Chemical- and Drug-Induced Allergic, Inflammatory, and Autoimmune Diseases Via Haptenation

SIMPLE SUMMARY: Allergic, inflammatory, or autoimmune diseases are characterized by exaggerated immune responses to harmless proteins such as pollen, dust mites, and foods in the environment or self-proteins. The number of cases has increased over the last 50 years. This is considered to be related to reduced exposure to pathogenic microorganisms, as well as a revolutionary rise in exposure to dietary chemicals and drugs via processed food, formula milk, preservatives, and antibiotics, presumably resulting in the breakdown of immune tolerance to proteins. Such chemicals and drugs may work as haptens, which are small molecules that only elicit an immune response when bound to proteins. Indeed, accumulating evidence revealed the involvement of haptens in the development of various autoimmune-like diseases, such as allergic, inflammatory, or autoimmune diseases including allergic contact dermatitis, atopy, asthma, food allergy, inflammatory bowel diseases, hemolytic anemia, liver injury, leukoderma, and even antitumor immunity. This review highlights recent advances in the chemical- and drug-induced development of these autoimmune-like diseases via haptenation together with possible molecular mechanisms and in vitro testing alternatives to evaluate in advance whether a substance might lead to the development of these diseases. ABSTRACT: Haptens are small molecules that only elicit an immune response when bound to proteins. Haptens initially bind to self-proteins and activate innate immune responses by complex mechanisms via inflammatory cytokines and damage-associated molecular patterns and the subsequent upregulation of costimulatory signals such as cluster of differentiation 86 (CD86) on dendritic cells. Subsequent interactions between CD86 and CD28 on T cells are critically important for properly activating naive T cells and inducing interleukin 2 production, leading to the establishment of adaptive immunity via effector and memory T cells. Accumulating evidence revealed the involvement of haptens in the development of various autoimmune-like diseases such as allergic, inflammatory, and autoimmune diseases including allergic contact dermatitis, atopy, asthma, food allergy, inflammatory bowel diseases, hemolytic anemia, liver injury, leukoderma, and even antitumor immunity. Therefore, the development of in vitro testing alternatives to evaluate in advance whether a substance might lead to the development of these diseases is highly desirable. This review summarizes and discusses recent advances in chemical- and drug-induced allergic, inflammatory, and autoimmune diseases via haptenation and the possible molecular underlying mechanisms, as well as in vitro testing alternatives to evaluate in advance whether a substance might cause the development of these diseases.