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

Recently, much interest has focused on viruses as the possible cause of multiple sclerosis. The generation of a predominately 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.^3,4

The human herpesvirus type 6 (HHV-6) has recently received 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 persistant and can be reactivated by stress or infection with other organisms.⁵ 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.⁶ It has been hyposethized that T cells infected with HHV-6 have elevated proinflammatory gene expression, which would indirectly induce oligodendrocyte death.⁷ 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.^8,9 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.¹⁰

Epstein-Barr virus (EBV), also a member of the herpes family, has also been associated with an increased risk of MS. It is a highly prevalent virus occurring worldwide. It is believed that EBV infection precedes the occurrence of the development of MS. 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.¹¹ A study has also suggested that EBV nuclear antigen-1 (EBNA-1) may be a target of oligoclonal bands. The investigators observed a distinctive oligoclonal antigen-specific banding pattern for EBNA-1 in patients with MS.¹²

Other viruses have also been suggested as the possible cause of MS, including 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.^13–15

Although the diagnosis of MS is based primarily on clinical presentation, magnetic resonance imaging (MRI) has become an invaluable diagnostic aid in the investigation of MS. MRI was recently recognized by the International Panel on MS as the most sensitive paraclinical test used in the diagnosis of MS.¹⁶ The standard of lesion detection during the course of MS is the focal enhancement of lesions in a MRI with FLAIR. MS plaques commonly can be observed in the periventricular and/or juxtacortical white matter; however, they can be seen anywhere in the CNS.¹⁷ Changes in cerebral perfusion before the formation of plaques has also been detected by newer MRI techniques,¹⁸ 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 an elevated 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 95% of patients with MS.^19,20 The synthesis of IgG has been found in CSF lymphocytes obtained from patients with MS, and plaque lesions contain abnormally high levels of immunoglobulins.^21,22 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.^23,24 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 a variety of laboratory animals by injecting them with CNS tissues in complete Freund's 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.^25,26 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.²⁷

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.^28,29 IFN-β has been established to significantly reduce the exacerbation rate in patients with relapsing-remitting MS and inhibit cognitive deteriation.^30,31 However, prolonged treatment with IFN-β may induce neutralizing antibodies against INF-β, thus reducing its effectiveness.^32,33

Patients with optic neuritis usually present with sudden onset of monocular visual loss, pain with extraocular movement, and an afferent papillary 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. Causes of optic neuritis other than MS include viral, vasculitic, or granulomatous processes.

IMMUNOPATHOLOGY

Oligoclonal IgG can be found in the CSF of 67% of patients with optic neuritis.³⁶ Patients may have elevated intrathecal titers of viral antibody to measles, varicella zoster, rubella, and mumps.³⁷ Many patients with optic neuritis also demonstrate free kappa and lambda oligoclonal bands in their CSF.³⁸

The histocompatibility antigens HLA-A3, HLA-A7, and HLA-LD-a have been reported to be increased in optic neuritis and MS.³⁹ In other studies, no significant differences were found in HLA distribution between patients with optic neuritis and controls.^40,41 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.^42,43 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 Optic Neuritis Treatment Trial (ONTT). Patients treated with standard-dose oral prednisone did not improve vision. Further, 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 can occur without any treatment. The recovery is rapid initially and visual improvement continues for up to 1 year.⁴⁴

IMMUNOPATHOLOGY

In 1960, Simpson⁴⁵ 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 only up to 0.2% of patients with Graves disease develop MG.⁴⁶

Antibodies to acetylcholine receptors (AChR) are present in as many as 85% of patients with MG.⁴⁷ The injection of sera from myasthenic patients into experimental animals produce electrophysiologic changes characteristic of MG, including reduction of successive muscle action potentials and postjunctional sensitivity to acetylcholine.⁴⁸ The active fraction in the serum has been identified as IgG, and its effect can be increased by the third component of complement. This and other experiments suggest that MG is the result of an antibody-mediated autoimmune attack on acetylcholine receptors at the neuromuscular junction.

The neuromuscular defect in MG is a result of a reduced number of functional AChR occurring by three different mechanisms: (1) accelerated endocytosis and degradation of AchR; (2) antibody blockage of acetylcholine receptor sites on the AchR; and (3) complement-mediated damage to the postsynaptic membrane. The cross-linking of the Fab fragment of the antibody with the AChR stimulates the internalization process of endocytosis and degradation by lysosomal enzymes. This reduces the half-life of AChR. In MG, the antibodies are directed against the a subunit of the AChR. By blocking the binding of the acetycholine to AChR, the antibody also inhibits the function of the AChR. The Ab-AChR complex initiates a complement-mediated destruction of postsynaptic membrane, resulting in a reduction of junctional folds.⁴⁹

Abnormalities of the humoral immune system are probably the most important abnormalities in MG, but the role of cellular immunity has also been undergoing investigation and is becoming increasingly more apparent. Peripheral lymphocytes from myasthenic patients are stimulated when exposed to purified acetylcholine receptor in vitro.⁵⁰ Delayed hypersensitivity to muscle and thymic antigens often occurs in patients with MG, and approximately half of all myasthenic patients show cellular immunity to myelin basic protein.^51,52 Lymphocytes from affected patients are cytotoxic to fetal muscle tissue when stimulated with phytohemagglutinin.⁵³ All of these investigations show the possible importance of cellular immunity to patients with MG, and the possible importance of an autoimmune mechanism is suggested by the fact that immune complexes containing IgG and C3 have been localized to the motor end plates of such patients.⁵⁴

Thymic abnormalities are reported in 80% of myasthenic patients: 70% have thymic hyperplasia with increased numbers of germinal centers, and 10% have true thymomas. These hyperplastic thymuses contain high levels of B lymphocytes. Two-thirds of the patients who undergo thymectomy have complete or partial remission of MG, suggesting that the thymus is a site for the production of a neuromuscular blocking agent. Soluble fractions of thymus gland show immunologic cross-reactivity with acetylcholine-receptor protein.

HLA typing of patients with MG shows that they have HLA-B3 more often than do normal subjects.⁵⁵ This association is particularly prevalent in females in whom the disease begins early and correlates with the presence of thymic follicular lymphoid hyperplasia. HLA-B3 is increased in males in whom the disease begins late and is common among myasthenics with thymomas.

Plasmapheresis has been used with considerable success in severe cases of MG. Presumably, this technique removes acetylcholine receptor antibodies or immune complexes that contribute to the patient's symptoms.

IMMUNOPATHOLOGY

Patients with diabetes show a greater than normal frequency of autoimmune disease of the thyroid gland, the adrenal glands, and the gastric mucosa (pernicious anemia). Thyroid microsomal antibody and gastric parietal cell antibody have been found, respectively, in 20% and 16% of patients with diabetes mellitus.⁵⁶ These antibodies, and antibodies to pancreatic islet cells, are particularly common in patients with juvenile diabetes mellitus of recent onset. The islet cell antibodies may precede the onset of diabetes by several years. Whether these antibodies and other autoantibodies are concerned in the genesis of diabetes or are a cause of diabetogenic islet cell damage is presently uncertain. Antibodies to pancreatic islet cells are IgG and are found by indirect immunofluorescence in patients with insulin-dependent diabetes.⁵⁷ In vitrectomy specimens from humans, there may be deposition of immunoglobulins and complement components.⁵⁸ However, there does not seem to be any unique pattern or one that differs from nondiabetic proliferative retinopathies. Unusual deposition patterns for complement components have been noted in the diabetic cornea.⁵⁹

Delayed hypersensitivity to crude pancreatic islet antigen in diabetic patients can be shown by the macrophage migration inhibition test.⁶⁰ Transient impairment of glucose tolerance occurs when mice are immunized with mouse pancreatic extract. Immunized animals show delayed hypersensitivity skin test reactions and inhibition of macrophage migration when tested with pancreatic islet antigen.

The histocompatibility antigen HLA-B8 is found with greater frequency in patients with insulin-dependent diabetes, Graves disease, and Addison disease than in normal subjects, and a high frequency of HLA-Bwl5 has been found in insulin-dependent diabetic subjects.^61,62

Because insulin is a foreign protein, it can evoke an antibody response, and repeated injections of insulin into humans can give rise to antibody formation.⁶³ (Beef insulin is apparently more antigenic for humans than pork insulin.) The immunologic response to insulin may take the form of an allergic reaction or of increasing resistance to the effects of insulin. The allergic reaction is usually a generalized urticaria, presumably mediated by IgE. Chronic insulin resistance seems to be caused by insulin-binding IgG antibodies.⁶³ Insulin resistance and allergy rarely occur in the same patient. Insulin antibody levels tend to be lower in pregnant patients than in others.⁶⁴

The vasoproliferative effects of insulin have been studied by Shabo et al.,^65,66 who suggest that vascular proliferation in diabetes may be caused by the immunogenic nature of insulin as well as to the intrinsic vascular abnormality of diabetics. Insulin injected intravitreally into sensitized monkeys causes proliferation of preretinal vessels and connective tissue. It also causes rubeosis iridis, vascular hemorrhages, vessel tortuosity, and the beading of vessels. In the development of this experimental neovascularization, inflammation may be a significant factor.

IMMUNOPATHOLOGY

Many lines of evidence point to the importance of autoimmunity in the pathogenesis of Graves disease. Thyroid antibodies are present in virtually all patients and in 50% of their relatives.^68,69 Other autoantibodies and certain autoimmune disorders may be found as well. Various immunoglobulins occur within the stroma of the thyroid gland, and lymphocytes and plasma cells infiltrate the thyroid gland and retro-orbital tissues.

Early studies of autoimmune thyroiditis suggested that thyroglobulin was a secluded antigen during fetal life; hence, no tolerance to it was developed. If the thyroid gland were damaged by trauma or infection, however, cytotoxic thyroid antibodies could be formed. This theory is no longer tenable, because although circulating thyroglobulin has been found in 60% of normal individuals, thyroglobulin antibodies are rarely found unless there is thyroid disease.⁷⁰ Experimental thyroiditis can be produced by immunizing animals with thyroid tissue emulsified in Freund's adjuvant, and it can then be transferred passively with immune serum or lymphocytes.⁷¹ Transfer with lymphocytes suggests that cell-mediated hypersensitivity may play a role in the development of the experimental disease.

The most compelling evidence that hyperthyroidism has an immunologic basis comes from studies of long-acting thyroid stimulator (LATS). When serum from patients with diffuse thyroid hyperplasia is injected into mice or guinea pigs, a prolonged stimulation of the animals' thyroid glands occurs. LATS, the substance responsible for this phenomenon, can be isolated in the gammaglobulin fraction of human serum. It is precipitated and neutralized by anti-IgG and is probably either an immunoglobulin or a soluble complex of thyrotropin and its antibody. LATS is found in 50% to 80% of patients with Graves disease.⁷²

Other immunoglobulin-containing substances have also been identified in the sera of patients with Graves disease. One such substance, known as LATS protector (LATS-p), can block the binding of LATS to a human thyroid protein fraction.⁷³ Human thyroid-stimulating substance stimulates intracellular colloid droplet formation in human thyroid slices and is found in virtually all LATS-negative patients with Graves disease.⁷⁴ Complement-fixing antibodies to thyroid microsomes are frequently found in hyperthyroidism and may increase the function of thyroid cells. As mentioned earlier, antibodies to thyroglobulin, predominantly of the IgG and IgA classes, may also be found.

Antibodies to eye muscle are found in 70% of patients with Graves disease,⁷⁵ and there can be a cross-reactivity between eye muscle antibodies and thyroid antigen.⁷⁶ IgE-positive material has been found in association with the majority of leukocytes and with muscle fibers found in orbital tissue.⁷⁷

The role of cell-mediated immunity may also be important in thyroid disorders. Lymphocytes from patients with Graves disease undergo blast transformation and produce migration inhibition factor (MIF) in response to human thyroid antigen (except during remissions of the disease when MIF is not produced).^78,79 MIF is also produced in response to liver mitochondrial antigens in patients with either Graves disease or Hashimoto thyroiditis, perhaps caused by cross-reactivity between the thyroid and the liver or by the presence of more than one population of sensitized T lymphocytes.

MIF production to retro-orbital muscle antigen can be demonstrated in patients with exophthalmos who have no evidence of either thyroid disease or cellular immunity to thyroid antigens.⁸⁰ It would appear, therefore, that antigens concerned with the production of the exophthalmos are separate from those responsible for the thyroid abnormality. Exophthalmos may be a separate autoimmune process that overlaps the process concerned with the hyperthyroidism of Graves disease.⁸¹ The cause of the exophthalmos in Graves disease is unknown, but immune factors may participate in its pathogenesis. Exophthalmos-producing factor (EPF) is derived from thyrotropin and binds to membrane receptors of retro-orbital tissues. This binding affinity is enhanced by serum immunoglobulins from patients with severe degrees of Graves ophthalmopathy.⁸² Both thyroglobulin and immune complexes bind to human extraocular muscle membrane.⁸³ Lymphatic connections between the thyroid gland and the orbits may exist so that exophthalmos in Graves disease could be the result of stimulation by thyroid glandular antigens or antibodies and their complexes. These elements, interacting with orbital muscle receptors, could then produce muscle injury and inflammation.⁸³

Unlike normal lymphocytes, the lymphocytes from patients with Graves disease can be stimulated by phytohemagglutinin (PHA) to produce thyroid-stimulating immunoglobulins.⁸¹ Because PHA stimulates only T lymphocytes, and because T lymphocytes cannot produce immunoglobulins, PHA must turn-on helper T lymphocytes, which in turn stimulate B lymphocytes to produce these immunoglobulins. It has been suggested that in Graves disease there is an inherited defect of immunologic control over a specific forbidden clone of helper T lymphocytes. If this clone appeared by normal, random mutation, it might not be destroyed. It would then proceed to interact with thyroid antigen, stimulate the replication of the forbidden T lymphocytes, and cooperate with B lymphocytes in the production of thyroid-stimulating immunoglobulins. Thus both cellular and humoral immune mechanisms would have roles to play in this hypothetical model.

Certain genetic factors may also participate in the pathogenesis of Graves disease. In whites, more patients with the disease have the histocompatibility antigen HLA-B8 than do control subjects, and in Japanese, more persons with the disease have HLA-Bw40 than do controls.⁸⁴ The concordance rate in monozygotic twins is high. The prevalence of Graves disease is much greater in women than in men, with the X chromosome or estrogens possibly playing a role in its development.

1. Kerrison JB, Flynn T, Green WR: Retinal pathologic changes in multiple sclerosis. Retina 14(5):445–451, 1994

2. Bachman DM, Rosenthal ARBBA: Granulomatous uveitis in neurological disease. Br J Ophthalmol 69(3):192–196, 1985

3. Stohlman SA, Hinton DR: Viral Induced Demyelination. Brain Pathol 11(1):92–106, 2001

4. Scarisbrick IA, Rodriguez M: Hit-Hit and Hit-Run: viruses in the playing field of multiple sclerosis. Curr Neurol Neurosci Rep 3(3):265–271, 2003

5. Swanborg RH, Whittum-Hudson JA: Human herpesvirus 6 and Chlamydia as etiologic agents in multiple sclerosis- a critical review. Microbes Infect 4:1327–1333, 2002

6. Cermelli C, Berti R, Soldan SS, et al: High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection. J Infect Dis 187(9):1377–1387, 2003

7. Kong H, Baerbig Q, Duncan L, Shepel N, Mayne M: Human herpesvirus type 6 indirectly enhance oligodendrocyte cell death. J Neurovirol 9(5):539–550, 2003

8. Wilborn F, Schmidt CA, Jendroska K, Oettle H, Siegert W: A potential role for human herpesvirus type 6 in nervous system disease. J Neuroimmunol 49(1–2):213–214, 1994

9. Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Killian JM, Zhang JZ: Detection of viral DNA and immune responses to the human herpesvirus 6 101-kilodalton virion protein in patients with multiple sclerosis and in controls. J Virol 76(12):6147–6154, 2002

10. Chapenko S, Millers A, Nora Z, Logina I, Kukaine R, Murovska M: Correlation between HHV-6 reactivation and multiple sclerosis disease activity. J Med Virol 69(1):111–117, 2003

11. Levin LI, Munger KL, Rubertone MV, et al: Multiple sclerosis and Epstein-Barr virus. JAMA 290(2):192–193, 2003

12. Rand KH, Houck H, Denslow ND, Heilman KM: Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173(1):32–39, 2000

13. Krametter D, Niederwieser G, Berghold A, et al: Chlamydia pneumoniae in multiple sclerosis: humoral immune responses in serum and cerebrospinal fluid and correlation with disease activity marker. Mult Scler 7(1):13–18, 2001

14. Derfuss T, Gurkov R, Then BF, et al: Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response. Brain 124(Pt 7):1325–1335, 2001

15. Sindic CJ, Monteyne P, Laterre EC: The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 54(1–2):75–80, 1994

16. McDonald WI CA, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS: Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50(1):121–127, 2001

17. Pretorius PM, Quaghebeur G: The role of MRI in the diagnosis of MS. Clin Radiol 58(6):434–448, 2003

18. Wuerfel J B-SJ, Brunecker P, Aktas O, McFarland H, Villringer A, Zipp F: Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain 1–9, 2003

19. Link H, Kostulas V: Utility of isoelectric focusing of cerebrospinal fluid and serum on agarose evaluated for neurological patients. Clin Chem 29(5):810–815, 1983

20. Andersson M, Alvarez-Cermeno J, Bernardi G, et al: Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 57(8):897–902, 1994

21. Link H, Muller R: Immunoglobulins in multiple sclerosis and infections of the nervous system. Arch Neurol 25(4):326–344, 1971

22. Mehta PDMJ, Tourtellotte WW: Oligoclonal IgG bands in plaques from multiple sclerosis brains. Neurology 32(4):372–376, 1982

23. Fagnart OC SC, Laterre C: Free kappa and lambda light chain levels in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J Neuroimmunol 19(1–2):119–132, 1988

24. Rudick RA FC, Breton D, Williams GW: Relative diagnostic value of cerebrospinal fluid kappa chains in MS: comparison with other immunoglobulin tests. Neurology 39(7):964–968, 1989

25. Hillert J: Human leukocyte antigen studies in multiple sclerosis. Ann Neurol 36(Suppl):S15–S17, 1994

26. Hillert J KT, Vrethem M, Fredrikson S, Ohlson M, Olerup O: The HLA-Dw2 haplotype segregates closely with multiple sclerosis in multiplex families. J Neuroimmunol 50(1):95–100, 1994

27. Ladiwala ULH, Antel JP, Nalbantoglu J: p53 induction by tumor necrosis factor-alpha and involvement of p53 in cell death of human oligodendrocytes. J Neurochem 73(2):605–611, 1999

28. Comi GFM, Wolinsky JS: European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 49:290–297, 2001

29. Dhib-Jalbut S: Glatiramer acetate (Copaxone) therapy for multiple sclerosis. Pharmacol Ther 98(2):245–255, 2003

30. Fernandez O, Arbizu T, Izquierdo G, et al: Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study. Acta Neurol Scand 107(1):7–11, Jan

31. Barak YAA: Effect of interferon-beta-1b on cognitive functions in multiple sclerosis. Eur Neurol 47(1):11–14, 2002

32. Bellomi FSC, Tomassini V, Gasperini C, Paolillo A, Pozzilli C, Antonelli G: Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years. Neurol Sci 215(1–2):3–8, 2003

33. Sorensen PSRC, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N: Danish Multiple Sclerosis Study Group. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 362(9391):1184–1191, 2003.

34. McAlpine D: Optic (retrobulbar) neuritis. In: Lumsden CE, Acheson ED, eds. Multiple Sclerosis: A Reappraisal. Churchill Livingstone: Edinburgh, 1972:148–163

35. Beck RW, Trobe JD, Moke PS, et al: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 121(7):944–949, 2003

36. Soderstrom M: The Clinical and paraclinical profile of optic neuritis: a prospective study. Ital J Neurol Sci 16(3):167–176, 1995

37. Frederiksen JL, Sindic CJ: Intrathecal synthesis of virus-specific oligoclonal IgG, and of free kappa and free lambda oligoclonal in acute monosymptomatic optic neuritis. Comparison with brain MRI. Mult Scler 4(1):22–26, 1998

38. Frederiksen JL: Can CSF predict the course of optic neuritis? Mult Scler 4(3):132–135, 1998

39. Platz P, Ryder LP, Nielsen LS, Svejgaard A, Thomsen M, Wolheim MS: HL-A and idiopathic optic neuritis. Lancet 1(7905):520–521, 1975

40. Stendahl LLH, Moller E, Norrby E: Relation between Genetic markers and oligoclonal IgG in CSF in optic neuritis. J Neurol Sci 27(1):93–98, 1976

41. Arnason BG, Fuller TC, Lehrich JR, Wray SH: Histocompatibility types and measles antibodies in multiple sclerosis and optic neuritis. J Neurol Sci 22(4):419–428, 1974

42. Behan PO, Lessell S, Roche M: Optic neuritis in the Landry-Guillain-Barre-Strohl syndrome. Br J Ophthalmol 60(1):58–59, 1976

43. Nadkarni N, Lisak RP: Guillain-Barre syndrome (GBS) with bilateral optic neuritis and central white matter disease. Neurology 43(4):842–843, 1993

44. Beck RW, Cleary PA, Trobe JD, et al: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med 329(24):1764–1769, 1993

45. Simpson JA: Myasthenia Gravis: A new hypothesis. Scot Med J 5:419, 1960

46. Yaman A, Yaman H: Ocular myasthenia gravis coincident with thyroid ophthalmopathy. Neurol India 51(1):100–101, 2003

47. Vincent A, McConville J, Farrugia ME, et al: Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 998:324–335, 2003

48. Pagala MK, Tada S, Namba T, Grob D: Neuromuscular transmission in neonatal mice injected with serum globulin of myasthenia gravis patients. Neurology 32(1):12–17, 1982

49. De Baets M, Stassen MH: The role of antibodies in myasthenia gravis. J Neurol Sci 202(1–2):5–11, 2002

50. Richman DP, Patrick J, Arnason BG: Cellular immunity in myasthenia gravis. Response to purified acetylcholine receptor and autologous thymocytes. N Engl J Med 294(13):694–698, 1976

51. Goust JM, Castaigne A, Moulias R: Delayed hypersensitivity to muscle and thymus in myasthenia gravis and polymyositis. Clin Exp Immunol 18(1):39–47, 1974

52. Kott E, Rule AH: Myasthenia gravis. Cellular response to basic myelin protein compared with cellular and humoral immunity to muscle antigens. Neurology 23(7):745–748, 1973

53. Armstrong RM, Nowak RM, Falk RE: Thymic lymphocyte function in myasthenia gravis. Neurology 23(10):1078–1083, 1973

54. Engel AG, Lambert EH, Howard FM: Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlations. Mayo Clin Proc 52(5):267–280, 1977

55. Fritze D, Herrman C, Naeim F, et al: HL-A antigens in myasthenia gravis. Lancet 1:240, 1974

56. Nerup J, Binder C: Thyroid, gastric and adrenal auto-immunity in diabetes mellitus. Acta Endocrinol 72(2):179–186, 1973

57. MacCuish AC, Irvine WJ, Barnes EW, Duncan LJ: Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet 28(2):1529–1531, 1974

58. Baudouin C, Gordon WC, Fredj-Reygrobellet D, et al: Class II antigen expression in diabetic preretinal membranes. Am J Ophthalmol 109(1):70–74, 1990

59. Weiss JS, Sang DN, Albert DM: Immunofluorescent characteristics of the diabetic cornea. Cornea 9(2):131–138, 1990

60. Nerup J, Andersen OO, Egeberg J, Poulsen JE: Anti-pancreatic cellular hypersensitivity in diabetes mellitus. Diabetes 20(6):424–427, 1971

61. Nerup J, Platz P, Andersen OO, et al: HL-A antigens and diabetes mellitus. Lancet 2(7885):864–866, 1974

62. Cudworth AG, White GB, Woodrow JC, Gamble DR, Lendrum R, Bloom A: Aetiology of juvenile-onset diabetes. A prospective study. Lancet 1(8008):385–388, 1977

63. Berson SA, Yalow RS: Insulin in blood and insulin antibodies. Am J Med 40:676, 1966

64. Exon PD, Dixon K, Malins JM: Insulin antibodies in diabetic pregnancy. Lancet 2(7873):126–128, 1974

65. Shabo AL, Maxwell DS: Insulin-induced immunogenic retinopathy resembling the retinitis proliferans of diabetes. Trans Am Acad Ophthalmol Otolaryngol 81(3 Pt 1):497–508, 1976

66. Shabo AL, Maxwell DS, Shintaku P, Kreiger AE, Straatsma BR: Experimental immunogenic rubeosis iridis. Invest Ophthalmolo Vis Sci 16(4):343–352, 1977

67. Kendall-Taylor P: The pathogenesis of Graves' ophthalmopathy. Clin Endocrinol Metab 14(2):331–349, 1985

68. Bastenie PA, Ermans AM: Thyroiditis and thyroid function: Clinical, morphological, and physiopathological studies. In International Series of Monographs in Pure and Applied Biology, Modern Trends in Physiological Sciences. Vol 36. Oxford: Pergamon Press, 1972

69. Volpe R, Farid NR, Von Westarp C, Row VV: The pathogenesis of Graves' disease in Hashimoto's thyroiditis. Clin Endocrinol 3:239, 1974

70. Roitt IM, Torrigiani G: Identification and estimation of undegraded thyroglobulin in human serum. Endocrinology 81(3):421–429, 1967

71. Nakamura RM, Weigle WO: Passive transfer of experimental autoimmune thyroiditis from donor rabbits injected with soluble thyroglobulin without adjuvant. Int Arch Allergy Appl Immunol 32(5):506–520, 1967

72. McKenzie JM: Humoral factors in the pathogenesis of Graves' disease. Physiol Rev 48(1):252–310, 1968

73. Adams DD, Kennedy TH: Evidence to suggest that LATS protector stimulates the human thyroid gland. J Clin Enocrinol Metab 33(1):47–51, 1971

74. Onaya T, Kotani M, Yamada T, Ochi Y: New in vitro tests to detect the thyroid stimulator in sera from hyperthyroid patients by measuring colloid droplet formation and cyclic AMP in human thyroid slices. J Clin Enocrinol Metab 35(5):859–866, 1973

75. Kahaly G, Moncayo R, Stover C, Beyer J: Relationship of eye muscle antibodies with HLA phenotypes and thyroid-stimulating immunoglobulins in endocrine orbitopathy. Res Exp Med 191(2):137–144, 1991

76. Weightman D, Kendall-Taylor P: Cross-reaction of eye muscle antibodies with thyroid tissue in thyroid-associated ophthalmopathy. J Endocinol 122(1):201–206, 1989

77. Raikow RB, Dalbow MH, Kennerdell JS, et al: Immunohistochemical evidence for IgE involvement in Graves' orbitopathy. Ophthalmology 97(5):629–635, 1990

78. Ehrenfeld EN, Klein E, Benezra D: Human thyroglobulin and thyroid extract as specific stimulators of sensitized lymphocytes. J Clin Enocrinol Metab 32(1):115–116, 1971

79. Lamki L, Row VV, Volpe R: Cellular immunity in Graves disease and Hashimoto's disease as shown by migration inhibition factor (abstr). Clin Res 20:431, 1972

80. Munro RE, Lamki L, Row VV, Volpe R: Cell-mediated immunity in the exophthalmos of Graves' disease as demonstrated by the migration inhibition factor (MIF) test. J Clin Enocrinol Metab 37(2):286–292, 1973

81. Volpe R: The pathogenesis of Graves' disease. Compr Ther 2:42, 1976

82. Rosenberg IN: Euthyroid Graves' disease. N Engl J Med 296:223, 1977

83. Kriss JP, Konishi J, Herman M: Studies on the pathogenesis of Graves' ophthalmopathy (with some related observations regarding therapy). Recent Prog Horm Res 31:533–566, 1975

84. Weise W, Wenzel KW: Distribution of HLA-antigens in Graves' disease and in autonomous adenoma of the thyroid. Diabete Metab 2(3):163, 1976