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Immune Cell Signaling

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.

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, and 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.

The nature series of scientific journals sponsors a data base that lists over 3700 signaling proteins that carry messages among cells of the body. Dove described the state of signaling science in 2006: “Ask a cell biologist to explain signal transduction, and you are in for a long story. The science of understanding how individual cells sense their environments and respond to stimuli fills library shelves, occupies whole departments of colleges and inspires the careers of thousands of researchers around the world. Even so, the field sometimes seems woefully understaffed. The advent of whole-genome sequencing and gene-expression profiling revealed what most biologists already suspected: we are just beginning to understand cell signaling. For example, cells rely heavily on surface receptor proteins to communicate with the outside world. Often, signals flows through receptors that are coupled to effector molecules called G proteins. Inside the cell, information flow often entails an enzyme finding a specific target protein and attaching or removing phosphates, lipid groups, or other chemical structures. The modified target commonly goes on to modify other targets and so on through baroque cascades of interactions.”

Scientists have described a bewildering complexity of immune signaling molecules such as cytokines and variable cytokine production in different humans. We know that humans are not created equal. One significant inequality lies in the ability to produce cytokines of different types. An individual’s cytokine profile will help to determine the response to antigen challenges, susceptibility to different diseases and the severity of the disease, once contracted.

Bidwell et al summarized basic knowledge of cell types and cytokine production: “Cytokines are humoral immunomodulatory proteins or glycoproteins which control or modulate the activities of target cells, generally those within the haematopoietic system. They act on target cells by binding to specific cytokine receptors, initiating signal transduction and second messenger pathways within the target cell. This can result in gene activation, leading to mitotic division, growth and differentiation, migration, or apoptosis. Cytokines are produced by a wide range of cell types and have been broadly classified as monokines (produced by cells of the monocyte lineage) or lymphokines (produced by lymphocytes): other classifications are based on functional or structural groupings. Cytokines act in a highly complex coordinated network in which they induce or repress their own synthesis as well as that of other cytokines and cytokine receptors. In addition, many cytokines appear to be pleiotropic, with the corollary that the cytokine network is highly flexible, since there is considerable overlap and redundancy between the function of individual cytokines. Cytokine production by the cells of the immune system may occur through antigen-specific and non-antigen specific stimuli. For example, monocytes when exposed to bacterial cell wall products, produce IL-12 and other cytokines which have multiple functions including influencing the expression of cytokines by other cells. Antigen-specific responses are generated by B and T cells through immunoglobulin and T cell receptors respectively. B cell activation may result in the production of IL-6 and other cytokines. T cells are central players in linking non-antigen specific, B cell and T cell responses together.”

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 an unwillingness to do anything, sometimes with a sense of impending doom.

The discovery of profound effects of cytokines on thinking, emotions, and behavior 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.

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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