Truly, the best questions are not the ones that inspire a quick ejaculation from one followed by a victory lap around the room, but those that settle in at the base of one’s brain and become sentient.
It was 08:30 hrs on that particularly gelid Thursday last week that our lab’s newest PhD was minted. Dr. Sumali Pandey appeared to be walking on sunshine as she outlined her research and her findings, and, I, as I guzzled my 22nd fl. oz. of coffee that day, was beginning to perk up as well. It was at the end of Sumali’s seminar, though, that I truly experienced an Awakening of sorts as Dr. Nathan Fisher asked a question of her. To paraphrase, the question went: “If asthma is thought to be an inappropriate immune response and if Aspergillus fumigatus is thought to be a pathogen, then is the immune response seen in allergic asthma appropriate or inappropriate?” What makes an immune response “appropriate” or “inappropriate,” you ask? Simply put, an inappropriate immune response would be one that would cause a pathology to develop either by not containing the infection efficiently or by launching a grand array of inflammatory cells and mediators that would cause tissue damage, despite “meaning well.”
Dr. Fisher’s question stayed with me all day, as I helped myself to more coffee, wrote a section of my thesis, sent a flirtatiously demure text to someone who totally deserves it, ran on the treadmill like one hunted, performed cardiectomies on artichokes…you get the picture. I am still mildly haunted by the question because my response to it would have been categorically different from Sumali’s. Allow me to make a case for myself here, if you’ll be so indulgent.
I posit that the immune response made to spores of A. fumigatus in allergic asthma is inappropriate. The skewing of the immune response in the Th2 direction is characterized by events such as the release of IL-4, IL-5, IL-9, IL-13 and TGFβ1 (and these are just the principal cytokines), which leads to granulocyte infiltration en masse and the degranulation of eosinophils and mast cells in an IgE-dependent fashion. The substances released from these cells include the likes of eiocasanoids, serine proteases, histamine and reactive oxygen moieties, which are decidedly nasty given the type of tissue damage they cause. In a self-perpetuating loop, these cells also release more Th2-type cytokines and inflammation abounds. The latter two cytokines mentioned in the list, IL-13 and TGFβ1, are fibrogenic in nature and work in conjunction with growth factors like VEGF to repair the tissue damage caused by the mediators listed above. Essentially, the series of damage/repair events potentiated by these cytokines and cell populations is what manifests itself as the sequelae seen in asthma.
The reason I still argue that this is an inappropriate response is because the immunologic program that is the Th2 response evolved to defend the human body against other metazoans. A helminthic invasion is never a clean-cut affair: the infective stages in the life cycle of the trematode, Schistosoma haematobium, as an example, come equipped with scythe-like appendages that help the worm bury its way through one’s unfortunate entrails. The mini hemorrhages caused by an event like this would indeed call for a rapid mechanism of not only repairing the damage made but also of ousting the offending parasite. In such a case, the marshaling of granulocytes and IgE production followed by a fibrogenic repair response is more than appropriate. Indeed, the fibrosis does not instantly reproduce the original architecture of the barrier that was breached, but seals the area from microbial contamination while more elegant tissue restoration mechanisms come into play.
Given that the conidia of A. fumigatus are as ubiquitous as Ugg boots (though far more innocuous than the latter), I find it odd that such a contretemps is inspired by conidia that one, under normal circumstances, can clear from the body fairly easily. The key to my line of reasoning lies in the phrase “under normal circumstances”: the propensity to develop allergies and being immunocompromised are aberrant conditions that will, indeed, give rise to aberrant immune responses. A. fumigatus is not a parasite on the scale of the Schistosoma spp. The Th2 response that develops in the case of allergic asthma that leads to an airway-wall remodeling job that no-one ordered is hardly immuneappropriate! And therein lies the reason why allergic asthma is the epidemic that it is—it is an inordinately inappropriate immune response to something that doesn’t warrant it, and delineating the mechanisms that cause such a situation to develop is where the challenge lies, and thusly, why we do what we do!
References: The pathogenesis of Schistosomiasis is elegantly dealt with on the CDC web-page that corresponds with the disease. An intriguing treatment of the evolutionary basis of the Th2 Response can be found here: Allen JE, Wynn TA (2011) Evolution of Th2 Immunity: A Rapid Repair Response to Tissue Destructive Pathogens. PLoS Pathog 7(5).