Endogenous glucocorticoids and human immunity: Time to revisit old dogmas

Glucocorticoids (GCs) are steroid hormones with diverse and important roles in the physiologic response to stress. These include permissive and suppressive effects on immunity, which help prepare the organism for future infectious stressors and control the immunological response to a recent stressor, preventing autoimmune damage. The ability of GCs to rapidly suppress an overactive immune system has been harnessed pharmacologically and synthetic GCs have played a central role in the treatment of inflammatory and autoimmune diseases for the past eight decades. Given their importance in clinical medicine, an emphasis on the anti-inflammatory and immunosuppressive effects of synthetic GCs has overshadowed the study of the physiologic roles of endogenous GCs in human immunity. The rising interest in the intersection between neurobiology and immunity, and the development of technologies that facilitate direct experimentation with human cells and tissues, make this an ideal time to critically review existing knowledge on this subject. In this review of the past 100 years of biomedical literature on the effects of endogenous glucocorticoids on human immunity, we summarize existing experimental evidence, reveal key knowledge gaps and misconceptions, and highlight specific areas of opportunity for new research.