Immunology of Neurologic and Endocrine Diseases that Affect the Eye
Phyllis Eze
Sharon K. Sra
Karan K. Sra
Mitchell Friedlaender
Stefan D. Trocme
Immunologic mechanisms in neurologic and endocrine diseases have become a focus of interest and investigation. In multiple sclerosis (MS), an infectious agent may trigger an immune response that affects the tissues of the nervous system. In other disorders, autoantibodies or immune cells may interact with and destroy host tissues. Although the complete pathogenesis of these diseases has not been fully understood, innovative research has led to the development of new methods of diagnosis and treatment.
MULTIPLE SCLEROSIS
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. It is the most common neurologic disease affecting young adults (20–40 years of age) and occurs more commonly in whites, especially those of European descent. Women are also more affected than men. The victims of this progressive, devastating disease have debilitating symptoms that last for many years, with periods of remission and exacerbation. The symptoms depend on the area affected by demyelination. Patients may exhibit motor difficulties or disturbances in sensation, and/or ocular disturbances. Ophthalmic findings, such as optic neuritis and ocular motility disturbances, are often among the early signs of the disease. There may also be an association between MS and uveitis as well as retinal phlebitis.1,2,3 Some debate exists in more recent studies as to whether ocular findings such as retinal nerve fiber layer atrophy, as measured via optical coherence tomography, and the presence of uveitis or retinal periphlebitis are associated with disease activity in multiple sclerosis.4,5
MS is closely associated with geographic factors, with its prevalence increasing as the victim’s distance from the equator increases, north or south. The risk of MS seems to be determined by some event that takes place in early childhood. If an adult moves from a high-risk to a low-risk area, the chance of MS developing is that of the original environment. However, if the move is made before the age of 15, the risk is that of the new environment. An environmental factor of infectious viral nature has been implicated from such observations.
Immunopathology
Much interest has been focused on viruses as the possible cause of multiple sclerosis. The generation of a predominantly cytotoxic cellular immune response suggests a viral role in inducing demyelination. Several theories have been hypothesized regarding the mechanism of how viruses may cause MS. Possible mechanisms include direct viral damage of oligodendroglia with resultant myelin degeneration and/or damage to the central nervous system (CNS) by mediators and cytokines released from inflammatory cells.6,7 Viral-induced molecular mimicry of CNS proteins leading to the priming of autoimmune T cells specific for CNS antigens has also been recently proposed as a plausible mechanism.8,9
The human herpesvirus type 6 (HHV-6) continues to receive great attention as a possible cause of MS. HHV-6 is a neurotropic and latent lymphotropic virus affecting the CNS. It can remain latent or persistent and can be reactivated by stress or infection with other organisms.10 HHV-6 DNA has been found to be significantly more common in MS plaques compared to normal-appearing white matter, thus implicating a pathogenic role of HHV-6 in the development of MS.11 It has been hypothesized that T cells infected with HHV-6 have elevated proinflammatory gene expression, which would indirectly induce oligodendrocyte death.12 HHV-6 may also play a role in MS pathology by inducing molecular mimicry, potentially triggering autoimmunity and subsequent tissue damage associated with MS lesions.13 Other findings associating HHV-6 with MS include increased titers of antibody to HHV-6 in the serum and cerebrospinal fluid (CSF) of patients with MS and the demonstration of HHV-6 DNA in serum of MS patients.14,15 HHV-6 reactivation has also been correlated with MS exacerbation via modulation of IL-12 synthesis. Patients with active MS have been shown to exhibit significantly higher levels of serum IL-12 concentrations than patients with latent MS.16
Epstein-Barr virus (EBV), a ubiquitous virus and another member of the herpes virus family, has also been associated with an increased risk of MS. It is a highly prevalent human DNA virus infecting more than 90% of the world’s population. The current belief is that the EBV infection precedes the development of MS, with MS patients showing elevated titers to EBV years before developing any neurologic symptoms.17 Investigators have found that elevated serum levels of IgG antibodies to EBV viral capsid antigen and EBV nuclear antigens are the strongest predictors of the development of MS.18 Theories of pathogenesis of EBV in MS include antigenic mimicry, immortalization of B-cell clones, and cytotoxic T-cell dysfunction against virally infected B cells.19 One study has suggested that EBV nuclear antigen-1 (EBNA-1) may be a target of oligoclonal bands as the investigators observed a distinctive oligoclonal antigen-specific banding pattern for EBNA-1 in patients with MS.20
Other organisms that have also been suggested as the possible cause of MS include Chlamydia pneumoniae and the measles virus. There is considerable evidence that C. pneumoniae and measles-specific antibody titers are elevated in CSF of patients with MS.21,22,23,24
Although the diagnosis of MS is based primarily on clinical presentation, and there is no single test that is diagnostic for MS, MRI has been recognized by the International Panel on MS as the most sensitive paraclinical test used in the diagnosis of MS.25,26 The standard of lesion detection during the course of MS is the focal enhancement of lesions in MRI with fluid-attenuation inversion recovery (FLAIR). MS plaques commonly can be observed in the periventricular and/or juxtacortical white matter; however, they can be seen anywhere in the CNS.27 Changes in cerebral perfusion before the formation of plaques has also been detected by newer MRI techniques,28 perhaps aiding in early diagnosis of the disease. Spinal cord MRI has also been advocated; however, the correlation between MRI findings and clinical findings remains weak.
One of the most common immunologic abnormalities of MS is the increased synthesis of intrathecal immunoglobulins. The specificity of these antibodies, although speculated to be of viral origin, remains obscure. IgG oligoclonal bands, the most prevalent CSF abnormality, are detectable in more than 95% of patients with MS and are now included in the MS diagnostic criteria.29,30,31 The synthesis of IgG has been found in CSF lymphocytes obtained from patients with MS, and plaque lesions contain abnormally high levels of immunoglobulins.32,33 Although elevated levels of kappa and lambda free light chains correlate with MS, the prevalence of free kappa light chains may be more specific to support a clinical diagnosis of MS.34,35 All of these antibody studies suggest that there is a local synthesis of antibodies to an unknown antigen within the CNS.
Much of the evidence that the immune system participates in MS comes from the study of an experimental model of the disease known as experimental allergic encephalitis (EAE). This disease was first recognized approximately 40 years ago among humans who were given rabies vaccine containing rabbit brain cells. EAE has been produced in various laboratory animals by injecting them with CNS tissues in complete Freund adjuvant. Within 2 weeks of the injection, the animals begin to lose weight, develop paralysis, and ultimately die.
EAE is mediated by T lymphocytes and can be transferred passively with lymph node cells containing sensitized T cells. The protein responsible for sensitization is known as myelin basic protein. Some investigators have been able to identify leukocytes sensitized to myelin basic protein in patients with MS. Interestingly, myelin basic protein not only initiates EAE but also can prevent its initiation and can alleviate or even stop its symptoms after they have begun. Myelin basic protein has even been used to treat a few carefully selected cases of MS, but whether EAE is in fact a good model of MS is controversial.
Genetic factors may play an important role in MS. Although the exact gene remains unknown, it is known that the human leukocyte antigen (HLA) phenotype Dw2 is associated with increased risk for MS.36,37,38 Tumor necrosis factor-alpha (TNF-α) has also been implicated in MS by causing oligodendrocyte cell death. Recent studies have suggested that levels of p53 increase after stimulation with TNF-α, resulting in apoptosis of oligodendrocytes.39,40
Immunomodulators, specifically interferon beta (IFN-β) and glatiramer, have been demonstrated to be effective in the treatment of MS. Glatiramer, a synthetic copolymer with an amino acid composition based on the structure of myelin basic protein, has been shown to significantly reduce enhancing lesions as measured by MRI and may have some neuroprotective role.41,42,43 IFN-β has been established to significantly reduce the exacerbation rate in patients with relapsing-remitting MS and inhibit cognitive deteroriation.44,45,46 However, it has been postulated that prolonged treatment with IFN-β may induce neutralizing antibodies against IFN-β, thus reducing its effectiveness, but there is currently insufficient data to fully support this claim.47,48,49
OPTIC NEURITIS
Acute optic neuritis is more frequently associated with MS than with any other disease entity, although the reported incidence of the association varies widely.50 Some 50% of patients with MS will develop optic neuritis whereas about 20% of patients with MS will present initially with optic neuritis.51,52 On the other hand, the probability that patients with optic neuritis will develop MS appears to increase with time—the longer they are followed up, the more MS is found. In a study by the Optic Neuritis Study Group, the 10-year risk for the development of MS after an initial episode of acute optic neuritis was 38%, with the risk increasing to 56% in patients who had at least one lesion on MRI. Over time, the 15-year risk for the development of MS in patients with no lesion on MRI was 25% and 72% in patients with one or more lesions. In the absence of MRI-detectable lesions, certain factors were associated with substantially lower risk of developing MS including male sex, optic disc swelling, and certain atypical features of optic neuritis.53 Although the presence or absence of lesions on MRI clearly affects the risk of developing MS, a higher number of lesions (more than one) was not associated with an increased risk.54
Patients with optic neuritis usually present with sudden onset of monocular visual loss, pain with extraocular movement, and an afferent pupillary defect, unless the optic neuropathy is bilateral. The retrobulbar form of optic neuritis occurs more commonly and is associated with a normal optic disc appearance. Other conditions associated with optic neuritis besides MS include viral, vasculitic, or granulomatous processes.
Immunopathology
Oligoclonal IgG can be found in the CSF of 67% of patients with optic neuritis.55 Patients may have elevated intrathecal titers of viral antibody to measles, varicella zoster, rubella, and mumps.56 Many patients with optic neuritis also demonstrate free kappa and lambda oligoclonal bands in their CSF.57
The histocompatibility antigens HLA-A3, HLA-A7, and HLA-LD-a have been reported to be increased in optic neuritis and MS.58 In other studies, no significant differences were found in HLA distribution between patients with optic neuritis and controls.59,60 Such discrepancies are probably caused by the different criteria that have been used by different observers to establish the diagnosis of optic neuritis.
Optic neuritis has also been reported in association with the Guillain-Barré syndrome.61,62 In vitro cellular immunity to central and peripheral nervous tissue myelin has been demonstrated by the macrophage migration inhibition test.
Corticosteroid therapy in the treatment of optic neuritis has been evaluated in the Optic Neuritis Treatment Trial (ONTT). Patients treated with standard-dose oral prednisone did not improve vision. In fact, patients treated with oral prednisone were found to have an increased rate of new attacks of optic neuritis. Patients treated with intravenous (IV) corticosteroids followed by oral prednisone recovered vision more rapidly in the first 2 weeks, but there was no long-term benefit to vision. Visual recovery, therefore, could occur without any treatment. The recovery is rapid initially and visual improvement continues for up to 1 year.63
MYASTHENIA GRAVIS
Myasthenia gravis (MG) is a chronic disease characterized by abnormal fatigability of striated muscle. The disease may last for many years and includes several remissions. It may be generalized or limited to a single muscle group. Severe wasting and weakening may eventually develop, leading to death if the respiratory muscles become affected. Ptosis, the most common sign of MG, and extraocular muscle abnormalities are seen in these patients. Recent investigations have suggested that autoimmune factors are important in the pathogenesis of MG. Patients develop antibodies directed toward acetylcholine receptors at the neuromuscular junction of skeletal muscles.
Immunopathology
In 1960, Simpson64 suggested an autoimmune basis for MG because of its association with other autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, pemphigus, pernicious anemia, and myxedema. The coexistence of MG and thyroid autoimmune diseases has also been well recognized. Up to 10% of patients with MG develop Graves disease, whereas up to 0.2% of patients with Graves disease develop MG.65
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