Immunological memory to toxic aldehydes

Abstract

We humans are exposed to a huge amount of chemical substances through our food and the environment. Exposome (exposure to environmental factors) throughout life is expected to be deeply involved in health and longevity. Among these chemical substances, aldehydes are one of the most familiar compounds, and there are many sources inside and outside of living organisms, including not only dietary and environmental factors but also fatty acids and carbohydrate metabolites. Even glucose itself exhibits aldehydic properties. In addition, the peroxidation of polyunsaturated fatty acids produces not only aliphatic aldehydes but also various reactive (toxic) aldehydes, such as α,β-unsaturated aldehydes and ketoaldehydes. Living organisms have defense mechanisms, such as detoxification metabolism against these toxic aldehydes. On the other hand, aldehydes react with nucleophilic amino acid residues on protein molecules, producing unique abnormal structures (adducts). The sum of countless adduct structures (“modification signature”) is memorized as a stimulus for biological responses and is expected to play a role in the biological response mechanism. The most typical response mechanism to adduct structures is the immune system. Recent studies have revealed that certain autoimmune diseases produce antibodies that display unique cross-reactivity to aldehyde modifications. For example, in systemic lupus erythematosus (SLE), which is known to cause overproduction of autoantibodies against DNA, the presence of bispecific IgG antibodies has been shown have affinity for not only DNA but also for modified proteins with toxic aldehydes. Moreover, IgM antibodies, which are involved in biological defense as innate immune proteins, show more diversity in terms of cross-reactivity than IgG antibodies. In particular, with regard to a carcinogenic acrolein, an interesting cross-reactivity of both IgM antibodies and B cells (B-1a cells) that recognize acrolein-modified proteins have been revealed. The existence of innate immune B cells against acrolein-modified proteins suggests that life had to deal with this toxic compound at the beginning of its life and had acquired the ability to use innate immunity as a means to do so. The fact that toxic aldehydes exist somewhere in the immunological memory, which plays an important role in biological defense, is extremely interesting when considering the relationship with health and disease.