Our appendix: expendable no more. An allegory that scientific ideas reflect the culture* of their times.

Textbooks teach us our appendix is a vestigial organ. Charles Darwin (1871, The Descent of Man and Selection in Relation to Sex) concluded that our appendix must be an evolutionary remnant from a primate ancestor that ate leaves.

I never thought to question received wisdom about our appendix until 2007 when I read a Journal of Theoretical Biology in-press article Biofilms in the large bowel suggest an apparent function of the human vermiform appendix proposing that our appendix is not vestigial but has an important immune function in maintaining symbiotic gut bacteria. Let's systematically consider what William Parker and colleagues at the Duke University Medical Center in Durham, North Carolina propose and how our appendix could function immunologically.

Our appendix has a narrow lumen and is located at the lower end of the cecum. As Bollinger et al's figure above shows, anatomy and location suggest that our appendix could selectively harbor beneficial microbes and prevent their contamination from potential pathogens in the fecal stream. Further, our appendix is rich in lymphoid tissue (Gut-Associated Lymphoid Tissue; GALT) and thereby rich in IgA and mucin. Bollinger et al show that IgA and mucin in turn provide a rich milieu that supports mutualistic biofilms of beneficial microbes. Bollinger et al propose that our appendix is optimally located and structured for maintaining gut bacteria in a protected manner from peristalsis-propelled expulsion.

As Laurin et al propose in the figure above (The Cecal Appendix: One More Immune Component With a Function Disturbed By Post-Industrial Culture), when infected, the gut uses diarrhea to purge the infection. Unfortunately, this eliminates beneficial microbes as well. They propose that during such purges, location and anatomy protect appendix-associated microbiota that are then ideally positioned to re-inoculate back into the now microbe-depleted colon. This theory ingeniously accounts for anatomy, position and physiology in proposing this novel function. Each aspect of our appendix considered in such fashion lends plausibility to the theory.

Another striking aspect of this story? Journal of Theoretical Biology and The Anatomical Record, respectable scientific publications though they may be, are not the journals an immunologist would likely think of when asked to list top-tier immunology journals. That honor goes to journals like Nature, Science, Nature Immunology, Immunity, The Journal of Experimental Medicine and their ilk. Yet this remarkably plausible theory did not originate on their august pages. As Anton Ego indelibly points out in the Pixar animated film Ratatouille (film), "Not everyone can become a great artist; but a great artist can come from anywhere". This theory published in a relatively low profile journal was even considered plausible enough to attract the attention (Your Appendix Could Save Your Life | Guest Blog, Scientific American Blog Network) of a major popular scientific magazine, Scientific American.

Even with her giddy extravaganza, Nature is purpose-driven parsimony personified. Yet, we looked at our finger-like appendix and thought expendable. It's inflamed? Cut it out. Our appendix could be a poster child metaphor for our foolhardy predilection for overlooking the important in life. I learned anew to question received wisdom after reading William Parker et al's ingenious new theory for the function of our appendix. This particular story reveals an emblematic truth about scientific discovery and the shaky ground of the much-vaunted scientific objectivity. Science is built on successive paradigms and a given paradigm reflects the popular culture of its times. Our appendix conveniently became an expendable organ when our culture was dominated by the idea of expendability. Now it's a "safe house" for symbiotic gut bacteria. Genius lies in teasing out a truth that stands the test of time. I hope this is the case for William Parker et al's proposed new immune function for our appendix.

*: pun intended

http://tirumalaikamala.quora.com/Our-appendix-expendable-no-more-An-allegory-that-scientific-ideas-reflect-the-culture*-of-their-times

Tissues and Immunity: Let No Human Put Asunder What Nature Put Together

What is immunocompetence? Seems like a simple enough question. In the past, we would have said, "That's easy. T cells and B cells, of course". Then along came a pantheon of innate immunocytes (dendritic cells, macrophages, NK cells, NK T cells to name a few), and the concept of immunocompetence expanded to include them. While traditional understanding of immune responses accorded major decision making powers to T and B cells, our newer expanded understanding accords considerable influence to these innate immunocytes. However, we have yet to take a critical conceptual step forward.

In particular, for the most part, we continue to consider tissues and organs to be passive players in immune responses. Instead, we accord to the innate (dendritic cells, macrophages, etc.) and adaptive (T and B cells) elements of the immune system the capacity to orchestrate an immune response from beginning to end. In response to alarm, we imagine that the tissue-resident dendritic cells are activated, that they mobilize and migrate towards the draining lymph node(s) where they engage with and activate antigen-specific T cells, which then orchestrate the rest of the immune response to resolve the alarm and re-establish homeostasis.  Of course, this scenario is not purely hypothetical: we do have an abundance of supporting experimental studies. Yet, is not this tapestry stitched according to our preconceived notions of what constitutes an immune response? Whither the tissue itself amidst the tumult of an immune response?

If we attend to the poor tissue at all, we imagine it doing its part in initiating the alarm and then passively waiting for the immune system to resolve the problem. On the other hand, if we accorded the property of immunocompetence to every cell in the body, we could perhaps perceive immune responses rather differently. Imagine if every cell in the body were immunologically competent, capable of not only responding to and communicating alarm to its neighbors and to immunocytes but also capable of actively participating in and regulating immune responses. Such a scenario would upend our current understanding of immune responses.

Imagine now, in health, a tissue in intimate contact with its environs, selectively welcoming the mobile elements of the traditional immune system to come and reside within it. Among others, these would be the progenitors of the tissue-resident dendritic cells and macrophages coming in and settling down to life within its environs, bathed in its unique interstitial fluids. Let's imagine that this tissue's unique immunological identity would ensue from its unique composition, embellished in its unique fashion with various elements of the immune system, and from its unique function. This would be why the anterior chamber of the eye and the seminal fluid would be rich in TGF-beta, while the liver would have an excellent capacity to regenerate. When an alarm is initiated within this tissue, instead of sitting passively in its immobility, we could instead imagine the events constituting an immune response differently.

This tissue with its unique composition and unique function, would it not respond in its unique fashion to a given alarm? Would it sit passively in wait while its tissue-resident dendritic cells mobilized towards the draining lymph node(s) to elicit T cells towards it? This tissue has spent its entire life assuming its identity, growing and developing and changing with time, performing its unique function, and responding to changes in its environment. When any change in its homeostasis necessitated an immune response involving this tissue, why would it not respond in a manner unique to itself?

If we agree that it makes sense for a given tissue to have unique structure and function, is it not reasonable to assume that it could also sound alarm in response to unique cues, have unique modes to communicate such alarm, and have unique approaches to elicit, control and resolve immune responses that occur within it? In its moment of trouble, when it and its body's very existence may be in question, is it reasonable to assume that a tissue would cede its raison d'etre to immunocytes? Yet, this is how we have tacitly envisaged immune responses. Why do we not conceptually accord greater decision-making powers in immune responses to tissues and organs? If we did so, we may improve our understanding of what constitutes an appropriate and adequate immune response at a particular site, better understand the immunological strengths and vulnerabilities of different tissues and organs, and be able to design more effective vaccines and immunotherapies.

http://tirumalaikamala.quora.com/Tissues-and-Immunity-Let-No-Human-Put-Asunder-What-Nature-Put-Together

Towards a Germophilic Definition of the Immune System

In 1906, a young Viennese pediatrician, Clemens von Pirquet coined the word "allergie" to define the essential features of an immune response, namely, as an "acquired, specific, altered capacity to react". According to Igea (The history of the idea of allergy), Von Pirquet's revolutionary insight was in conceptualizing the function of the immune system as one whose contact with an antigen changes the reactivity of an individual not as one that rids the body of disease.

To appreciate how revolutionary Von Pirquet's concept was, let's remember that even today we are taught that the immune system functions to rid the body of disease, particularly disease caused by microbes. Implicit in this definition is the notion that germs cause disease, i.e. Germ theory of disease. Yet today, thanks to exponential technology breakthroughs and large government initiatives like the Human Microbiome Project, we are being forced to confront an essential limitation of the Germ theory based definition of immune system function. The Germ theory is predicated on an adversarial and confrontational approach towards microbes. Then how did we evolve to be multi-cellular organisms that house trillions of microbes? We obviously didn't evolve multi-cellularity in a vacuum or on a non-microbial planet, and then drop down onto earth to become associated with microbiota de novo. Multicellular evolution and microbiota obviously went hand in hand. How to reconcile our microbiome with the Germ theory based definitions of immune system function. Can we? Should we?

It is one thing to say that germs can and do cause disease, quite another to hold onto a theory that implies that they only cause disease. Maybe it's time to bring Von Pirquet's original concept back into play? Let's think about that for a bit: Per my understanding of Von Pirquet, the immune system does not function to rid the body of disease, rather when the immune system responds, it changes the body's reactivity. Such a definition does not suggest that the immune system is not capable of ridding the body of disease. It instead suggests that ridding the body of disease is an ancillary, not primary, goal of the immune system. The Von Pirquet definition could be surprisingly a propos: it does not require convoluted posturing to explain how our immune system accommodates our body's microbiota. With such a definition of immune function, our microbiota could have starring or supporting roles as need be. Our immune system and our microbiota working together could explain some scenarios while their relationship breakdown could explain others. All said, accommodating and working with our microbiota would be a given for an immune system functioning not to rid our body of disease but rather to calibrate in real time our body's reactivity to its environment. With such a definition, our immune system would navigate our body-microbiota landscape without contradicting the evolutionary dictate.

http://tirumalaikamala.quora.com/Towards-a-germophilic-definition-of-the-immune-system