Historical anecdotes and breakthroughs of histamine: from discovery to date

Aim: Investigating about the history of allergies and discovery of the histamine's role in the immune response through historical references, starting with ancient anecdotes, analysing the first immunization attempts on animals to understand its importance as the anaphylaxis mediator. Moreover, we shortly resume the most recent discoveries on mast cell role in allergic diseases throughout the latest updates on its antibody-independent receptors. Methods: Publications, including reviews, treatment guidelines, historical and medical books, on the topic of interest were found on Medline, PubMed, Web of Knowledge, Web of Science, Google Scholar, Elsevier's (EMBASE.comvarious internet museum archives. Texts from the National Library of Greece (Stavros Niarchos Foundation), from the School of Health Sciences of the National and Kapodistrian University of Athens (Greece). We selected key articles which could provide an historical and scientific insight into histamine molecule and its mechanism of action's discovery starting with Egyptian, Greek and Chinese antiquity to end with the more recent pharmacological and molecular discoveries. Results: Allergic diseases were described by medicine since ancient times, without exactly understanding physio-pathologic mechanisms of immuno-mediated reactions and of their most important biochemical mediator, histamine. Researches on histamine and allergic mechanisms started at the beginning of the 20th century with the first experimental observations on animals of anaphylactic reactions. Histamine was then identified as their major mediator of many allergic diseases and anaphylaxis, but also of several physiologic body's functions, and its four receptors were characterized. Modern researches focus their attention on the fundamental role of the antibody-independent receptors of mast cells in allergic mechanisms, such as MRGPRX2, ADGRE2 and IL-33 receptor. Conclusion: New research should investigate how to modulate immunity cells activity in order to better investigate possible multi-target therapies for host's benefits in preclinical and clinical studies on allergic diseases in which mast cells play a major role.