Molecular mimicry in multiple sclerosis MIREIA SOSPEDRA 1 & ROLAND MARTIN 1,2 1 Unitat de Neuroimmunologia Clinica, Hospital Universitari Vall d’Hebron, Pg.Vall d’Hebron, 119-129, Barcelona 08035, Spain, and 2 Institucio Catalana de Recerca i Estudis Avanc ¸ats (ICREA), Barcelona, Spain Abstract Two main etiological components are considered important in human autoimmune diseases including multiple sclerosis (MS), first the immunogenetic background and second environmental factors. Among the latter, infectious organisms are probably the most relevant, and epidemiological studies in MS firmly support that viral infections often precede disease exacerbations or the onset of MS. Infectious agents can contribute to disease development or phenotypic expression in different ways. Our focus will be directed on molecular mimicry, i.e. antigenic similarity between structural epitopes or peptide sequences from infectious organisms with those found in self proteins of the host. The intriguing concept of molecular mimicry has evolved substantially since its introduction over 20 years ago. We will summarize the most important developments and discuss puzzling questions, which remain open despite many claims that molecular mimicry is involved in the development of human autoimmune disease after infections or vaccinations. Keywords: Multiple sclerosis, antigen-presenting cells, toll-like receptors, T cells Introduction Infectious agents may lead to the onset or exacerbation of autoimmune diseases by different mechanisms. These include: (a) direct damage of a target tissue such as axons, myelin or oligodendro- cytes in MS and subsequent immune responses to the released autoantigens or (b) indirect damage via activated immune cells that secrete proinflammatory cytokines and radicals, alteration of the stimulatory requirements of immune cells such as increased expression of costimulatory molecules and expression of molecular structures that activate either antigen-presenting cells (APCs) via toll-like receptors (TLRs) or T cells via superantigens. Both types of damage can lead to bystander activation of innate and adaptive immune mechanisms, but also to specific immune responses via molecular mimicry between infectious agent and self protein. Only molecular mimicry will be addressed here, and we will focus on antigen-specific T cells due to space limitations. Molecular mimicry in the context of antibody- mediated immune responses refers primarily to the recognition of structural determinants on macromolecules such as lipids, proteins or sugar moieties [1–5]. Molecular mimicry and cross-recog- nition by T cells usually refers to the response to short peptide fragments that are generated from foreign or self proteins by the proteolytic machinery of APCs and then loaded onto to self major histocompatibility complex (MHC; human leukocyte antigens or HLA in humans) molecules. Since T cells do not recognize peptide in free form, but only as a complex with an MHC molecule, the distinction between structural or sequence mimicry is artificial, as will become clear below. Since the term molecular mimicry first appeared in the immunological literature over two decades ago [1–5], many studies have tried to establish its biological relevance in the context of the induction of autoimmune diseases or adverse events following vaccinations [6 – 8]. While there is no doubt that the ability for cross-recognition of antigens by both T cells and antibodies are essential properties of our adaptive immune system that assure protection from infections, it has become clear that molecular similarities between foreign and self proteins are usually not sufficient to lead to pathologic consequences. ISSN 0891-6934 print/ISSN 1607-842X online q 2006 Taylor & Francis DOI: 10.1080/08916930500484922 Correspondence: R. Martin, Institucio Catalana de Recerca i Estudis Avanc ¸ats (ICREA), Barcelona, Spain. E-mail: roland.martin@icrea.es Autoimmunity, February 2006; 39(1): 3–8