ReviewViruses and vitamin D in the etiology of type 1 diabetes mellitus and multiple sclerosis
Introduction
Autoimmune diseases arise from an overactive immune response against substances or tissues normally present in the body. The target organs are quite specific, i.e., beta cells of the pancreas in diabetes, connective tissue in rheumatoid arthritis, and basement membrane of lung and kidney in Goodpasture's disease. For many autoimmune diseases the onset occurs in adolescence or young adulthood and affects females more frequently than males. The exact etiology of autoimmune diseases is unknown. Genetic predisposition may exist for some, but many researchers acknowledge that environmental factors are necessary to trigger onset of illness (Cho and Gregersen, 2011). The low concordance rates in monozygotic twin and geographic distribution of disease point toward environmental factors, including viruses, as cofactors in the etiology and pathogenesis of autoimmune diseases.
How might viral infection trigger autoimmunity? Several mechanisms have been described to explain how viruses might activate and expand T cells and other components of the immune system to initiate and/or promote autoimmune diseases. Two of the most cited mechanisms are referred to as “molecular mimicry” and “bystander activation.” Molecular mimicry occurs when a T- or B-cell receptor recognizes a viral peptide that is structural similar to a self-peptide. The immune response initially directed at the virus spreads to tissues presenting the cross-reactive peptide. Bystander activation refers to the activation and/or expansion of an immune response directed at tissues altered by inflammation surrounding a viral infection (Munz et al., 2009, Delogu et al., 2011).
We will focus on two autoimmune diseases that have unique epidemiologic characteristics related to seasonality and geographic variation. The increased incidence of type 1 diabetes mellitus and multiple sclerosis in northern latitudes relative to equatorial areas raises the possibility that infectious agents and vitamin D deficiency may play a role in etiology. Like others, we postulate that the cause(s) of selected autoimmune diseases may be complex and multifactorial. We will invoke Kenneth Rothman's sufficient-component causal model to explain the etiology of diabetes and multiple sclerosis. In the model he suggests that the cause of a disease is not due to a single agent or virus, and testable by Koch's postulates. Rather, Rothman defines a sufficient cause as a set of minimal conditions and events that invariably produce disease (Rothman, 1976). We will review the epidemiology of type 1 diabetes mellitus and multiple sclerosis, list hypotheses of causation, and suggest research approaches to test them.
Section snippets
Type 1 diabetes mellitus (DM1)
Type 1 diabetes mellitus (DM1) is the most common life-threatening endocrine disorder of children and young adults worldwide and its incidence appears to be increasing. Originally coined juvenile diabetes or insulin-dependent diabetes, DM1 has traditionally been considered a pediatric disease. In a recent multicenter American study the incidence of DM1 was approximately 20 per 100,000 among youth less than 20 years of age; no gender differences were noted (SEARCH, 2007). There are currently
Multiple sclerosis
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS). Approximately 350,000 individuals in the United States and over 1 million individuals worldwide are affected by MS, with the most frequent onset of clinical symptoms between the ages of 18 and 45 (Anderson et al., 1992). It is characterized by focal inflammation, destruction of myelin, and axon degeneration in a heterogeneous clinical pattern. Commonly the clinical course is
Discussion
No single virus has yet been proven solely responsible for the development for any single autoimmune disease, including diabetes or multiple sclerosis. It is more likely that an underlying genetic predisposition allows vulnerability to multiple environmental triggers. Factors may act sequentially over time to modify risk in genetically susceptible individuals. One environmental factor may act during childhood, and a second factor later in life. This concept follows along the lines established
Acknowledgments
We thank Drs. Robert Vigersky, Jeffrey Millegan, Lynn Levin, and Jack Lewi for comments on a draft of the manuscript. The views expressed are those of the authors and do not represent the official policy or position of the U.S. Department of Defense, the U.S. Navy, the Uniformed Services University of the Health Sciences, or the U.S. Government.
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