Guillain-Barré syndrome

Although the immune system evolved to protect the host from foreign infection, it can sometimes recognize and attack host tissues, a phenomenon known as autoimmunity. In addition to genetic factors, environmental elements such as viruses and bacteria are thought to play a role in the development of autoimmune diseases. The major hypothesized mechanism by which infection with these agents can lead to autoimmunity is termed molecular mimicry. Here, immune responses initiated against foreign antigens are cross-reactive with self-antigens. This is thought to occur especially it the foreign antigen is similar in structure or amino acid sequence to the self-antigen. In this review, we explore evidence for the role of molecular mimicry in neurological diseases. (Neurol Res 2005; 27: 726-733)

Keywords: Autoimmunity; disease models; immunology; molecuar mimicry

INTRODUCTION

Molecular mimicry is defined as immunologie crossreactivity between self-epitopes and epitopes from a foreign source. For many autoimmune diseases, mimicry between infectious agents and self-antigen is postulated to be a factor in disease initiation or progression, especially when disease occurrence is associated exclusively or mainly with infection by a specific pathogen.

Pathogen infection results in the recruitment and activation of the immune system, and molecular mimicry can involve several different arms of this system. Antigen-presenting cells (APCs) take up and process antigen for presentation to T cells. Antigen is processed into small peptides and loaded onto major histocompatibility complex (MHC) class I molecules for presentation to cytotoxic T (Tc) cells that are activated and capable of lysing infected target cells. Peptides are loaded onto MHC class Il activate helper T (Th) cells; the cytokines and chemokines produced by these cells can further activate other arms of the immune system. Antigen can also be recognized by B cells through cell surface B cell receptors (BCR). B cells recognize intact antigen and mature into plasma cells that secrete antibodies specific for the activating antigen.

Figure 1 illustrates the different ways that infection may cause activation of self-specific immune cells via molecular mimicry, leading to tissue destruction and eventually disease symptoms. The immune response is initiated in peripheral lymphoid compartments. Antigen from the invading pathogen is taken up by APCs and processed into peptide epitopes that are presented by MHC to T cells. Foreign epitopes similar in amino acid sequence to self-epitopes can result in the activation of T cells that cross recognize self-epitopes. Activated selfspecific Tc cells traffic across the blood-tissue barrier and cause tissue destruction by direct lysis of cells. Cytokines and chemokines produced by activated Th cells recruit and activate tissue-resident monocytes/macrophages (Mφ) that induce tissue destruction; in addition, the cytokines themselves are often damaging to tissues. Antigens present on the surface of the infecting pathogen that are structurally similar to self-antigen can activate B cells to produce self-reactive antibody. Antibody that binds to selftissue may directly interrupt the function of an organ; alternately, they can cause pathology by simultaneously binding to and activating Mφ. The self-antigen released following tissue destruction can be taken up by tissue-resident APCs and this allows the further propagation of the autoimmune response.

This review explores the putative role of molecular mimicry in human neurological diseases. The nervous system, particularly the brain, is thought to be a site of immune privilege where aggressive immune responses are limited1. Important in maintaining this privilege is the blood-brain barrier (BBB) which regulates the entry of substances and cells2. However, T cells upregulate certain adhesion molecules that allow them to adhere to and penetrate the BBB (Figure 1). It is less well understood how antibodies can traverse the BBB, but conditions produced during infection can disrupt the integrity of the BBB and allow it to become more 'leaky'. Inflammatory cytokines as well as oxidative stress are thought to do this3,4. In addition, the invading pathogens themselves may be responsible, as several studies have shown that human immunodeficiency virus (HIV) proteins can increase the permeability of the BBB in in vitro models1 . The same principles apply to the blood-nerve barrier (BNB) that protects the peripheral nervous system (PNS), except that the BNB may not be as tight as the BBB8.

Table 1 summarizes the neurological diseases for which molecular mimicry is thought to play a role. The evidence for this association is explained in detail below to illustrate the various ways that autoimmunity and molecular mimicry are studied. The role of molecular mimicry in animal models of these diseases is also discussed.

MULTIPLE SCLEROSIS

Multiple sclerosis (MS), one of the most prevalent neurological diseases, is characterized by a loss of the myelin sheath surrounding axons in the central nervous system (CNS)9. MS is generally considered to be an autoimmune disease as demyelination is associated with elevated levels of CD4^sup +^ Th cells specific for major myelin proteins10-12. Although it is not definitively known what triggers the development of MS, epidemiological evidence suggests that environmental factors play a role. There is a higher incidence of MS for people living in areas with moderate to cold climates (northern and central Europe, North America, Australia, New Zealand) than for people living in warmer climates (Asia, Africa). This susceptibility to disease remains in individuals that migrate from highrisk areas to low-risk areas, but only if relocation occurs after the age of 15 years13. These data and the fact that MS is rarely diagnosed in young children suggest that risk factors accrue for many years before onset of MS. Epidemics of MS have been reported in Iceland, the Faroe Islands and the Shetland-Orkney Islands14-16. Together, these studies provide strong circumstantial evidence that infectious agents, particularly those endogenous to areas of high risk in genetically susceptible individuals, may play an important role in triggering MS. Furthermore, it is well established that relapses or disease flares in patients diagnosed with relapsing-remitting MS are often associated with exogenous infections, particularly upper respiratory infections. In total, over 24 viral agents have been linked to MS17,18.

Several reports have shown that MS patients have activated T cells specific for myelin basic protein (MBP)19-21. Subsequently, eight pathogen-derived peptides were identified that were able to activate MBPspecific T cell clones derived from MS patients22. These molecular mimics included epitopes from herpes simplex virus, adenovirus and human papillomavirus. Significantly, these peptides were found to be presented most efficiently by subtypes of the HLA-DR2 MHC class Il molecule that have been associated by genetic studies with susceptibility to MS. Although these findings demonstrate that molecular mimicry is a feasible theory explaining the link between infection and MS, the search continues for direct evidence to support this phenomenon in human disease.

The most studied animal model of MS is experimental autoimmune encephalomyelitis (EAE), wherein rodents primed with myelin peptides in complete Freund's adjuvant develop paralytic disease23. T cells from mice primed with MBP87_99 were cross-reactive with peptides from six separate viruses and bacteria24. Similarly, Carrizosa et al., used T cell hybridomas specific for myelin proteolipid protein PLP139_151 to identify five peptide mimics derived from pathogenic agents25. Mice primed with these peptides developed T cell responses cross-reactive to PLP139-151. Subsequently, Olson et al, inserted one of the identified PLP139_151 mimics into the genome of the CNS tropic Theiler's murine encephalomyelitis virus (TMEV)26. This provided an MS model for mimicry directly in the context of infection rather than peptide priming in adjuvant. Mice infected with this virus developed an early-onset gait abnormality that correlated with Th1 responses to PLP139_151. Another experimental model of MS is the Semliki Forest virus (SFV) model. Infected C57/BL6 mice develop an acute encephalomyelitis followed after viral clearance by demyelination that appears to be T cell mediated27. Computer algorithms uncovered homology between an epitope in the SFV surface glycoprotein E2 and myelin oligodendrocyte glycoprotein MOG1 s-32(28). Priming mice with either MOG18_32 or its SFV-derived mimic produced an EAE-like disease whose histopathology resembled demyelination after SFV infection. These results suggest that molecular mimicry may be an important factor in demyelination, as seen in the SFV model of MS.

An interesting idea emerging from animal models of MS is the possibility that mimicry to self-epitopes can actually ameliorate disease as well as exacerbate it. Preimmunization with peptides derived from human papilloma virus and Bacillus subtilis was able to prevent EAE induction in mice29. EAE was also suppressed by treatment with butryophilin, a protein found in cows' milk30. In both studies, homology to myelin proteins allowed the mimics to act as altered peptide ligands. Possible mechanisms of disease inhibition include deviation of the immune response away from secretion of inflammatory cytokines that characterize the disease, anergy and/or induction of regulatory cells.

GUILLAIN-BARRE SYNDROME

Guillain-Barré syndrome (GBS) is an acute paralytic illness affecting both myelin and axons of the PNS8. Numerous studies have demonstrated anti-glycolipid antibodies in the serum of a proportion of patients31. There are several clinical variants of the disease, which can correlate with the specific type of glycolipid targeted by the antibodies. Glycolipids found most commonly in neural tissues include the gangliosides and cerebrosides. Onset of GBS occurs days or weeks after an infection or immunization32. Of the many types of vaccinations and microorganisms associated with the development of GBS, Campylobacter jejuni is the most extensively studied pathogen. In addition to being a common antecedent to GBS, there is mounting evidence suggesting that lipopolysaccharide (LPS) on the outer core of the bacteria can mimic host gangliosides. LPS from C. jejuni serotypes associated with GBS bears structural similarity to human gangliosides33,34, and priming of mice, rats and rabbits with C. jejuni LPS induced production of the corresponding anti-ganglioside antibodies35-37. Furthermore, several studies have shown that C. jejuni serotypes associated with GBS are more likely to contain ganglioside-like epitopes as compared with serotypes isolated from patients with uncomplicated C. jejuni-induced gastroenteritis, with one study linking ganglioside mimicry to specific GBS clinical subtypes38,39. Recently, Yuki et al, reported that rabbits immunized with C. jejuni LPS developed flaccid limb weakness that was associated with anti-GM1 antibodies and peripheral nerve pathology identical to that seen in GBS40. This report is thus far the most convincing animal model of pathogen-induced GBS.

Patients infected with Mycoplasma pneumoniae before the development of GBS often have antibodies to galactocerebroside. Antibodies to galactocerebroside can cross-react with glycolipids on M. pneumoniae41,42. Associated antibodies to the ganglioside GM1 have also been reported43. Similar to C. jejuni, patients infected with H. influenzae can develop antibodies to bacterial LPS that are cross-reactive with ganglioside44. In addition, the presence of a ganglioside-like structure on its surface suggests that molecular mimicry may explain its association with GBS induction45,46.

HUMAN T CELL LYMPHOTROPIC VIRUS TYPE I-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS

Human T cell lymphotropic virus type l-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive disease of the CNS that principally affects the thoracic area of the spinal cord47. The disease, which occurs in

MYASTHENIA GRAVIS

Myasthenia gravis (MG) is caused by an autoimmune attack of the acetylcholine receptor (AChR) of the neuromuscular junction leading to loss of motor control51. Sera from patients with MG contain antibodies that react to the α-subunit of AChR, which both directly down-regulate the receptor and compete with cholinergic agents for binding. The disease is also HLA-linked (associated with the expression of genes encoding particular subtypes of human MHC), suggesting a T cell component54,59. AChR-specific serum antibody from MG patients also cross-reacts with herpes simplex virus (HSV); an epitope on the type I glycoprotein of the virus shares significant structural homology to the host receptor56. Deitiker ef al. used previously identified antigenic regions on AChR to search a protein database for cross-reactive microbial peptidess57. Four microbial peptides per antigenic region were then synthesized and tested. The majority of human sera tested cross-reacted with one or more of the microbial peptides. Although significant as compared with healthy controls, the number of samples in these studies was small (11 or less), so the significance of the observed cross-reactivity to MG patients in general remains to be determined. Another intriguing study worth further investigation is the identification of a homologous T cell epitope in H. influenzae that was shown to be protective upon preimmunization in an experimental rat model of MCP"; this is similar to the 'protective' mimic peptides identified for the EAE model of MS discussed above.

LYME DISEASE (CHRONIC NEUROBORRELIOSIS)

Lyme disease is caused by the tick-borne spirochete Borrelia burgdorferi (Bb). Neurological complications, including myelitis and peripheral neuropathy, can occur in 10-12% of untreated patients and can arise even after antibiotic treatment59. It is thought that these symptoms may be autoimmune mediated; patients have been reported to have anti-axonal antibodies in their serum60 as well as antibodies and T cells specific for MBP in spinal fluid61,62. Patient serum that was reactive to axons and neuroblastoma cells was also cross-reactive with Bb flagellin60,63. It was subsequently discovered that an anti-flagellin monoclonal antibody cross-reacted with human heat shock protein 60 and with neuroblastoma cell lines64,65 and slowed neurite outgrowth in culture66. Antibody cross-reactivity has also been described between human CNS proteins and Bb outer surface protein A67. Using peptide libraries and biometric data analysis, several host neural peptides were identified as cross-reactive with Sb-specific T cells from cerebrospinal fluid (CSF) of a patient with chronic neuroborreliosis68. However, it is still uncertain whether chronic neuroborreliosis is due to postinfection autoimmunity or to persistent 86 infection69.

DISORDERS ASSOCIATED WITH ASTIBASAL GANGLIA (NEURONAL) ANTIBODIES

A growing group of movement and behavioral disorders are thought to be precipitated by infection with Streptococcus pyogenes (S. pyogenes), including Sydenham chorea, Tourette's syndrome and obsessivecompulsive disorder70,71. Patients with these disorders often have antibodies to the basal ganglia in the brain. Molecular mimicry between proteins on 5. pvogenes and basal ganglia remains the major postulated mechanism of disease induction, but direct evidence for this in humans is not extensive. Rabbits immunized with streptococcal M protein (the major virulence factor of Group A streptococci) developed antibodies crossreactive with several human brain proteins, and synthetic M-derived peptides inhibited brain crossreactive antibodies from the serum of a patient with Sydenham chorea72. An early paper demonstrated antibody cross-reactivity between S. pyogenes membrane and neuronal cytoplasm in patients with Sydenham chorea73. Using serum, CSF and monoclonal antibodies derived from Sydenham chorea patients, dual-specific antibodies were found that react with both the immunodominant carbohydrate epitope on S. pyogenes cell wall and with lysoganglioside GMI on the surface of neurons74.

Interestingly, the most direct evidence linking S. pyogenes infection with neurological diseases comes from mice primed with bacterial homogenate. A subset of infected mice acquired movement and behavioral disorders; these mice had antibody deposits in their brains and serum antibody reactive to several regions of the brain75. Despite the above-mentioned evidence, this area remains controversial as several studies have failed to decisively link S. pyogenes infection with this group of diseases76,77 or even decisively link ABGA with the development of some diseases in this group78,79.

HIV-ASSOCIATED NEUROLOGICAL DISEASES

Individuals infected with HIV are at increased risk of developing neurological abnormalities, the most frequent being AIDS dementia complex80. These symptoms may arise from the direct viral infection of CNSresident cells or bystander immune response to the virus, but several reports of antibodies directed against CNS antigens have raised the possibility of an autoimmune component81-83. Approximately one-half of AIDS patients have CSF antibodies directed against the HIV protein gp41(84). Yamada et al. demonstrated binding of human and rodent CNS astrocytes by monoclonal antibody raised against gp41(83). Alphaactinin was subsequently identified as the membraneassociated protein on astrocytes that can mimic gp41(85). In a similar fashion, a monoclonal antibody raised against the viral gp120 protein was cross-reactive with human brain proteins, including one protein whose expression appeared to be restricted to the CNS86.

CONCLUSIONS

The extent to which molecular mimicry plays a role in human disease is in debate. Microorganisms are capable of inducing autoimmune disease in several different ways. Immune cells targeting the pathogen may induce bystander damage to the surrounding tissue and lead to the generation of auto-reactive T cells (epitope spreading), or normally sequestered tissue antigens may be released during infection and activate a tissue-specific reaction17,103. Therefore, even if epidemiological studies show a strong association between infection with a specific pathogen and development of a disorder, it may be difficult to say for certain that mimicry is the major mechanism by which disease is induced, even if structural similarity is found between pathogen epitopes and self-epitopes. Furthermore, some viral infections are so prevalent in the population that it may be difficult to establish a solid link between pathogen and disease (e.g. rotavirus and uveitis, EBV and MS). Despite these uncertainties, the experimental evidence for this phenomenon in animal models is growing, and further study of the pathobiological consequences of mimicry-induced disease in these systems can be the major step in developing treatments for patients. These results suggest that molecular mimicry may be an important factor in the demyelination seen in the SFV.

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Anne M. Ercolini and Stephen D. Miller

Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA

Correspondence and reprint requests to: Anne M. Ercolini, Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E.Chicago Avenue, Chicago, IL 60611, USA. [s-d-miller@northwestern. edu] Accepted for publication July 2005.

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