The role of histamine in allergic disease: re-appraisal of its inflammatory potential.

Abstract

Studiesofallergicdiseases,inparticularasthma,rhinitisand urticaria, have suggested that histamine, a biogenicamine synthesized and stored mainly in mast cells andbasophils, plays a prominent role in the pathophysiol-ogy of these diseases (1–3). Several immunologic andnonimmunologic stimuli, such as allergen, immunoglo-bulin (Ig)E, cytokines (interleukin (IL)-1, IL-3, IL-8,GM-CSF), substance P, complement C3a and C5a,platelet-activating factor (PAF), hyperosmolarity, phy-sical stimuli (vibration, heat, cold), etc., induce therelease of histamine from mast cells and basophils,following which it diffuses rapidly into the surroundingtissues and exerts its effects, before being metabolismand excreted in the urine (4).In experimental asthma induced by allergen orexercise challenge, it has been demonstrated that thelevels of histamine are increased in the circulation andimplicated in bronchoconstriction (5–7). Studies ofsymptomatic asthmatics have also demonstrated thathistamine levels are significantly increased in thebronchoalveolar lavage (BAL) of these individuals,compared with histamine levels in BAL of asympto-matic asthmatics (8,9). Similarly, allergen challenge inpatients with allergic rhinitis significantly increases thelevels of histamine in nasal secretions of theseindividuals (10–12), implicating a role for this mediatorin the pathophysiology of allergic rhinitis. Indeed, nasalchallenge with histamine has been shown to inducenasal blockage, sneezing and rhinorrhoea (13,14), likelyas a result of sensory nerve stimulation in the nasalmucosa (15). In patients with cold urticaria, challengewith ice-water leads to a rapid rise in plasma histamineconcentration within 2 min, which peaks at 5 min andreturns to baseline values by 15–30 min (16).Investigations of patients with chronic urticaria havealso indicated that histamine is a central mediator inthis allergic condition, with increased levels detectedboth in the lesions and normal skin of patients withurticaria, compared with skin of healthy individuals(17–19). Furthermore, the responsiveness of skin tohistamine is also increased in patients with urticaria(19).Apart from the classical activities of histamine, thereis an increasing body of evidence that histamine alsoelicits pro-inflammatory and immune-modulatoryeffects, whichmight be of pathophysiological relevance.The findings of histamine receptors expressed on avarietyof immuneandnonimmunecellssuggesta muchwider and more critical role of this mediator in allergicdisease, than is considered presently. Consequently, it islikely that antihistamines have a wider impact onallergic inflammation, and that effects on immune cellswhich have been linked to nonreceptor mediatedpathways so far, may actually be receptor-dependent.This review aims to give an overview on a currentlyemerging new understanding of the role of histamine inallergic disease.