harm but to recognize, maintain and nurture beneficial microbes. Detecting and deterring harmful invaders still part of the mandate, just not the whole piece. Proposers? Margaret McFall-Ngai, Professor Emeritus of Medical Microbiology and Immunology, University of Wisconsin-Madison, USA. Eric T. Harvill, Distinguished Professor of Microbiology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, Pennsylvania, USA. In two separate papers (1, 2).

However we need to go even further. Not in a silo, but in tandem with the rest of the body and the microbiota, the immune system functions as an exquisitely sensitive calibrator for maintaining their homeostasis. Tissues are the missing piece in McFall-Ngai and Harvill‘s ideas. However, their ideas combined with the role of tissues (3) completes the picture.

Why tissues? Let’s consider any tissue. For it, both microbes and the immune responses they elicit are a burden. They come in and gum the works of their smooth functioning. Examined this way, it’s clear that tissues and organs would have a say in how immune responses play out within them. Unlikely they’d be sitting around passively while the immune system and the microbes duked it out in their midst. After all, what guarantee the tissue could continue to function normally if it got destroyed by an exuberant and disproportionate immune response, i.e., immunopathology? Stands to reason then that a tissue with an ongoing immune response within it would offer contextual signals to guide and shape those responses as best it can and for as long as it can. After all, the stakes couldn’t be higher. Its own survival and maybe even that of the body may depend on such contextual signals. The kind of immune responses that the skin could tolerate may be intolerable and even utterly destructive inside the brain, and so on.

Tissues and microbiota make the dynamics just that much more interesting. Let’s consider a tissue that harbors microbiota as an example. Say lungs. Healthy lungs are associated with particular microbes. Stands to reason that lung tissue function itself would be intrinsically different when lung microbiota changes from this equilibrium. Stands to reason further that such changed lung tissue function would also alter immune responses within the lungs. Alterations would be temporary when the underlying changes are so, more permanent when they are changed more unalterably.

Consequence? Immune function can no longer be interrogated in isolation. Rather full meaning can only be derived from studying the context as well, i.e. microbiota and tissue responses as well. The former is already being studied, albeit in the extremely reductionist format of molecular identities of the players, the latter yet awaits its moment in the sun, the inevitable paradigm shift.

The papers:

  1. McFall-Ngai, Margaret. “Adaptive immunity: care for the community.” Nature 445.7124 (2007): 153-153. Page on wisc.edu
  2. Harvill, Eric T. “Cultivating our “frienemies”: viewing immunity as microbiome management.” MBio 4.2 (2013): e00027-13. Viewing Immunity as Microbiome Management
  3. Matzinger, Polly, and Tirumalai Kamala. “Tissue-based class control: the other side of tolerance.” Nature Reviews Immunology 11.3 (2011): 221-230.