Is there a causative role for tetanus toxoid vaccination in the development of allergy-like symptoms and in the increasing prevalence of atopic diseases?

Abstract

Allergic diseases are a worldwide health problem. They mainly affect people living in developed countries where an increasing prevalence of allergy symptoms has been recorded in the last 20-30 years. The cause of this increase is still disputed, and, among others, the "hygiene hypothesis" supported the concept that relevant changes in lifestyle could have a relationship with the phenomenon. More recently the recorded parallel increase in autoimmune diseases has suggested to consider the "hygiene hypothesis" as a cause of a more general disregulation of the immune system leading to both allergy and to autoimmunity. Here are reported a series of observations, evidence, and data from the literature leading to a different hypothesis. The key points are: (1) the presence of two subsets of patients having allergy symptoms based on an IgE-mediated mechanism or not; (2) the positive results obtained with the autologous serum skin test in either cutaneous or respiratory affected subjects, mainly in children and adult females; (3) the presence of IgG autoantibodies against the alpha-chain of the high affinity IgE receptor (FcepsilonRIalpha) in non-IgE-mediated urticaria and even in respiratory subjects; (4) the cross-reactivity between epitopes of the tetanus toxoid molecule and the FcepsilonRIalpha detected by means of an alpha-chain affinity purified IgG fraction; (5) the positive skin reactivity obtained using IgG anti-tetanus toxoid preparations in allergic and non-allergic volunteers. The presence of IgG autoantibodies actively generated by the population-based vaccination with tetanus toxoid could induce both mediator release from activated mast cell and Th2 cytokine production early in life. There are epidemiological evidences that tetanus toxoid vaccination could be linked with an increased tendency to have allergy symptoms. The different epidemiological distribution of non-IgE-mediated symptoms, mainly affecting young infants would be in agreement with the present hypothesis. The prevalent mother-to-child relationship in terms of risk for allergy symptoms could be explained with the trans-placenta transfer of IgG. A similar transfer could also take place through the mother milk during breast feeding. It may thus be hypothesized that the increased prevalence of allergic diseases could be caused by the generalized tetanus toxoid immunization procedure, progressively extended to most of the countries worldwide in the last 30-40 years. Both the induction of non-IgE-mediated symptoms caused by the mast cell activation via the anti-FcepsilonRIalpha IgG and the long lasting Th2 inflammation of affected tissues would be the inducing mechanisms. This hypothesis would re-configure part of the allergic diseases as a Th2 phenotypic expression of an autoimmune disease.