Why do MS patients have an immune response in their CNS

Mrs. Smith, a 26-year-old interpreter, was in good health until one morning she noticed a loss of vision in her left eye. Her physician referred her to a neurologist, who found that her eye movement was normal and not accompanied by any pain. The visual acuity in her eye was 20/100 and in her right eye 20/20. Her retina was normal, and a detailed neurologic examination also proved normal. The neurologist diagnosed optic neuritis (inflammation of the optic nerve). Her family history was informative, however, in that her mother had severe multiple sclerosis (MS) and was permanently disabled, and a magnetic resonance imaging (MRI) brain scan was ordered. Mrs. Smith was given a 5-day course of intravenous corticosteroids, and her vision returned to normal over the next 3 weeks. The MRI scan revealed multiple lesions in the white matter of the brain under the cortex and around the ventricles. Intravenous injection of gadolinium, a contrast agent that leaks from blood vessels in recently inflamed tissue, showed that some of the brain lesions were probably of recent origin. The neurologist told Mrs. Smith that she had a high probability of developing MS and advised her to return for frequent neurologic examinations. She remained well for a further 3 years and then developed weakness of the muscles on the left side of her face that are innervated by the seventh cranial nerve. A repeat MRI scan with gadolinium enhancement showed new lesions in the left middle cerebellar peduncle and in the pons. Cerebrospinal fluid (CSF) was obtained by lumbar puncture. It contained 28 mg dl−1 protein (normal) and 8 lymphocytes ml−1 (normal 0–3 ml−1). At this point a firm diagnosis of MS was made. Despite the normal level of protein in the CSF, the IgG content was raised. On electrophoresis, discrete bands of IgG were observed, indicating clonal expansion of restricted B-cell populations in the central nervous system (CNS). Another 5-day course of corticosteroids was administered intravenously, and her symptoms improved. Weekly intramuscular injections of interferon (IFN)-β were started to prevent progression of the disease. Mrs. Smith did well for 3 more years, after which she developed a weakness in her left leg and left hand. Her speech became slurred. She developed nystagmus (rapid uncontrolled horizontal jerking eye movements when attempting to fix the gaze on something) and ataxia (wide-based staggering gait). She was given another course of corticosteroids, after which her symptoms improved, but 8 months later they recurred. The injections of IFN-β were stopped and she was put on high doses of cyclophosphamide and corticosteroids at monthly intervals. After 3 months of this therapy, the cyclophosphamide and corticosteroid injections were gradually reduced to every 12 weeks. Her neurological examination became normal and no new lesions were observed on gadolinium-enhanced MRI. Five years later, she was diagnosed with thyroid cancer. She underwent surgery to remove the thyroid and during recovery from the surgery, she suffered from a new episode of MS and the MRI confirmed a new area of damage in her brain. Case Questions 1. Is it a coincidence that this patient was a woman? (1 point) 2. Why do MS patients have an immune response in their CNS? Against which molecule and cells is it directed? (1 point) 3. Oligoclonal immunoglobulins were found in Mrs. Smith’s central nervous system. How do you explain this? (1 point) 4. If MS patients have inflammation in their brain. Which cytokines could you measure as indicators of an inflammatory response in the brain? (1 point) 5. Mrs. McKenzie was treated with corticosteroids, cyclophosphamide, and IFN-β. What was the aim of this therapy? (1 point) 6. An attempt has been made to treat MS patients with IFN-γ. Can you predict what the outcome was and why? (1 point) 7. Which experimental animal model/s are available to investigate MS? Explain how do they work, what endpoints are measured and what are the differences with human MS? (1 points) 8. Do microglial cells play a role in MS immune responses? If so, what is their role? (1 point) 9. What is the prevalence of MS around the world? Is it evenly distributed? If not, which countries/ethnicities have the highest prevalence of MS in the world? (1 point) 10. Why do you think surgery/cancer treatment may have triggered a new MS episode in this patient? (1 point)

 

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