Letter to the editor

Abstract

The recent study by de Jong et al., demonstrating an association between dog exposure in early adolescence and increased MS risk adds to the evidence supporting our hypothesis that canine distemper virus (CDV) plays a role in MS etiology. However, we respectfully take issue with the authors’ assertion that “the common practice to vaccinate dogs against CDV combined with no apparent decrease in MS incidence has further diminished [the likelihood that CDV is associated with increased MS risk]” ( de Jong et al., 2019 de Jong HJI. Tremlett H Zhu F Ascherio A Munger KL. Animal exposure over the life-course and risk of multiple sclerosis: a case-control study within two cohorts of US women. Mult. Scler. Relat. Disord. 2019; 27: 329 Google Scholar ). In fact, as we and others have demonstrated, dog vaccination rates are highly variable worldwide, and many dogs, after receiving initial vaccination, are not revaccinated on time, if at all. Furthermore, it is estimated that more than half of dog CDV infection is subclinical ( Daniela and Gerhauser, 2019 Daniela K Gerhauser I. Interferon-stimulated genes—mediators of the innate immune response during canine distemper virus infection. Int. J. Mol. Sci. 2019; 20: 1620 Google Scholar ). The authors proceed to cast doubt on CDV as a causative factor in MS based on insufficient epidemiological evidence. Yet they do not address the sizable body of other circumstantial evidence implicating CDV. Briefly, this evidence includes the following: •Canine distemper virus causes disease in dogs and other animals that is remarkably similar to multiple sclerosis in humans. As Klutz and Gerhauser state, “the demyelinating canine distemper virus-leukencephalitis represents a translational animal model for multiple sclerosis….” Furthermore, we now know that CDV afflicts a wide range of species and that “the last decade has seen the effect of numerous CDV outbreaks in various wildlife populations.” ( Evermann and Kennedy, 2011 Evermann J Kennedy M. Viral infections. Small Animals Pediatrics. Elsevier, St. Louis, MO2011: 119-129 Google Scholar ) - and it is now known that these wildlife populations include various primate species ( Sakai et al., 2013 Sakai K Nagata N Ami Y Seki F Suzaki Y et al. Lethal canine distemper virus outbreak in cynomolgus monkeys in Japan in 2008. J. Virol. 2013; 87: 1105-1114 Google Scholar ; Beinekeab et al., 2015 Beinekeab A Baumgärtnerab W Wohlsein P Cross-species transmission of canine distemper virus—an update. One Health. 2015; 1: 49-59 Google Scholar ). •Humans make antibodies to canine distemper virus, indicating that the virus spreads from animals to humans. •Measles virus, which others have implicated as a possible causative agent in MS, is strikingly similar to CDV. Multiple sclerosis patients have high levels of antibodies to both measles virus and CDV, and infection with one virus may result in partial immunity against the other ( Cook et al., 1979 Cook S Dowling P Russell W Neutralizing antibodies to canine distemper and measles virus in multiple sclerosis. J. Neurol. Sci. 1979; 41: 61-70 Abstract Full Text PDF PubMed Scopus (39) Google Scholar ; de Vries et al., 2014 de Vries R Ludlow M Verburgh R van Amerongen T Yüksel S et al. Measles vaccination of nonhuman primates provides partial protection against infection with canine distemper virus. J. Virol. 2014; 88: 4423-4433 Google Scholar ). However, one key area where the viruses differ is in the region of the hemagglutinin (H) gene. Critically, we have shown that MS patients, in comparison to the general population, have elevated levels of antibodies to a peptide sequence present in the surface CDV hemagglutinin (H) protein but not to the corresponding measles virus peptide - providing powerful evidence of a unique association between CDV infection and MS ( Rohowsky-Kochan et al., 1995 Rohowsky-Kochan C Dowling P Cook S Canine distemper virus-specific antibodies in multiple sclerosis. Neurology. 1995; 45: 1554-1560 Google Scholar ). Reply to letter to the editorMultiple Sclerosis and Related DisordersVol. 34PreviewDrs. Cook and Dowling raise some interesting points regarding CDV and MS. However, as they recognize, the evidence presented is circumstantial. While the role for other viruses cannot be discounted, there is substantial epidemiologic evidence that the Epstein-Barr virus has a causal role in MS development (Ascherio and Munger, 2016). Primary infection with EBV in healthy young adults is associated with a strong increased risk of MS (Levin et al., 2010) and individuals who remain seronegative for EBV infection have a near zero risk of MS (Ascherio and Munger, 2007). Full-Text PDF