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The study of immunology has revealed a complexity of immune cell types
and prolific interactions that overwhelm even the experts. The emerging
description of chemical signaling that occurs among immune cells and between
immune cells and all other tissues of the body has become especially complicated.
The nature series of scientific journals sponsors a data base that lists
over 3000 signaling proteins that carry messages among cells of the body
When immune cells are excited by antigen, they release a cascade of molecular
signals that cause systemic symptoms and local target organ dysfunction.
Each signal produces its own signature of symptoms. Prostaglandins, for
example, are short-lived, cause flushing, pain, shortness of breath, fast
heart rate, constricted or dilated blood vessels, diarrhea and abdominal
cramps. A variety of locally released and systemically effective mediators
act in concert. When cell-mediated immune responses are activated, a continuous
series of mediators is released, amplifying and prolonging disturbances
for days to months.
When you develop a bacterial or viral infection, immune mediators
produce fever, headache, generalized aching, fatigue, weakness and
clouded consciousness. The general impact of these chemical messages is
to amplify a small triggering event into a large response. We used to call
this the "Philadelphia Effect" after Philadelphia police burned down several
city blocks by using a smoke bomb to flush out some alleged terrorists from
one apartment.
Mediator Generated Symptoms
Once excited by antigen, a cascade of mediators establish emergency,
dysfunctional conditions systemically and locally in target organs. Each
mediator produces its own signature of symptoms. Some mediators, such as
histamine, serotonin, bradykinin, mast-cell peptides and the prostaglandins,
are better known. Prostaglandins have short-lived effects. They cause flushing,
pain, dyspnea, tachycardia, constricted or dilated blood vessels, diarrhea,
and abdominal cramps. A variety of locally-released and systemically-effective
mediators act in concert. Once inflammation is initiated in tissues by immune
cell invasion and mediator release, the tissue disturbance tends to persist.
When cell-mediated immune responses are activated, a continuous series of
mediators is released, amplifying and prolonging disturbances for days or
weeks.
Histamine Symptoms
Histamine is the prime mediator in type 1 allergic
reactions such as hay fever. Almost everyone has taken an antihistamine
to treat hay fever and itching, to relieve nausea and vomiting or cold symptoms,
or as an aid to sleep. The popularity of antihistamines is a mute testimony
to the negative effects of histamine in the body. To get a good idea of
what histamine can do, let us imagine the effects of an injection of a small
amount.
Histamine carries its message to a large number of cells by attaching to
a special receptor on the cells' surfaces. There are two kinds of histamine
receptors, H1 and H2. The H1 and H2 receptors both receive histamine as
a messenger, but the meaning taken by the different receptors is different.
H1 receptors tend to produce the symptoms already listed and activate the
allergic reaction. H2 receptors tend to act as negative feedback receptors
and turn the allergic reaction off. H2 receptors also exclusively activate
the acid-producing, parietal cells of the stomach lining.
Histamine dilates blood vessels and
acts with prostaglandins, PGE2 and PGI2, to produce the early swelling,
redness and heat of an inflammatory response. The same mediators may sensitize
nerve endings to other pain-producing mediators such as bradykinin. An initial
burst of mediator activity will often set a series of cell responses in
motion which will amplify and prolong disturbances for days or weeks. Once
inflammation is established in tissues by immune cell invasion and mediator
release, recovery may take several weeks.
Cytokines
are potent mediators of immune activity. These
chemicals carry messages from one cell group to another and invoke the most
powerful of whole-body defense responses. The cytokines include the interferons
and interleukins, which cause many of the symptoms of bacterial and viral
infections - fever, headache, generalized aching, fatigue, weakness, and
clouded consciousness. The same symptoms are produced by cytokines during
food allergic reactions. Overproduction of one or more cytokines may be
responsible for non-specific hypersensitivity. Patients presenting with
chronic fatigue, muscle aching, and brain dysfunction often have increased
blood cytokine activity. If they are reacting to food the elevations
of cytokines would be variable and inconsistent and are therefore are not
likely to be reliable tests of food allergy.
Interferons
and interleukins cause many of the symptoms of bacterial and viral infections
- fever, headache, generalized aching, fatigue, weakness, and clouded consciousness.
Some of these cytokines produce dramatic mental and emotional effects. Overproduction
of one or more cytokines may be responsible for non-specific hypersensitivity.
Patients presenting with chronic fatigue, muscle aching, and brain dysfunction
may have increased blood cytokine activity.
The discovery of strong effects of cytokines on thinking, emotions,
and behavior has opened a new window on mental illness as it relates to
immune-mediated disease, especially food allergy. Hypersensitive people
probably produce more cytokines, more often, and suffer more symptoms from
their local and systemic activity. In a variety of clinical experiments,
cytokines have been administered to human subjects with the hope that they
would help them combat cancer or other severe diseases. These human trials
have revealed how many symptoms are produced by cytokines.
Interferons
are proteins which have anti-viral and anti-tumor effects. Interferon-alpha
(INF-a) causes a flu-like illness with fever, chills, malaise, drowsiness
and confusion. Fatigue persists for up to 4 weeks after treatment. Higher
doses of interferons produce major disturbances in thinking, with a particular
inertia or "unwillingness to do anything" and often with a sense of impending
doom.
Another set of cytokines, the interleukins, have profound effects
on the mental status of patients receiving them. Interleukin 1 is secreted
by activated macrophages and induces fever, fatigue and excessive sleepiness;
one theory of chronic fatigue and depression suggests that if IL1 overproduction
is prolonged secondary neuroendocrine changes combine to produce the clinical
syndrome. Interleukin 2 (IL-2) produces fever, chills, and mental changes
which range from confusion and depression to dementia to somnolence and
coma. Some patients become belligerent and confused after IV infusion of
IL2 and some developed symptoms of psychotic illness. Tumor necrosis factor
(TNF) suppresses appetite, and regularly triggers headaches often described
as an "exploding sensation". Other symptoms include fatigue, progressing
to lethargy, memory loss, and dysphasia.
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