Psychoneuroimmunology (PNI) is a field of research that deals with the interactions between psyche, nervous, endocrine, and immune systems. Investigating these complex PNI relationships under asecologically validas possible conditions ("life as it is lived") necessitates a paradigm change in research. This shift placesfactors such as "time" and "subjective meaning" of personal experiences at the center of the research methodology. For this purpose, the biosemiotic-systemic research design "Integrative Single-Case Study" was developed. Initial results from healthy individuals as well as patients with systemic lupus erythematosus (SLE), breast cancer, and rheumatoid arthritis(RA) support the validity of the research approach. Specifically, in connection with the occurrence ofemotionally meaningful everyday incidents, we repeatedlyobserved stress system reactions, which were(1) delayed over several days, (2) cyclically patterned, (3) anticipatory, and (4) opposing, depending on a)whether participants experienced emotionally positive or negative everyday incidents, b)whether they were healthy or ill, and c)which stress system parameter was investigated. In this chapter, the Integrative Single-Case Study design is introduced as a holistic research option, presented in detail in its methodology, and critically discussed in terms of its limitations.
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