Effect of mast cell derived mediators
LIF, OSM, CCL2, CCL3 and CCL4 were released both by high and low
affinity IgE signalling, with CCL3 being the only mediator still
differentially upregulated by low affinity stimulation 24 hours after
activation. This is in contrast to comparable results from a murine
response at six hours, where CCL2, CCL3 and CCL4 were predominantly
induced by low affinity IgE (2). Possible explanations for this are the
lesser difference in IgE affinity in our model (200-fold) than in the
murine model (1600-fold), and the inbred nature of the murine model
compared with the outbred human mast cell cultures derived from
independent individuals. Moreover, the extreme difference in affinity of
the murine system is due to different antigens, and not due to
difference in antibody affinity for the same allergen, which is used in
our system employing well characterized recombinant human IgE clones.
The affinity related differential mediator response was demonstrated to
have functional consequence in the previously mentioned mouse model; the
distinct signaling profile including IL-8 elicited from the high
affinity stimulation accumulated more neutrophils than
monocytes/macrophages whereas the low affinity stimulation recruited
fewer neutrophils and more monocytes(2). Increased amounts of CCL2, CCL3
and CCL4 have been measured in BAL of patients with severe asthma
compared with controls(19,20). Our data suggests that these chemokines
could be derived from activated mast cells as part of their modulation
of the late phase response.
The presence of neutrophils in induced sputum or BAL of patients with
allergic asthma is associated with severe, chronic asthma (21), but the
relationship of neutrophils to mast cell induced T2 disease is less
clear. The murine study and our human data suggest that sputum
neutrophilia may also be explained by high affinity IgE in addition to
corticosteroid use or Th1/Th17 immunity (22). Neutrophils release
elastase which activates matrix metalloproteinases (MPPs) and degrades
extracellular matrix proteins such as collagens to contribute to the
development of chronic airway inflammation (23). IL-8 recruits and
activates neutrophils during the late phase reaction(24) and elevated
levels of IL-8 have been found in BAL fluid from asthmatic patients(25).
We observed a significant increase in IL-8 with high affinity IgE
compared to low affinity IgE and baseline. Considering the strong effect
of IL-8 on neutrophils, our results indicate that the presence of high
affinity IgE antibodies may increase the number of neutrophils and
thereby the risk for developing chronic allergic inflammation. The role
of monocytes/macrophages in allergic asthma is less well understood
(26). IL-13 is secreted by Th2 cells, mast cells and basophils(27). It
induces IgE class-switch recombination in B-cells and activates,
recruits and promotes survival of mast cells and eosinophils(28).
Consistent with results from BMMCs(2) we observed a significant increase
in IL-13 with high affinity IgE stimulation compared to low affinity IgE
and baseline. (29) These observations suggest that mast cells may have a
role in both neutrophil, eosinophil and granulocytic asthma, and that
affinity of IgE for allergen may explain the shift from one endotype to
another.