are likely significant in triggering CRS, evidence supporting a

role for specific environmental agents remains largely indirect,

as no widely accepted animal model of CRS exists. Host genetic
variation, particularly governing the sinonasal epithelium and
immune response, also plays a major role but given that age
of onset of CRS is typically in the fifth decade, environmental
and epigenetic effects likely dominate from the standpoint of
causation. Relatively few high-quality genetic studies have been
performed to this point, but using adult onset asthma as a model,
multiple genes are involved, each typically conferring a relatively
small effect size and most having functional implications
for the epithelial barrier and immune response(426). CF, with mutation
of the CFTR gene, is a notable exception demonstrating a
strong association of the homozygous mutation with childhood
onset CRS(427). Presence of the heterozygous CFTR mutation is
also associated with a CRS signal albeit less than clinical CF, and
usually presenting in adulthood(428). The impaired mucociliary
flow seen with CFTR mutations is presumed to intensify microbial
exposure driving the process(429). The importance of CFTR in
childhood onset CRS suggests that other barrier-related genes
may play a role in CRS initiation.
The identity of the antigens triggering CRS is another area
where we have little information. The limited data available suggests
that common nasal bacteria, including S. aureus, are targeted
by the host immune system in CRSwNP(172). In AFRS, fungi
are likely targeted as well. Both nasal bacteria and fungi should
induce a Type 3 immune response, yet nearly 90% of Western
CRSwNP patients (and over 50% of surgical CRSsNP patients)
exhibit a significant if not predominant Type 2 cytokine profile.
indicating that interactions between host and bacteria are not
solely driven by Type 3 mechanisms(153, 342, 400, 430-434). Although the
reason for Type 2 skewing is very unclear, it suggests that some
of the inter-related hypotheses which have been used to explain
atopy including dysbiosis, may be operative in Type 2 CRS as
well. Alternatively, it has been proposed that S. aureus, via multiple
pathobiologic mechanisms including superantigens, is capable
of shifting the immune response in a Type 2 direction(170).
Some evidence also suggests that environmental proteases and
host anti-proteases interact at the mucosal surface, setting a
threshold for barrier penetrance as well as skewing the immune
response in the Type 2 direction(196, 400, 435). One key pathway
for Type 2 skewing may include the gene ALOX15, as a loss of
function variation protects against nasal polyposis(436). This gene
encodes the enzyme 15LO (15 lipoxygenase), which is up-regulated
by IL-13 and promotes eoxtaxin 3 expression