Dr. Kern also pointed out that, in ongoing research, mRNA for the cytokine TSLP is upregulated in nasal polyps. That would certainly suggest the hypothesis that stimuli-whether it be bacteria, fungi, or whatever-are stimulating toll receptors with an augmented TSLP response, Dr. Kern said. TSLP may secondarily lead to an accentuated TH2 immune response with eosinophil recruitment, additional characteristics of CRS with nasal polyps, he said.
Explore this issue:June 2009
The ligand BAFF, which activates B-cells, also appears to be present in greater amounts in polyp patients, Dr. Kern said. BAFF recruits B-cells and triggers them to secrete IgA. Probably the most potent stimulant for eosinophilic degranulation is IgA, Dr. Kern said.
Taken together, this evidence suggests the hypothesis that nasal polyposis is mediated by a defective innate immune barrier and an excessive compensatory acquired immune response, Dr. Kern said. The latter is characterized by a skewed TH2 and IgA response directed against a variety of microbial antigens, probably both bacterial and fungal. The excessive IgA may be one mechanism for excessive eosinophil degranulation that has been proposed as a final common pathway for polyp formation.
Future treatments are likely going to be targeted to these and other specific defects in the patient, rather than [using] broad-spectrum antibiotics, antifungals, or corticosteroids, he said.
The Debate Continues
Dr. Ponikau defended his hypothesis that fungi are the crucial trigger of chronic rhinosinusitis. I’m able usually to induce an eosinophilic inflammation [with fungi], he said. I have not seen any data that show that actual bacterial antigens are capable to produce eosinophils. I’ve never seen a single study that has demonstrated that. And at the end of the day these are the granulocytes that release the proteins that do the damage to our patients.
But Dr. Kern found that unpersuasive. Showing that activated eosinophils from the bloodstream attack fungi is not particularly surprising. They probably attack everything-they’re activated eosinophils. But the question is: Did the fungi elicit a T-cell mediated response? And we have no evidence of that.
Dr. Ponikau said his data on production of IL-5 and IL-13, which are the cytokines crucial for the eosinophilic inflammation in CRS and are the ones produced by the T-cells, indicates that the fungi are causing that kind of response. These were actually lymphocytes, including the T-cells, which were stimulated by the fungal antigens and they showed those responses, he said. They responded with a production of IL-5 and IL-13. These are exactly the cytokines we see in our patient populations being elevated.