Biology Reference
In-Depth Information
activated in a B cell through stimulation of an immunoreceptor (CD86) and a neurore-
ceptor (
2
AR) converge to regulate the magnitude of an IgG
1
response. These findings
were confirmed
in vivo
when B cells alone were adoptively transferred to NE-depleted
or NE-intact immunodeficient mice and the mice were administered an intraperitoneal
injection of anti-CD40 antibody and IL-4, an anti-CD86 antibody, and/or the
2
AR ago-
nist terbutaline. The level of serum IgG
1
was increased almost twofold following
2
AR
stimulation and almost threefold following CD86 stimulation, and this level was further
increased by almost sixfold when both CD86 and the
2
AR were stimulated. Likewise,
the level of mature IgG
1
transcript and Oct-2/OCA-B transcript and protein produced by
splenocytes from these mice positively correlated with the increased level of serum IgG
1
protein. Therefore, the level of mature IgG
1
transcript and IgG
1
protein increase after
2
AR and/or CD86 stimulation on a B cell, and this change appears to be associated
with a similar increase in the level of Oct-2 and OCA-B transcript produced
in vitro
and
in vivo
. Thus, for one antibody isotype, that is, Th2/IL-4-dependent IgG
1
, we now know
the mechanism by which NE and
2
AR stimulation exert their enhancing effect.
An understanding of the regulatory mechanism by which CD86 and/or
2
AR stimu-
lation increases the level of IgG
1
produced by a murine B cell may help to explain the
linkage of acute stress to an enhancement of IgG immunity in humans. For example,
the drug ephedrine exacerbates lupus symptoms in lupus-prone mice, via a mechanism
that appears to involve stimulation of the
2
AR on a B cell to increase the level of IgG
[146]
, suggesting that NE stimulation of the
2
AR on a B cell could potentially regu-
late the severity of this disease process. In acute stress, an increase in the level of NE
released from lymphoid organ nerve terminals might overstimulate the
2
AR on a B cell
to induce a higher level of IgG, as has been reported in mice
[63,140,141]
. While in
chronic stress, the
2
AR may be down-regulated, thus preventing optimal
2
AR stimula-
tion on a B cell and, consequently, preventing optimal IgG production. However, chronic
stress in mice was shown to be associated with no change in NE levels, but associated
with an increase in
2
AR expression on immune cells, which could explain the increased
sympathetic effect on T and B cell responses
[147]
. The latter findings may have rel-
evance for vaccination protocols in which the goal might be to raise the level of humoral
immunity in patients dealing with undue stress; for example, cancer patients who need
IgG
1
to fight against pneumonia, but who cannot respond well to a vaccine.
The information available regarding IgG
2a
is virtually nonexistent, and information
concerning IgE is only now being reported. Although one might have predicted that the
mechanism responsible for the
2
AR-mediated increase in the Th2/IL-4-dependent IgE
response would be similar to that for the Th2/IL-4-IgG
1
response, the signaling inter-
mediates used to induce the enhancing effects are quite different (see
Figure 5.6
and
Ref.
[148]
). In contrast to PKA-dependent activation of camp response element bind-
ing (CREB) that mediates an increase in IgG
1
, PKA instead regulates a phosphatase
called hematopoietic protein tyrosine phosphatase (HePTP), which is involved in p38
MAPK regulation, to mediate an increase in the level of IgE
[149]
. The resulting
2
AR-
induced increase in p38 MAPK activity regulates the level of IgE produced in a CD23-
and CD21/CD19-dependent manner that increases the rate of IgE mRNA transcription
and the amount of IgE produced per cell, without affecting class switch recombina-
tion
[150]
. Thus,
2
AR-mediated enhancement of the IgG
1
response appears to use the
