Jane E. Libbey

Autistic disorder and viral infections

Autistic disorder (autism) is a behaviorally defined developmental disorder with a wide range of behaviors. Although the etiology of autism is unknown, data suggest that autism results from multiple etiologies with both genetic and environmental contributions, which may explain the spectrum of behaviors seen in this disorder. One proposed etiology for autism is viral infection very early in development. The mechanism, by which viral infection may lead to autism, be it through direct infection of the central nervous system (CNS), through infection elsewhere in the body acting as a trigger for disease in the CNS, through alteration of the immune response of the mother or offspring, or through a combination of these, is not yet known. Animal models in which early viral infection results in behavioral changes later in life include the influenza virus model in pregnant mice and the Borna disease virus model in newborn Lewis rats. Many studies over the years have presented evidence both for and against the association of autism with various viral infections. The best association to date has been made between congenital rubella and autism; however, members of the herpes virus family may also have a role in autism. Recently, controversy has arisen as to the involvement of measles virus and/or the measles, mumps, rubella (MMR) vaccine in the development of autism. Biological assays lend support to the association between measles virus or MMR and autism whereas epidemiologic studies show no association between MMR and autism. Further research is needed to clarify both the mechanisms whereby viral infection early in development may lead to autism and the possible involvement of the MMR vaccine in the development of autism.

Molecular Mimicry as a Mechanism of Autoimmune Disease

A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

Axonal Injury Heralds Virus-Induced Demyelination

Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theilers murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I(+) microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.

Innate but not adaptive immune responses contribute to behavioral seizures following viral infection.

Purpose:  To examine the role of innate immunity in a novel viral infection–induced seizure model.

Seizures following picornavirus infection

Purpose: We demonstrate the establishment and characterization of a novel virus infection‐induced seizure model in C57BL/6 mice.

Molecular Mimicry in Multiple Sclerosis

One of the most common demyelinating central nervous system (CNS) diseases in humans is multiple sclerosis (MS). The disease can be very debilitating with vision loss, motor and sensory disturbances, and cognitive impairment. The clinical course may present as a relapsing‐remitting disease course, a progressive disease course, or a combination thereof. The etiology of MS is unknown. Though many viruses have been shown to be associated with MS, no one virus has ever been demonstrated to be the cause of MS. In addition, MS is thought to have an autoimmune component. Molecular mimicry is one hypothesis put forth which could reconcile the diverse pathology and etiology of MS. Molecular mimicry occurs when peptides from pathogens share sequence or structural similarities with self‐antigens. Infection with various pathogens, each with its individual molecular mimic to a CNS antigen, may explain the inability of investigators to link one specific virus to MS. Molecular mimicry may be mediated through human leukocyte antigen class I‐ and class II‐restricted T cells and antibodies, which may explain the diversity in phenotype. Aspects of molecular mimicry will be discussed in relation to each of these immune system components. Examples of various molecular mimics will be discussed with a particular focus on the CNS and MS. Molecular mimicry alone may not be able to induce disease; priming of the immune system by infection with a pathogen that carries a molecular mimic to self may have to be followed by a later nonspecific immunologic challenge in order for disease to be initiated. Recent research into this priming and triggering of disease will be discussed in relation to an animal model for MS.

Alterations in cytokine but not chemokine mRNA expression during three distinct Theiler's virus infections

DA, GDVII and H101 are neurovirulent strains of Theilers murine encephalomyelitis virus that cause very different neuropathology and CNS disease when inoculated into SJL/J mice. DA virus causes a chronic demyelinating disease, GDVII virus causes an acute fatal polioencephalomyelitis, and H101 virus causes an acute pachymeningitis with hydrocephalus. Performing RNase protection assays, we detected the same pattern of chemokine (RANTES, MCP-1, IP-10, MIP-1beta, MIP-1alpha and MIP-2) mRNA expression in brain and spinal cord during all three infections. In contrast, IFN-beta and IL-6 mRNA were highly expressed only in GDVII virus infection, whereas high levels of LT-alpha mRNA were only found during DA virus infection. Our study demonstrates that proinflammatory cytokines are involved in the neuropathogenesis of CNS disease and modulate the acute and chronic process underlying different pathologic features of disease.

Interleukin-6, Produced by Resident Cells of the Central Nervous System and Infiltrating Cells, Contributes to the Development of Seizures following Viral Infection

ABSTRACT Cells that can participate in an innate immune response within the central nervous system (CNS) include infiltrating cells (polymorphonuclear leukocytes [PMNs], macrophages, and natural killer [NK] cells) and resident cells (microglia and sometimes astrocytes). The proinflammatory cytokine interleukin-6 (IL-6) is produced by all of these cells and has been implicated in the development of behavioral seizures in the Theilers murine encephalomyelitis virus (TMEV)-induced seizure model. The assessment, via PCR arrays, of the mRNA expression levels of a large number of chemokines (ligands and receptors) in TMEV-infected and mock-infected C57BL/6 mice both with and without seizures did not clearly demonstrate the involvement of PMNs, monocytes/macrophages, or NK cells in the development of seizures, possibly due to overlapping function of the chemokines. Additionally, C57BL/6 mice unable to recruit or depleted of infiltrating PMNs and NK cells had seizure rates comparable to those of controls following TMEV infection, and therefore PMNs and NK cells do not significantly contribute to seizure development. In contrast, C57BL/6 mice treated with minocycline, which affects monocytes/macrophages, microglial cells, and PMNs, had significantly fewer seizures than controls following TMEV infection, indicating monocytes/macrophages and resident microglial cells are important in seizure development. Irradiated bone marrow chimeric mice that were either IL-6-deficient mice reconstituted with wild-type bone marrow cells or wild-type mice reconstituted with IL-6-deficient bone marrow cells developed significantly fewer behavioral seizures following TMEV infection. Therefore, both resident CNS cells and infiltrating cells are necessary for seizure development.

Role of Pathogens in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS). Although the etiology of MS is unknown, genetic and environmental factors play a role. Infectious pathogens are the likely environmental factors involved in the development of MS. Pathogens associated with the development or exacerbation of MS include bacteria, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, the Staphylococcus aureus-produced enterotoxins that function as superantigens, viruses of the herpes virus (Epstein-Barr virus and human herpesvirus 6) and human endogenous retrovirus (HERV) families and the protozoa Acanthamoeba castellanii. Evidence, from studies with humans and animal models, supporting the association of these various pathogens with the development and/or exacerbation of MS will be discussed along with the potential mechanisms including molecular mimicry, epitope spreading and bystander activation. In contrast, infection with certain parasites such as helminthes (Schistosoma mansoni, Fasciola hepatica, Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercolaris, Enterobius vermicularis) appears to protect against the development or exacerbation of MS. Evidence supporting the ability of parasitic infections to protect against disease will be discussed along with a brief summary of a recent Phase I clinical trial testing the ability of Trichuris suis ova treatment to improve the clinical course of MS. A complex interaction between the CNS (including the blood-brain barrier), multiple infections with various infectious agents (occurring in the periphery or within the CNS), and the immune response to those various infections may have to be deciphered before the etiology of MS can be fully understood.

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

ABSTRACT Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theilers murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.