Parasite Immunology, 2006, 28, 515–523 BPRlEarVcaksIiwEtiWeclwPAourRmbTliIsaChniLndEginLﬂtadmmatorydiseAasesrticle Review Parasitic worms and inﬂammatory diseases P. ZACCONE,* Z. FEHERVARI,* J. M. PHILLIPS, D. W. DUNNE & A. COOKE Department of Pathology, Tennis Court Road, Cambridge, UK DOI: 10.1111/j.1365-3024.2006.00879.x SUMMARY The debate on whether infection precipitates or prevents auto- immunity remains a contentious one. Recently the suggestion that some unknown microbe can be at the origin of some chronic inﬂammatory diseases has been countered by accumulating evidence that decreasing infection rates might have an important role to play in the rising prevalence of autoimmune disorders. The ‘Hygiene Hypothesis’ was initially postulated to explain the inverse correlation between the incidence of infections and the rise of allergic diseases, particularly in the developed world. Latterly, the Hygiene Hypothesis has been extended to also incorporate autoimmune diseases in general. Amongst the various infectious agents, a particular emphasis has been put on the interaction between parasitic worms and humans. Worm parasites have co-evolved with the mammalian immune system for many millions of years and during this time, they have developed extremely effective strategies to modulate and evade host defences and so maintain their evolutionary ﬁtness. It is therefore reasonable to conclude that the human immune system has been shaped by its relationship with parasitic worms and this may be a necessary requirement for maintaining our immunological health. Fully understanding this relationship may lead to novel and effective treatments for a host of deleterious inﬂammatory reactions. Keywords helminth, Hygiene Hypothesis, immunomodulation, Schistosoma mansoni, type 1 diabetes Correspondence: A. Cooke, Department of Pathology, Tennis Court Road, Cambridge, CB2 1QP, UK (e-mail: ac@mole.bio.cam.ac.uk). *Authors contributed equally to this work Received: 6 February 2006 Accepted for publication: 6 March 2006 Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2·5, which does not permit commercial exploitation. © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd INTRODUCTION The last three decades have witnessed a dramatic increase in the incidence of autoimmune inﬂammatory diseases in developed countries, including type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA), and Crohn’s disease, to name but a few (1,2). Autoimmune disease is characterized by an immune-mediated attack on a target organ that it is no longer recognized by the immune system as self. Autoimmune pathology can be caused by both antibody and cell-mediated components. Predisposition to autoimmunity is under polygenic control, but studies on identical (monozy- gotic) twins demonstrate that environmental factors might be equally important (3,4). The rising trend in autoimmune diseases looks set to continue and the projected incidences over the next 30 years are potentially catastrophic. The countries that have seen the most pronounced rise in autoimmunity have over the same period seen tremendous improvements in sanitation and socioeconomic status. Moreover, the steady migration from rural to urban areas has dramatically reduced childhood exposure to infectious organisms. Rapid anthro- pogenic transformation of the environment and life style has not allowed time for the human immune system to adjust to these changes. The very characteristics of the immune system that had previously been so advantageous for combating infections might now be the principal contributing factor for the increasing prevalence of autoimmune disease. Improve- ments in living conditions and the reduced exposure to childhood infections in particular, have been suggested to contribute to the increase in atopy and autoimmunity (5). This so-called Hygiene Hypothesis has, in recent years, attracted interest and controversy in equal measure. Epidemiological data from the World Health Organization (WHO) largely support the hypothesis, indicating that autoimmune inﬂam- matory diseases like T1D and MS are extremely rare in most African and Asian populations, yet increase conspicuously when these same populations migrate to a modern setting (6,7). In this piece we will review the evidence for the Hygiene Hypothesis particularly with regard to parasitic worm 515