messages synchronizing the target cells or organs. In turn, many target cells provide feedback information in the form of humoral signals, for example, through cytokines or polypeptide hormones and neurotransmitters that act on the superimposed neuroendocrine structures and modify their response (Blalock, 1992, 1994). The interactions of the neuroendocrine and immune system are time dependent and follow rhythmic patterns in multiple frequencies. In some frequencies, the rhythms are adjusted in time (externally synchronized) by periodic environmental factors like light-darkness, social routine, the work schedule, and to some extent the time of food uptake. The spontaneous rhythms encountered are complemented by reactive, rhythmic response patterns to environmental stimuli, some of which may equally be genetically fixed (endogenous) in nature. Such rhythmic response patterns can be triggered by single stimuli (e.g., the introduction of an antigen) and in their timing relate to the time of stimulation and not to environmental rhythms, for example, the calendar week. Environmental stimuli may also change some rhythm parameters like timing or amplitude transiently for only as long as the environmental stimulus persists (''masking'' the rhythm).

The complexity of the human time structure and its adaptation to changing environmental conditions, presumably including geophysical factors (Breus et al., 1989; Lipa et al., 1976; Sitar, 1991), make it necessary to qualify the assumption that sampling at a fixed time of the day, the week, and/or the season will "control" rhythmic variables, and that the need for the observation of rhythms could be avoided.

The rhythmically changing physiologic state of the organism determines the response to environmental stimuli like physical exercise, pain perception, mental stress, toxic substances, bacterial and viral infections, antigenic stimulation, and drugs used in clinical medicine. The state of the host organism at the time of stimulation often determines critically the response to a stimulus in extent, and in some instances, in direction. This is shown dramatically in the response of mice to the injection of Escherichia coli endotoxin (Figure 20-1). Death or survival can be made experimentally a function of the time when the agent is injected.

The development of an immune response involves a series of interactions between lymphocytes and other mononuclear cells that may include cell-to-cell communication; generation of immunoreactive molecules; immunoglobulin synthesis and secretion; expression of cell surface markers that are not generally found on resting cells or changes in their receptor density and activity; and finally cell proliferation of immunocompetent cells. An effective immune response requires a balance in the function of lymphocyte subsets (e.g., helper and cytotoxic T-cells, and antibody-producing B-cell lymphocytes), macrophages, and natural killer (NK) cells, and a balance in the production of enhancing or inhibiting soluble factors or cytokines as expressed in the Th1 or Th2 response to immune stimulation. Each of these factors is directly or indirectly under the influence of neuroendocrine rhythmic variables directing