Peptide motif analysis predicts lymphocytic choriomeningitis virus as trigger for multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic immune-mediated neurological disease that affects approximately 1.3 million people worldwide. It is generally accepted that both genetic and environmental factors are involved, but disease etiology remains poorly understood after decades of research. Recent advances have identified a number of genetic risk factors, with HLA DRB1*1501 haplotype continuing to provide the strongest association (Gourraud et al., 2012, Wu et al., 2010, Qiu et al., 2011, Link et al., 2012, Nolan et al., 2012). Yet, with approximately 9% of the world’s population carrying this allele (Solberg et al., 2008) and a global MS prevalence of 0.03% (World Health Organization, 2008), the proportion of DRB1*1501-positive individuals who develop MS is low, on the order of 0.3%. Among environmental factors, a viral agent has been postulated to instigate immune recognition of self-antigens (Fujinami, 2001), hypothetically by means of a mechanism termed “molecular mimicry” (Olson et al., 2001). Under this model, structural similarities between a viral peptide and a self-peptide cause activation of autoreactive T cells. Although a range of viruses has been considered over the past 50 years, including poliovirus, measles, rabies, herpes family viruses, mumps, canine distemper, and retroviruses (Kakalacheva et al., 2011), the identity of a causative virus remains elusive.
A popular candidate for an etiologic role in MS is Epstein–Barr virus (EBV), as antibodies against its nuclear antigen-1 (EBNA1) have been found in MS patients (Kakalacheva et al., 2011). However, the distribution of EBV worldwide does not provide a good fit to the epidemiology of MS. MS is concentrated in the temperate zone, with highest prevalence in Europe, Canada, the United States, and Australia (World Health Organization, 2008). Within the temperate zone, MS shows a gradient of prevalence that increases with latitude (Simpson et al., 2011) and is interspersed with regional pockets of exceptionally high prevalence. Although some of these differences can be explained by genetic factors, MS concordance across monozygotic twin pairs is low, ranging from 13% to 31%, based on studies in Canada, the United States, the British Isles, Finland, and Italy (Willer et al., 2003, Islam et al., 2006, Mumford et al., 1994, Kuusisto et al., 2008, Ristori et al., 2006, Sadovnick et al., 1993). This suggests that the environmental trigger for MS in genetically susceptible individuals is somewhat uncommon or has low infectivity. In contrast, the EBV seropositivity rate in adults is in excess of 90% (Kakalacheva et al., 2011). Further, exposure to EBV occurs earlier in life among children in developing countries, with universal seroconversion by age 3–4, whereas infection in developed countries often is delayed until adolescence (Hjalgrim et al., 2007). The high seroprevalence of antibodies against EBV, together with earlier exposure in countries with lower MS prevalence, are not fully consistent with the latitudinal gradient and low twin concordance rates seen for MS. In fact, some researchers suggest that EBV is a marker of chronic brain inflammation rather than causative per se (Castellazi et al., 2014).
The ideal candidate for an infectious trigger interacting with DRB1*1501 under the molecular mimicry hypothesis would satisfy both molecular biological and epidemiological criteria. The infectious agent would contain a peptide that binds to HLA in a similar way as the self-antigen and lies in a similar configuration. The bound peptide would activate the same T cell clones as those that recognize the self-antigen. The infectious agent would be somewhat uncommon or have low infectivity in order to explain the low MS concordance across monozygotic twin pairs. The agent would be most prevalent in the temperate geographic zone. Its distribution would be consistent with the latitudinal gradient observed for MS. It would show higher prevalence or infectivity in regions that report elevated incidence or prevalence of MS.
The aim of this investigation was to predict the viral peptide most closely matching these criteria. A set of proteins from viruses capable of causing encephalitis was scanned for regions of sequence similarity to myelin basic protein (MBP) residues 85–99. The peptides with highest sequence homology were then compared to MBP 85–99 on five scales representing characteristics predictive of protein binding and configuration. The highest scoring viral peptides were evaluated for similarity to a binding motif that has been determined experimentally to activate MBP-reactive T cell clones from MS patients with DRB1*1501 haplotype. Finally, the plausibility of the top predicted virus was evaluated through a review of its epidemiology and a comparison to the prevalence patterns observed for MS.
Section snippets
General
All computations were done with custom programs written in the R language (Hornik, 2014).
Viral proteins
A list of viruses capable of causing encephalitis was generated from review of medical reference texts. Encephalitogenic viruses endemic to equatorial regions were excluded as unlikely to be causative, since MS is most prevalent in the temperate zone. Protein sequences derived from the viral capsid or envelope or previously observed to be antigenic were selected for testing. Protein sequences were obtained
Viral peptide homology search
Ten viruses that have the potential to cause encephalitis in regions with a temperate climate were identified from a review of medical reference texts. From these 10 viruses, sequences for 17 proteins were obtained from the UniProt database and searched for regions of homology with MBP 85–99 using overlapping windows of varying lengths. These proteins are listed in Table 1.
Virtually all encephalitogenic viral proteins in the test set showed some degree of homology with MBP 85–99. The highest
Epidemiological evaluation
LCMV is a zoonotic agent of the family Arenaviridae. Its primary host is the common house mouse, Mus musculus (Lehmann-Grube, 1971), although other rodents, including pets, may become infected (Biggar et al., 1975). The virus persists in asymptomatic carrier mice and is discharged in nasal secretions, saliva, milk, blood, and urine (Lehmann-Grube, 1971, Traub, 1938, Childs et al., 1992). The distribution of LCMV-seropositive mice is uneven and locally clustered within a mouse population,
Discussion
While rapid advances have been made in identifying genetic factors associated with MS, the identity of an infective agent triggering the disease in genetically susceptible individuals remains uncertain. Many agents have been proposed, based primarily on their correlation with disease exacerbation or their isolation from CSF or brain tissue (Kakalacheva et al., 2011). Yet none of these have been linked to a specific causative mechanism, nor do they explain the prevalence patterns long observed
Acknowledgments
The author thanks Elizabeth A. Holly of the University of California – San Francisco, Brad Efron and Susan Holmes of Stanford University, Betz Halloran of the Fred Hutchinson Cancer Research Center, and Norm Breslow of the University of Washington for helpful comments and suggestions. Acknowledgments also go to the many biologists, physicians, epidemiologists, virologists, and other scientists whose meticulous work provided the foundation for this analysis, and to the patients, whose cause
References (68)
- et al.
Zoonotic aspects of arenavirus infections
Vet. Microbiol.
(2010) Can virus infections trigger autoimmune disease?
J. Autoimmun.
(2001)- et al.
Conformation of amino acid side-chains in proteins
J. Mol. Biol.
(1978) - et al.
IFN-β inhibits the ability of T lymphocytes to induce TNF-α and IL-1β production in monocytes upon direct cell-cell contact
Cytokine
(2001) - et al.
Viral triggers of multiple sclerosis
Biochim. Biophys. Acta
(2011) - et al.
Structural basis for the binding of an immunodominant peptide from myelin basic protein in different registers by two HLA-DR2 proteins
J. Mol. Biol.
(2000) - et al.
Epidemiology of multiple sclerosis in Croatia
Clin. Neurol. Neurosurg.
(2002) - et al.
Region with persistent high frequency of multiple sclerosis in Croatia and Slovenia
J. Neurol. Sci.
(2006) - et al.
Identification of MaTu-MX agent as a new strain of lymphocytic choriomeningitis virus (LCMV) and serological indication of horizontal spread of LCMV in human population
Virol
(1999) - et al.
Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies
Hum. Immunol.
(2008)
The DRB1 Val86/Val86 genotype associates with multiple sclerosis in Australian patients
Hum. Immunol.
Prediction of sequential antigenic regions in proteins
FEBS Lett.
T cell receptor recognition of self and foreign antigens in the induction of autoimmunity
Semin. Immunol.
Lymphocytic choriomeningitis outbreak associated with pet hamsters. Fifty-seven cases from New York State
JAMA
Congenital lymphocytic choriomeningitis virus infection: spectrum of disease
Ann. Neurol.
Type I IFN and TNFα cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance
Arthritis Res. Ther. 12
Epstein–Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies
J. Neuroinflammation
Lymphocytic choriomeningitis virus infection and house mouse (Mus musculus) distribution in urban Baltimore
Am. J. Trop. Med. Hyg.
Epidemiology of multiple sclerosis in south-western Sardinia
Mult. Scler.
A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis
Brain
Multiple sclerosis: autoimmunity and viruses
Curr. Opin. Rheumatol.
High prevalence of antibodies to lymphocytic choriomeningitis virus in a murine typhus endemic region in Croatia
J. Med. Virol.
Increased seroprevalence of lymphocytic choriomeningitis virus infection in mice sampled in illegal waste sites
Parasites Vectors
The hydrophobic moment detects periodicity in protein hydrophobicity
Proc. Natl. Acad. Sci.
The genetics of multiple sclerosis: an up-to-date review
Immunol. Rev.
Multiple sclerosis in the province of Ferrara: evidence for an increasing trend
J. Neurol.
The epidemiology of multiple sclerosis in three Australian cities: Perth, Newcastle and Hobart
Brain
Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition
J. Immunol.
Amino acid substitution matrices from protein blocks
Proc. Natl. Acad. Sci.
The epidemiology of EBV and its association with malignant disease
Differential twin concordance for multiple sclerosis by latitude of birthplace
Ann. Neurol.
Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group
N. Engl. J. Med.
Prediction of chain flexibility in proteins—a tool for the selection of peptide antigens
Naturwissenschafren
Cited by (12)
Arboviruses (Alphavirus) related to autoimmune rheumatic diseases: Triggers and possible therapeutic interventions
2023, Translational Autoimmunity: Volume 6: Advances in Autoimmune Rheumatic DiseasesEBV and MS: Major cause, minor contribution or red-herring?
2017, Multiple Sclerosis and Related DisordersCitation Excerpt :This was based on a convincing set of information concerning this virus. First, LCMV has greater structural homology to MBP (85–99) than the EBV peptide of EBNA-1 (86% vs 63%, respectively); Second, LCMV was the only viral protein tested that met all the cross-reactivity criteria (surface accessibility, antigenicity, flexibility, hydrophobicity, and hydrophilicity); Third, Hogeboom also argued that LCMV is more consistent with epidemiological features of MS compared to EBV (Hogeboom, 2015). These include, a higher prevalence farther from the equator, increased incidence of infection in regions of peak MS incidence and increased concentration of incidence in temperate regions (such as Europe and Southern Australia).
Corrigendum to ‘Multiple sclerosis: New insights and trends’ (Asian Pacific Journal of Tropical Biomedicine (2017) 7(5) (493–504) (S2221169116302453) (10.1016/j.apjtb.2016.03.009))
2017, Asian Pacific Journal of Tropical BiomedicineBioinformatics evaluation of the possibility of heat shock proteins as autoantigens in multiple sclerosis based on molecular mimicry hypothesis
2016, Journal of NeuroimmunologyCitation Excerpt :The infectious agent would possess a peptide that binds to HLA in a resembling manner as the self-antigen and lies in a similar configuration. The bound peptide would activate the same T cell clones as those that recognize the self-antigen (Hogeboom, 2015). HSPs can be considered as potential candidates for molecular mimicry and act as harmful auto-antigens.
Multiple sclerosis: New insights and trends
2016, Asian Pacific Journal of Tropical BiomedicineCitation Excerpt :MS starts attacks people from age 20–50 years old and the records investigated that females' attacks double than males' attacks [5,6]. Disseminated sclerosis and encephalomyelitis disseminate are two alternative names of MS. The MS is autoimmune disease combined both genetic and environmental factors such as viral-induced immune disturbances [7]. There are many types of MS, sometimes occurring in isolated neuron (relapsing type) or spreading to few or many neurons (progressive type) [8].
Peptide motif analysis predicts alphaviruses as triggers for rheumatoid arthritis
2015, Molecular ImmunologyCitation Excerpt :Further, there is evidence that IRF7 may inhibit CXCL13 (Esen et al., 2014); thus, STAT1 inhibition by alphaviruses could potentially act by downregulation of IRF7, allowing an excess of CXCL13 to accumulate and accelerate the production of both citrulline and NO. Further experimental studies would be required to confirm or refute such conjectures. In an analysis parallel to this one, the virus predicted as trigger for multiple sclerosis (MS) blocks induction of type 1 interferon (Hogeboom, 2015). Consistent with a reduced IFN level, a subset of MS patients shows symptomatic improvement when treated with exogenenous IFN-β, which then results in upregulation of IFN effector genes (Comabella et al., 2009; van Baarsen et al., 2008).