Biology Reference
In-Depth Information
PKA-dependent CREB-mediated pathway to do so, whereas enhancement of the IgE
response appears to use the PKA-dependent HePTP/p38 MAPK-mediated pathway.
An understanding of the mechanism by which
2
AR stimulation regulates IgE may
be useful for developing therapies to treat allergic asthma, a disease that involves IgE.
At present, all therapies used to treat allergic asthma target some biological mediator
along the allergic response cascade. For example, a
2
AR agonist targets the bron-
chial smooth muscle cell to relieve bronchoconstriction, an antihistamine targets his-
tamine to prevent an inflammatory response, a glucocorticoid receptor agonist targets
immune cells to suppress cell reactivity, and an anti-IgE antibody targets free IgE to
prevent IgE-induced symptoms in general and lung pathology in particular
[151]
.
When glucocorticoids are used with one of the other therapies, IgE levels decrease
and asthmatic symptoms disappear, most likely because of a global suppression of
immune-cell activity
[152]
. However, the major disadvantage of the glucocorticoid
co-therapeutic approach is that the side effects from long-term use are severe
[153]
,
particularly because the glucocorticoid-induced immune suppression renders an indi-
vidual prone to infections. Also, if the key to the success of the glucocorticoid co-
therapy is an overall suppression of immune cell activity, then it is possible that
2
AR
agonist therapy alone contributes to asthma pathology by enhancing B-cell activity
that would be suppressed by glucocorticoids. The need to determine if this possibility
is true became paramount when the FDA issued an alert, in January of 2006, regarding
the use of long-acting -agonists, which were found to increase the severity of asthma
responses and the number of asthma-related deaths
[154]
. Although the causes of
and treatments for allergy/asthma are varied and controversial, the symptoms associ-
ated with allergic asthma appear to be precipitated by the presence of IgE
[155-157]
.
Because anti-IgE monoclonal antibodies are an effective therapy for inhibiting both
early and late allergic reactions in humans [158], it would be beneficial for us to iden-
tify a homeostatic mechanism that targets the B cell itself to regulate IgE so that we
can modulate the activity of this cell therapeutically. The finding that NE and
2
AR
stimulation use different signaling intermediates to regulate the level of IgE versus
IgG
1
[148,150]
suggests that we may be able to locate such a sensitive target. Such
findings might also explain why long-term conventional
2
AR agonist therapy stops
working after a few years and/or why stress exacerbates an asthmatic episode.
5.12 Concluding Remarks
In this chapter we focused on the association that exists between the SNS and the
immune system.
We know that lymphoid tissue is innervated with sympathetic nerve fibers that
contain NE, which is released when antigen enters the immune system. We know that
most immune cells express b2AR for NE, but that the Th2 cell represses expression as
it differentiates from a naïve T cell. We know that engagement of b2AR on immune
cells activates a cascade of distinct signaling intermediates that affect gene expression
for certain antibody isotypes. And finally, we know that b2AR-induced changes in
CD86 gene expression on a B cell are associated with changes in CD86 function in
the B cell, which is responsible for changes in immune-cell activity and function.
