Annikki
Senior Member
- Messages
- 146
Sorry for the cumbersome title, but the following study is definitely worth looking at. I love it because it reflects my idea that an external trigger, i.e. an entity with different DNA (or RNA) from your own triggers ME. Many of us got ME after having a "run of the mill" viral infection. I never thought that just a coincidence. I probably never will.
This study I'm sharing looks at MS and other autoimmune diseases of the brain. It doesn't mention CFS/ME, but I cannot help think it relates in a critical way. LOL, I found it down a winding path which began with reading about the structure of coronavirus from a great article in the Washington Post. Somehow I wound up looking up glycoproteins and autoimmunity after this and found this gem of a study:
This study I'm sharing looks at MS and other autoimmune diseases of the brain. It doesn't mention CFS/ME, but I cannot help think it relates in a critical way. LOL, I found it down a winding path which began with reading about the structure of coronavirus from a great article in the Washington Post. Somehow I wound up looking up glycoproteins and autoimmunity after this and found this gem of a study:
See text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971377/Virus infection, antiviral immunity, and autoimmunity
Daniel R. Getts,1 Emily M. L. Chastain,1 Rachael L. Terry,1 and Stephen D. Miller1
Author information Copyright and License information Disclaimer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971377/
The publisher's final edited version of this article is available at Immunol Rev
See other articles in PMC that cite the published article.
Go to:
Summary
As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.
Keywords: autoimmune disease, molecular mimicry, epitope spreading, bystander activation, T-cell receptor affinity, microbial superantigens
Go to:
Introduction
The ability to recognize self and non-self is a pillar of the adaptive immune response, with deficiencies in these mechanisms leading to increased susceptibility to infection and cancer, or conversely, aberrant immune responses resulting in immunopathology and autoimmunity (1–4). Genome-wide association studies have identified polymorphisms in numerous genes associated with immune activation and regulation predisposing to development of autoimmune disease (5, 6); however, manifestation of autoimmunity may only occur after infection with certain pathogens (7). A precise set of pathogens as well as distinct autoimmune-associated immune responses remain to be elucidated (8). To the contrary, data suggest that autoimmunity may result from numerous immune pathways triggered by a plethora of microorganisms (9). In the case of multiple sclerosis (MS), viruses such as Epstein–Barr virus (EBV) and measles virus (MV) have been implicated in humans; however, a precise causal relationship between these ubiquitous viruses and MS has yet to be elucidated (10, 11). On the other hand, there are clear examples of rodent neurotropic viruses, such as Theiler’s murine encephalomyelitis virus (TMEV) and mouse hepatitis virus (MHV), which infect neurons and other cells within the central nervous system (CNS) resulting in deregulation of antiviral immune mechanisms and culminate in development of autoimmunity (12–14). It remains to be confirmed whether exposure of the brain parenchyma to pathogenic infection is critical for autoimmune induction in humans, or whether infection of the periphery is a sufficient trigger. However, following TMEV infection, viral persistence in the CNS is an essential requirement for autoimmunity induction (15). Using such surrogate virus-induced rodent MS models, numerous aberrant innate and adaptive immune responses that are associated with or support the breakdown of self-tolerance and subsequent propagation of autoimmunity have been discovered. These pathways, including how pathogens circumvent or trigger certain innate immune system functions, as well as the intricate interplay between professional antigen-presenting cells (APC) and elements of the cellular immune response, are discussed in this review. Based on our experience and that of others, it is clear that infection-triggered autoimmune disease is the result of dynamic, interrelated, and non-mutually exclusive mechanisms. Understanding how viral infection results in autoimmunity must be viewed as a process that can occur through numerous simultaneous and/or sequential pathways, which depend on the nature of the pathogen as well as the genetics and the immune response of the host.
Go to:
Viruses associated with CNS autoimmunity
While this review focuses on viruses associated with triggering CNS autoimmune disorders, there are a number of bacteria and other microbes that have been associated with peripheral autoimmune disease, for example the Group A Streptococcus family can cause heart, joint, or brain autoimmunity (16). A significant amount of our current understanding of how self-tolerance is overcome comes from viral models of CNS infection and other rodent models of MS.
Infection of the CNS represents the failure of critical immune surveillance mechanisms and is most common in immune-compromised individuals, often times leading to morbidity in survivors (17–19). Numerous highly pathogenic viruses, including those from the paramyxoviridae, flaviviridae, and herpesviridae families are known to infect cells within the brain (Table 1); however, only a handful including EBV, MV, and HTLV-1 have been linked with MS or other demyelinating disorders (10, 11, 20).
Table 1
Select viruses associated with central nervous system autoimmune diseases
Virus Species Family Associated with autoimmune disease Mechanism Reference(s) Measles virusHumanParamyxoviridaeYes – multiple sclerosis (MS)Bystander activation*
Molecular mimicry*(11, 31)Epstein–Barr virusHumanHerpesviridaeYes – MSBystander activation*
Molecular mimicry*(56, 134)HTLV-1HumanRetroviridaeYes – HTLV-1-associated myelopathy/tropical spastic paraparesisBystander activation*
Molecular mimicry*(20)Theiler’s murine encephalomyelitis virus (TMEV)MousePicornoviridaeYes – TMEV-induced demyelinating diseaseMolecular mimicry
Epitope spreading bystander activation(35, 37, 116)Japenese encephalitis virus (JEV)MouseFlaviviridaeYesMolecular mimicry(43)Sindbis virusMouseFlaviviridaeYesMolecular mimicry(163)Semliki Forest virusMouseFlaviviridaeYesMolecular mimicry(41, 42)WNVHuman/MouseFlaviviridaeYesImmune decoy*
Bystander activation*(57, 158)
Open in a separate window
*Suggested or proposed mechanism.
The association of EBV with MS remains controversial. EBV is a double-stranded DNA human herpes virus that primarily not only infects B cells (21) but can also infect endothelial cells (22). Approximately 95% of the general population is infected with EBV, and EBV remains latent within B cells for the life of the individual (23, 24). The incidence of MS is increased in those who are seropositive for EBV compared to those who are seronegative (25, 26). Also, there is evidence supporting a potential role for molecular mimicry in activation of myelin-specific T cells in MS patients (27). However, considering the large number of seropositive patients that do not have MS and the difficulty in isolating infected B cells from the CNS, the link is arguably weak (25, 28–30).
In addition to EBV, MS patients generally have higher titers of MV, an RNA virus (31). Unlike EBV, a cause-and-effect relationship for MV has been shown, with 1 in 1000 patients likely to suffer a myelin basic protein (MBP)-specific postinfectious encephalomyelitis (32).
While HTLV-1 is not directly associated with MS, infection can result in a very similar disease, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/ TSP) (20). Autoimmunity and molecular mimicry are believed to play a role in the pathogenesis of HAM/TSP, as antibodies cross-reactive to both HTLV-1 and neurons have been found in HAM/TSP patients (33).
Although direct evidence linking certain CNS infections with autoimmune disease in humans is correlative and non-definitive, strong support for virus-triggered CNS autoimmunity is derived from animal models. This includes infection with TMEV, Semliki Forest virus (SFV), Sindbis virus (SV), and MHV (34). Furthermore, using such tools as tetramers and transgenic mice, it has been elegantly shown that TMEV infection of the brain, as an example, is a critical step in the initiation of full-blown T-cell-mediated autoimmunity (13, 35)
While RNA viruses have been primarily used to investigate CNS infection and the development of autoimmunity, they represent a group of diverse pathogens, which are capable of eliciting an array of innate and adaptive immune responses. Using TMEV, we and others have unearthed numerous mechanisms through which viral infection of the CNS can initiate autoimmunity (35–37). TMEV is a single strand RNA virus of the picornovirdae family. A number of strains of TMEV have been characterized and differ in infectivity and pathogenicity. The GDVII strain is extremely neurovirulent and causes acute encephalitis typically resulting in mortality (38). The BeAn and DA strains, however, are able to persist in the CNS after their initial acute encephalitis and cause chronic immune-mediated demyelinating disease (39).
The ability of TMEV to chronically persist is evidently required for the eventual induction of CNS autoimmunity. A natural murine pathogen, TMEV is transmitted via the fecal-oral route (40). In laboratory models, the virus is usually injected into the CNS via intracranial injection. In many strains of mice, including C57BL/6, the innate immune and adaptive immune responses adequately resolve the infection with no lasting sequelae. However, in other strains that are deficient in certain elements of the immune response, such as SJL/J mice that lack natural killer dendritic cells (E. M. L. Chastain, D. R. Getts, S. D. Miller, unpublished observation), the virus establishes a long-term persistent infection within the CNS. In such situations, the infection leads to a chronic antiviral immune response, which at some point moves from a centrally focused antiviral response, to one that also targets myelinated axons. At this point, a fulminant autoimmune disorder characterized by CNS-infiltrating myelin specific CD4+ T cells develops and is referred to as TMEV-induced demyelinating disease (TMEV-IDD).
In addition to TMEV, the positive-stranded RNA alphavirus SFV results in acute encephalitic disease that lasts 7 days, after which time the virus is cleared. Interestingly, a week to several weeks later, cytotoxic CD8+ T cells as well as antibodies reactive to MBP and MOG epitopes are found in the brain and periphery. Together these cause CNS demyelination that is observed clinically with symptoms such as aberrant gate, reduced activity, and even death (41, 42). Similarly to SFV virus, in which autoimmunity appears secondary to the primary infectious process, SV infection results in rapid paralysis within 6 days post infection. In the case of this positive-stranded RNA alphavirus, the initial immune responses are specific for SV; however, auto-specific immunity arises via epitope spreading (34).
JEV is a positive-sense strand RNA flavivirus that is closely related to WNV and St. Louis encephalitis virus. JEV spreads to the CNS after amplification in peripheral lymph nodes and can infect both neurons and astrocytes. Clinical symptoms in mice occur within the first week of infection and results in abnormal gait and hind limb paralysis (43, 44). Autoimmunity may contribute to disease progression as both MPB-specific antibodies and T cells were observed in infected mice (43). In addition to experimental models of JEV infection, clinical myasthenia gravis development has been described in patients previously exposed to WNV. Together the data show that there are a number of viruses that may increase, if not directly trigger autoimmunity in humans.
Go to:
General pathogenesis of viral infection of the brain
Although plastic and physiologically well supported, the neuron, the central player in the organization of the CNS, is not readily replenished after development early in life (45). Thus, it is not surprising that infection of CNS, especially the brain, represents a potentially life-threatening event. The outcome of CNS infection is dependent on the interaction of the immune system, the nervous system, and the invading pathogen. A battle driven by the primal evolutionary need for survival of both virus and host, ultimately determines the fate of the challenged host. In many cases, this interaction has been optimized over time by coevolution of virus and host, resulting in the survival of both at the population level. However, in individual cases, the outcome may be dire, with, at best survival with severe neurological sequelae, and at worst, significant neurochemical disturbance leading to coma and death (46, 47). Historically, the CNS has been described as an immune privileged organ; however, it is now well known that the brain is more than capable of eliciting an internal immune response, as well as calling upon peripheral immune elements as needed.
The development of autoimmunity as result of CNS infection requires a significant number of events to occur (Fig. 1). The mechanisms by which viruses gain access to the CNS, directly/indirectly cause cell damage and death, activate the immune response, and initiate autoreactive responses are discussed here.
Open in a separate window
Fig. 1
Schematic outlining the potential pathway(s) through which infection may trigger autoimmunity.
Last edited by a moderator:
