Immune Mediators:

Immune Mediators:

Chemical Communication
in Immune Networks

From the Book of Allergy and Immunology
by Stephen Gislason MD

Introduction to Immunity

Hypersensitivity Disease Study Guide

Immune cells communicate by releasing chemicals messages or mediators. These chemicals carry messages from one cell group to another and invoke the most powerful of whole-body defense responses that cause many of our symptoms. 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, for example, are short-lived, cause flushing, pain, dyspnea, tachycardia, constricted or dilated blood vessels, diarrhea, 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.

Patients with delayed patterns of food allergy often describe prolific symptoms in interesting and varied distribution in terms of body systems and sequences. The pathophysiology of adverse food reactions may include the actions of cytokines released by activated immune cells. 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 profound 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.