History of MS

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History of MS

  1. 1. History of MS <ul><li>1396: Saint Lidwina van Schiedam </li></ul><ul><ul><li>Relapsing and progressive neurological illness </li></ul></ul><ul><li>1838: Robert Carswell </li></ul><ul><ul><li>First pathologic drawing of what would later be known as MS </li></ul></ul>
  2. 2. History of MS <ul><li>1868: Jean-Martin Charcot </li></ul><ul><ul><li>Framed the disease and thoroughly described the clinical and pathologic features of MS </li></ul></ul><ul><ul><li>Utilized the previous observations of Carswell, Curveilhier, Hall, Frerichs, and others </li></ul></ul><ul><ul><li>Called it “sclerose en plaque” or disseminated sclerosis </li></ul></ul><ul><ul><li>Charcot’s triad: scanning speech, nystagmus, and intention tremor </li></ul></ul>
  3. 3. History of MS <ul><li>1873: William Moxon </li></ul><ul><ul><li>Called the disease insular sclerosis and described 8 features: </li></ul></ul><ul><ul><ul><li>Paralytic weakness, nystagmus, speech abnormalities, and changes in mental state </li></ul></ul></ul><ul><ul><li>1871: William Hammond </li></ul></ul><ul><ul><ul><li>Published a chapter “Multiple Cerebral Sclerosis” </li></ul></ul></ul><ul><li>1878: Dr. Ranvier discovered myelin </li></ul>
  4. 4. History of MS <ul><li>ARNMD report of 1922 </li></ul><ul><ul><li>Brought together many of the observations made by previous clinicians and pathologists </li></ul></ul><ul><ul><li>Thought the disease was initially inflammatory and later degenerative </li></ul></ul>
  5. 5. History of MS <ul><li>1948: genetic theory </li></ul><ul><ul><li>23% concordance rate in identical twins </li></ul></ul><ul><ul><li>10 times more common in families with MS </li></ul></ul><ul><li>Immunological theory </li></ul><ul><ul><li>1932: hypersensitivity reaction </li></ul></ul><ul><ul><li>1946: McAlpine </li></ul></ul><ul><ul><ul><li>Suggested that MS was an immune reaction following infection </li></ul></ul></ul>
  6. 6. History of MS <ul><li>1955: McAlpine, Compson, and Lumsden </li></ul><ul><ul><li>Multiple Sclerosis text published and established the name “multiple sclerosis” for the disease </li></ul></ul>
  7. 7. History of MS <ul><li>1950s: North–South gradient </li></ul><ul><li>Faroe Islands </li></ul><ul><ul><li>No record of MS prior to 1949 </li></ul></ul><ul><ul><li>24 cases between 1949 and 1960 </li></ul></ul><ul><ul><li>British soldiers occupied Islands in the 1940s </li></ul></ul><ul><ul><ul><li>Infection? </li></ul></ul></ul>
  8. 8. History of MS: More Recently <ul><li>Thought to be immune mediated </li></ul><ul><ul><li>Virally triggered in genetically susceptible host </li></ul></ul><ul><li>Treatments </li></ul><ul><ul><li>Acute attacks: ACTH in 1970s –19 80s </li></ul></ul><ul><ul><li>Disease modification in 1990s </li></ul></ul><ul><ul><li>Symptomatic management </li></ul></ul><ul><li>Diagnostic tests </li></ul><ul><ul><li>MRI in 1980s </li></ul></ul><ul><ul><li>New MRI techniques </li></ul></ul>
  9. 9. What We Know Now… <ul><li>Most common neurological disease of young adults </li></ul><ul><li>Chronic disease of the CNS </li></ul><ul><ul><li>Inflammation, demyelination, axonal degeneration </li></ul></ul><ul><li>Approximately 350,000 cases in US </li></ul><ul><li>2/3 of MS patients are women </li></ul><ul><li>Associated with Northern European ancestry </li></ul><ul><li>Age of onset: 15 – 55 </li></ul><ul><ul><li>Usually diagnosed in 20s – 30s </li></ul></ul>
  10. 10. Statistics <ul><li>Incidence = number of new cases beginning in a unit of time within a special population </li></ul><ul><ul><li>Annual incidence per 100,000 population </li></ul></ul><ul><li>Prevalence = number with the diagnosis within the community at one point in time </li></ul><ul><ul><li>Expressed in unit per population </li></ul></ul><ul><ul><li>Provides the best information regarding distribution of the disease </li></ul></ul>
  11. 11. Statistics <ul><li>Worldwide distribution </li></ul><ul><ul><li>High prevalence 30+/100,000 </li></ul></ul><ul><ul><ul><li>Northern US and Canada </li></ul></ul></ul><ul><ul><ul><li>Most of Europe </li></ul></ul></ul><ul><ul><ul><li>Southern Australia </li></ul></ul></ul><ul><ul><ul><li>New Zealand </li></ul></ul></ul><ul><ul><ul><li>Northeast Russia </li></ul></ul></ul>
  12. 12. Pathology <ul><li>White matter lesions in CNS </li></ul><ul><ul><li>Surrounded by plasma cells, immunoglobulins, macrophages, and lymphocytes </li></ul></ul><ul><li>Inflammation </li></ul><ul><li>Myelin injury and destruction </li></ul><ul><li>Axonal injury and destruction </li></ul>
  13. 13. Demyelination and Axonal Transection 64  m 45  m A B Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright  1998 Massachusetts Medical Society. All rights reserved.
  14. 14. Disease Course <ul><li>85% – 90% of patients present with a RR pattern of neurological symptoms </li></ul><ul><li>10% – 15% never have relapses (PP) </li></ul><ul><li>After approximately 10 years, nearly 50% of RR patients will show a progressive pattern to their disease </li></ul><ul><li>This percentage grows with time </li></ul>
  15. 15. Disease Courses in MS Adapted with permission from Lublin FD et al. Neurology . 1996;46:907-911. (http://lww.com) RRMS PPMS Disability Time Time Disability SPMS PRMS Time Time Disability Disability
  16. 16. Natural History Over Time Weinshenker BG et al. Brain. 1989;112:133-146. RRMS PPMS Disease Type at Diagnosis Disease Type at 11 – 15 Years After Diagnosis (Among Those With RRMS at Diagnosis) SPMS RRMS 42% 58% 15% 85%
  17. 17. Symptoms <ul><li>Fatigue </li></ul><ul><li>Sensory disturbances </li></ul><ul><li>Visual disturbances </li></ul><ul><li>Elimination dysfunction </li></ul><ul><li>Spasticity </li></ul><ul><li>Pain </li></ul><ul><li>Tremor </li></ul><ul><li>Cognitive </li></ul>Symptoms vary widely in incidence and severity. <ul><li>Gait disturbances </li></ul>
  18. 18. MS Prognosis <ul><li>Gender: women  , men  </li></ul><ul><li>Age of disease onset: <35 years  , >35 years  </li></ul><ul><li>Monoregional  , polyregional  </li></ul><ul><li>Complete recovery after relapse  , poor recovery after relapse  </li></ul><ul><li>Brainstem symptoms (nystagmus, tremor, ataxia, dysarthria)  </li></ul><ul><li>High incidence of attacks  </li></ul><ul><li>Number of lesions on MRI </li></ul>
  19. 19. Diagnosis of MS <ul><li>Basic principles </li></ul><ul><ul><li>Demographic profile </li></ul></ul><ul><ul><ul><li>Female, Caucasian, young adult, latitude </li></ul></ul></ul><ul><ul><li>Clinical presentation </li></ul></ul><ul><ul><ul><li>Symptomatic disease, abnormal exam, white matter involvement, consistent </li></ul></ul></ul><ul><ul><li>Laboratory profile </li></ul></ul><ul><ul><ul><li>MRI </li></ul></ul></ul><ul><ul><ul><li>CSF </li></ul></ul></ul><ul><ul><ul><li>Evoked potentials </li></ul></ul></ul><ul><ul><ul><li>Exclusion of other diagnoses </li></ul></ul></ul>Coyle P. Diagnosis and classification of inflammatory demyelinating disorders. In: Burks J, Johnson K, eds. Multiple Sclerosis, Diagnosis, Medical Management and Rehabilitation . New York: Demos; 2000:81-97.
  20. 20. Clinical Presentation <ul><li>Sensory tracts </li></ul><ul><ul><li>21% – 55% of patients </li></ul></ul><ul><ul><li>Most common presenting symptom </li></ul></ul><ul><ul><li>Often begins in the limbs and migrates proximally </li></ul></ul><ul><ul><ul><li>Tingling, burning, “Novocain-like,” band-like, squeezing </li></ul></ul></ul><ul><ul><ul><li>Lhermitte’s </li></ul></ul></ul><ul><ul><ul><li>Neuritic pain </li></ul></ul></ul><ul><ul><ul><li>Diminished vibratory sensation </li></ul></ul></ul><ul><ul><ul><li>Impaired position sense </li></ul></ul></ul><ul><ul><ul><li>“ Useless hand” syndrome </li></ul></ul></ul><ul><ul><ul><ul><li>Sensory loss, loss of position sense </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Mobility preserved </li></ul></ul></ul></ul>
  21. 21. Clinical Presentation <ul><li>Corticospinal tracts </li></ul><ul><ul><li>32% – 41% of patients </li></ul></ul><ul><ul><ul><li>Heaviness, weakness </li></ul></ul></ul><ul><ul><ul><li>Abnormal DTRs </li></ul></ul></ul><ul><ul><ul><li>Positive Babinski response </li></ul></ul></ul><ul><ul><ul><li>Spastic limb weakness </li></ul></ul></ul>
  22. 22. Clinical Presentation <ul><li>Brainstem </li></ul><ul><ul><li>Eye movement abnormalities </li></ul></ul><ul><ul><ul><li>Diplopia at onset in about 7% of patients </li></ul></ul></ul><ul><ul><ul><li>Nystagmus, INO </li></ul></ul></ul><ul><ul><ul><li>Bilateral INO is almost pathognomonic for MS </li></ul></ul></ul><ul><ul><li>Vertigo </li></ul></ul><ul><ul><li>Infrequently </li></ul></ul><ul><ul><ul><li>Dysarthria </li></ul></ul></ul><ul><ul><ul><li>Peripheral 7th </li></ul></ul></ul><ul><ul><ul><li>Hearing loss and tinnitus </li></ul></ul></ul>
  23. 23. Clinical Presentation <ul><li>Visual pathway </li></ul><ul><ul><li>Optic neuritis </li></ul></ul><ul><ul><ul><li>Presenting symptom in up to 25% of patients </li></ul></ul></ul><ul><ul><ul><ul><li>Dimming or visual loss </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Loss of color vision </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Visual field defect </li></ul></ul></ul></ul><ul><li>Cerebellar </li></ul><ul><ul><li>Gait ataxia, limb ataxia, tremor </li></ul></ul>
  24. 24. Clinical Presentation <ul><li>Frontal lobe </li></ul><ul><ul><li>Cognitive dysfunction </li></ul></ul><ul><ul><li>Emotional dysinhibition </li></ul></ul><ul><li>Temporal lobe </li></ul><ul><ul><li>Aphasia </li></ul></ul><ul><li>Corpus callosum </li></ul><ul><ul><li>Cognitive dysfunction </li></ul></ul>
  25. 25. Clinical Presentation <ul><li>Fatigue </li></ul><ul><ul><li>Present in up to 90% of patients </li></ul></ul><ul><ul><li>Very common but nonspecific </li></ul></ul><ul><li>Elimination: brainstem/spinal cord </li></ul><ul><ul><li>Occasionally present at onset of disease </li></ul></ul><ul><ul><li>Bladder urgency, frequency, hesitation, nocturia </li></ul></ul><ul><ul><li>Bowel constipation, infrequently involuntary bowel movements </li></ul></ul>Clinical presentation from: Miller A. Clinical features. In: Cook S, ed. Handbook of Multiple Sclerosis , 3rd edition. New York: Marcel Dekker; 2001:213-224. Paty D. Initial symptoms. In: Burks J, Johnson K, eds. Multiple Sclerosis Diagnosis, Medical Management and Rehabilitation. New York: Demos; 2000:75-93.
  26. 26. Sources of Symptoms Symptoms vary widely in incidence and severity. Sensory symptoms: Lhermitte’s Pain Proprioception Optic neuritis Diplopia Vertigo Dysarthria INO Tremor Ataxia Cognitive loss Emotional disinhibition Bladder dysfunction
  27. 27. Diagnosis of MS <ul><li>Laboratory profile </li></ul><ul><ul><li>CSF </li></ul></ul><ul><ul><li>Evoked potentials </li></ul></ul><ul><ul><li>Serum evaluation </li></ul></ul><ul><ul><li>MRI </li></ul></ul>
  28. 28. CSF <ul><li>Invasive </li></ul><ul><li>Used as supporting evidence or may suggest another diagnosis </li></ul><ul><li>Not indicated if history, exam, and MRI are clearly consistent with MS </li></ul><ul><li>For MS, look for </li></ul><ul><ul><li>Elevated IgG index, presence of oligoclonal bands in CSF, but not serum </li></ul></ul><ul><li>Other diagnoses may demonstrate elevated cell counts and/or elevated protein </li></ul>
  29. 29. Evoked Potential Testing <ul><li>Visual, auditory, and somatosensory </li></ul><ul><li>Used less frequently, particularly if history, exam, MRI, and CSF are consistent with the diagnosis of MS </li></ul><ul><li>Can help to document dissemination in space by demonstrating a brainstem or cord lesion </li></ul><ul><li>Looking for slowed conduction described as prolonged evoked response latency </li></ul>
  30. 30. Differential Diagnosis <ul><li>Infection </li></ul><ul><ul><li>Lyme, syphilis, PML, HIV, HTLV-1 </li></ul></ul><ul><li>Inflammatory </li></ul><ul><ul><li>SLE </li></ul></ul><ul><ul><li>Sj ö gren’s, vasculitis, sarcoidosis, Behçet’s disease </li></ul></ul><ul><li>Metabolic </li></ul><ul><ul><li>B 12 deficiency, rare familial diseases </li></ul></ul><ul><li>CNS lymphoma </li></ul><ul><li>Degenerative spinal disease </li></ul><ul><li>Motor neuron disease </li></ul>Cohen J, Rensel M. The differential diagnosis and clues to misdiagnosis. In: Burks J, Johnson K, eds. Multiple Sclerosis Diagnosis, Medical Management and Rehabilitation . New York: Demos; 2000:127-138.
  31. 31. Serum Testing <ul><li>B 12 , folate </li></ul><ul><li>RPR, FTA </li></ul><ul><li>HIV </li></ul><ul><li>HTLV-1 </li></ul><ul><li>ANA, SS-A, SS-B </li></ul><ul><li>Antiphospholipid antibodies </li></ul><ul><li>ESR, C-reactive protein </li></ul><ul><li>Thyroid function </li></ul><ul><li>Angiotension-converting enzyme </li></ul><ul><li>Anti-acetylcholine receptor antibodies </li></ul><ul><li>Long-chain fatty acids </li></ul>
  32. 32. MRI in MS <ul><li>MRI demonstrates approximately 90% – 95% of white matter lesions in brain </li></ul><ul><li>MRI demonstrates 50% – 75% lesions in spinal cord </li></ul>
  33. 33. Use of MRI <ul><li>MRI is a useful tool in helping to make the diagnosis of MS </li></ul><ul><li>MRI may also be helpful in clinical decision making </li></ul><ul><li>Cost and availability are limiting factors in repeated MRIs in the clinical setting </li></ul>
  34. 34. MRI Basics <ul><li>MRI uses a strong magnetic field to align the hydrogen nuclei (protons) in the direction of the magnetic field </li></ul><ul><li>A radio frequency electromagnetic pulse is then used to knock the protons off their axes, thus sending them out of alignment with the magnetic field </li></ul>
  35. 35. MRI Basics <ul><li>The pulse is then stopped and the protons return to their alignment with the magnetic field </li></ul><ul><li>This return to alignment is known as relaxation </li></ul><ul><li>Different tissues “relax” at different rates, which gives the anatomic contrast seen with the MRI </li></ul>
  36. 36. T1-Weighted Images <ul><li>The time it takes the protons to return to their original orientation after the pulse stops is the longitudinal relaxation time or T1 </li></ul><ul><li>Emphasizes the differences between the tissues and shows excellent anatomic detail </li></ul><ul><li>Areas of abnormality show up dark on T1, and therefore these images do not often demonstrate pathology best </li></ul>
  37. 37. T1-Weighted Images
  38. 38. T1 With Gadolinium <ul><li>Demonstrates breakdown of BBB </li></ul><ul><li>Areas of active inflammation </li></ul><ul><li>New lesions remain enhanced for brief time </li></ul>
  39. 39. T1 With Gadolinium
  40. 40. T1 Hypointensities <ul><li>“ Black holes” </li></ul><ul><li>Thought to be areas of axonal loss </li></ul><ul><li>Can be “black holes” that are temporary with a new lesion </li></ul><ul><li>Black holes not associated with a new lesion are thought to be areas of permanent damage </li></ul>
  41. 41. T1 Black Holes
  42. 42. T2-Weighted Images <ul><li>The time it takes for the protons to dephase and for the signal to die away is known as transverse relaxation time or T2 </li></ul><ul><li>Relaxation time for T2 images are usually long </li></ul><ul><li>Show contrast between normal and abnormal tissue better than T1 </li></ul><ul><li>Abnormal increases in water content appear bright on T2 </li></ul>
  43. 43. T2-Weighted Images Conventional T2 FLAIR
  44. 44. FLAIR Image
  45. 45. FLAIR Image and T1 Black Holes
  46. 46. MS Lesions on MRI T2 BOD T1/gadolinium postcontrast disease activity T1 precontrast black holes T2-FLAIR A B C D
  47. 47. Spinal MRI in MS <ul><li>Spinal cord lesions in 75% of MS patients </li></ul><ul><li>Predominantly in C-spine </li></ul><ul><li>Usually dorsolateral or central and 0.5 cm by 1 – 2 cm, and 1 – 2 vertebral segments </li></ul><ul><li>Less likely to enhance or cause cord swelling </li></ul><ul><li>More likely to cause progressive disease </li></ul><ul><li>T2 less predictive of disability than atrophy </li></ul>
  48. 48. Cord Lesion
  49. 50. Brain Atrophy <ul><li>Cerebral atrophy is a global measure of disease that measures irreversible tissue damage </li></ul><ul><li>Serial measures may reflect disease progression </li></ul><ul><li>“ Potentially” the most valid MRI surrogate marker </li></ul><ul><li>May be “faster, simpler, and better” than current measures (Jagust WJ, Noseworthy JH. Neurology. 2000;54:782-783.) </li></ul>
  50. 51. Examples of BPF in MS 36-year-old woman RRMS (2 years) 43-year-old woman SPMS (19 years) 31-year-old male Healthy control BPF 0.87 z score = 0 BPF 0.85 z score = – 2.6 BPF 0.71 z score = – 20.8 Reprinted with permission from Rudick RA et al. Neurology . 1999;53:1698-1704.
  51. 52. McDonald Diagnostic Criteria <ul><li>Preserve traditional diagnostic criteria of 2 attacks of disease separated in space and time </li></ul><ul><ul><li>Must be no better explanation </li></ul></ul><ul><ul><li>Add specific MRI criteria, CSF findings, and analysis of evoked potentials as means of identifying the second “attack” </li></ul></ul>McDonald WI et al. Ann Neurol . 2001;50:121-127.
  52. 53. McDonald Diagnostic Criteria <ul><li>Conclude that the outcome of the diagnostic workup should yield 1 of 3 outcomes: </li></ul><ul><ul><li>MS </li></ul></ul><ul><ul><li>Possible MS </li></ul></ul><ul><ul><li>Not MS </li></ul></ul><ul><li>New criteria utilize MRI, CSF, or evoked potential testing when only one lesion found and/or only one attack or when onset is insidious neurological progression </li></ul>McDonald WI et al. Ann Neurol . 2001;50:121-127.
  53. 54. MRI Evidence of Dissemination in Time <ul><li>A gadolinium-enhancing lesion demonstrated in a scan done at least 3 months following onset of clinical attack at a site different from attack </li></ul><ul><li>In absence of gadolinium-enhancing lesions at 3-month scan, follow-up scan after an additional 3 months showing gadolinium-enhancing lesion or new T2 lesion </li></ul>McDonald WI et al. Ann Neurol . 2001;50:121-127.
  54. 55. McDonald MRI Criteria <ul><li>Abnormal MRI consistent with MS defined as: </li></ul><ul><ul><li>Must have at least 3 of the following: </li></ul></ul><ul><ul><ul><li>1 gadolinium-enhancing lesion or 9 hyperintense lesions if no gadolinium-enhancing lesion </li></ul></ul></ul><ul><ul><ul><li>1 or more infratentorial lesions </li></ul></ul></ul><ul><ul><ul><li>1 or more juxtacortical lesions </li></ul></ul></ul><ul><ul><ul><li>3 or more periventricular lesions </li></ul></ul></ul><ul><ul><ul><ul><li>1 cord lesion = 1 brain lesion </li></ul></ul></ul></ul>McDonald WI et al. Ann Neurol . 2001;50:121-127.
  55. 56. McDonald MRI Criteria Gd-enhancing T2 hyperintense Juxtacortical Periventricular Spinal Cord Infratentorial
  56. 57. Other Paraclinical Evidence <ul><li>Abnormal CSF </li></ul><ul><ul><li>Oligoclonal IgG bands in CSF and not in serum </li></ul></ul><ul><ul><li>Or elevated IgG index </li></ul></ul><ul><li>Abnormal evoked potentials </li></ul><ul><ul><li>Delayed but well-preserved waveform </li></ul></ul>
  57. 58. Application of New Diagnostic Criteria  3 months T2 Gadolinium
  58. 59. Proposed Diagnostic Criteria <ul><li>An effort to expedite diagnosis </li></ul><ul><li>Have become part of inclusion/exclusion for newer clinical trials </li></ul><ul><li>Makes an effort to define clinically isolated syndrome to enable earliest treatment </li></ul>
  59. 60. Natural History of MS Adapted from Wolinsky JS. Multiple sclerosis. In: Appel SH, ed. Current Neurology . Vol. 13. Chicago, Ill: Mosby Year Book, Inc.; 1993:167-207, with permission from Elsevier. Time Disability Measures of brain volume Relapses and impairment MRI burden of disease MRI activity A B C D A B C D SPMS RRMS Preclinical
  60. 61. Immune-Mediated Disease <ul><li>Inflammation </li></ul><ul><li>Demyelination </li></ul><ul><li>Axonal degeneration and loss </li></ul><ul><li>Must be knowledgeable about the normal immune system and the dysregulation in MS </li></ul>
  61. 62. Immunological Basis for MS: Normal Immune System <ul><li>Protects from pathogens such as </li></ul><ul><ul><li>Bacteria </li></ul></ul><ul><ul><li>Viruses </li></ul></ul><ul><ul><li>Parasites </li></ul></ul><ul><ul><li>Fungi </li></ul></ul><ul><li>Protects through </li></ul><ul><ul><li>Innate immunity </li></ul></ul><ul><ul><li>Adaptive immunity </li></ul></ul>
  62. 63. The Immune System <ul><li>Innate immunity </li></ul><ul><ul><li>Immunity to certain pathogens that is common to all healthy individuals </li></ul></ul><ul><ul><li>Does not require prior exposure to the pathogen </li></ul></ul><ul><ul><li>Immediate destruction of some pathogens by phagocytic cells, such as macrophages and neutrophils, and natural killer cells </li></ul></ul>Macrophage Pathogen
  63. 64. The Immune System <ul><li>Adaptive immunity </li></ul><ul><ul><li>Requires exposure to pathogen to stimulate immune system response </li></ul></ul><ul><ul><li>Cellular immunity </li></ul></ul><ul><ul><ul><li>Cytotoxic T cells (CD8) </li></ul></ul></ul><ul><ul><ul><li>Th1 cells (CD4) </li></ul></ul></ul><ul><ul><li>Humoral immunity </li></ul></ul><ul><ul><ul><li>Th2 cells (CD4) </li></ul></ul></ul><ul><ul><ul><li>B lymphocytes </li></ul></ul></ul><ul><ul><ul><li>Antibodies </li></ul></ul></ul><ul><ul><ul><li>Activation of complement </li></ul></ul></ul>
  64. 65. The Immune System <ul><li>B cells recognize antigen that is present outside of cells in its natural state </li></ul><ul><li>T cells detect antigen generated inside host cells and presented on the cell surface </li></ul><ul><li>Both B cells and T cells must receive an additional (co-stimulatory) signal in order to be activated </li></ul>
  65. 66. Humoral Immunity <ul><li>B cells have specific antibodies on their surface </li></ul><ul><li>They circulate looking for a recognizable antigen </li></ul><ul><li>Under the influence of cytokines released from Th2 cells, B cells give rise to plasma cells that secrete large amounts of antibodies </li></ul><ul><li>Plasma cells do not leave the lymphoid tissue </li></ul>
  66. 67. Humoral Immunity <ul><li>Antibodies work by </li></ul><ul><ul><li>Neutralization </li></ul></ul><ul><ul><ul><li>Binding to pathogens and blocking the path to body cells </li></ul></ul></ul><ul><ul><li>Opsonization </li></ul></ul><ul><ul><ul><li>Enabling phagocytic cells to recognize pathogens by coating the pathogen </li></ul></ul></ul><ul><ul><li>Complement </li></ul></ul><ul><ul><ul><li>Some antibodies activate a series of proteins called complement that have been circulating, inactive, in the blood. Complement and the antibody combine in a partnership that can react to an antigen and help to destroy it. </li></ul></ul></ul>B cells give rise to plasma cells, which are antibody-producing factories.
  67. 68. Cellular Immunity <ul><li>T lymphocytes each have cell-surface receptors </li></ul><ul><ul><li>Distinct from lymphocyte to lymphocyte </li></ul></ul><ul><ul><li>This enables lymphocytes to recognize a wide variety of antigens </li></ul></ul>
  68. 69. Cellular Immunity <ul><li>Once a T cell is activated by antigen presentation: </li></ul><ul><ul><li>It proliferates in a process known as clonal expansion </li></ul></ul><ul><ul><li>These activated cells produce cytokines that can activate the “killer” mechanism of macrophages </li></ul></ul><ul><ul><li>Antigen-specific lymphocytes undergo apoptosis once the antigen is removed </li></ul></ul><ul><ul><li>Some antigen-specific lymphocytes persist and are the basis for immunological memory </li></ul></ul>
  69. 70. Cellular Immunity <ul><li>The cells that present antigen to T cells are antigen-presenting cells </li></ul><ul><ul><li>Dendritic cells </li></ul></ul><ul><ul><li>Macrophages </li></ul></ul><ul><ul><li>B cells </li></ul></ul><ul><li>These cells display antigen protein particles on specialized cell surface molecules known as MHC </li></ul>
  70. 71. Cellular Immunity <ul><li>2 classes of MHC molecules </li></ul><ul><ul><li>MHC I </li></ul></ul><ul><ul><li>MHC II </li></ul></ul><ul><li>MHC I are recognized by cytotoxic T cells (CD8) </li></ul><ul><li>MHC II are expressed on the surface of macrophages or B cells and are recognized by Th1 or Th2 cells (CD4) </li></ul>
  71. 72. Cellular Immunity Resting T cell Activated Th1 or Th2 APC (Macrophage) Virus MHC II APC processing virus Presentation of virus protein to resting Th1 cell T-cell receptor Costimulatory molecules Activated Th1 or Th2 Activated Th1 or Th2 Activated Th1 or Th2
  72. 73. CD4 Cell Cytokine Production <ul><li>Th1 cells activate macrophages and produce: </li></ul><ul><ul><li>IFN-  </li></ul></ul><ul><ul><li>TNF-  </li></ul></ul><ul><ul><li>IL-2 </li></ul></ul><ul><ul><li>Lymphotoxin </li></ul></ul><ul><li>Th2 cells activate B cells and produce: </li></ul><ul><ul><li>IL-4 </li></ul></ul><ul><ul><li>IL-5 </li></ul></ul><ul><ul><li>IL-10 (regulatory cytokine) </li></ul></ul><ul><ul><li>IL-13 </li></ul></ul><ul><ul><li>TGF-  </li></ul></ul>
  73. 74. Immune Dysregulation <ul><li>T cells that recognize self-antigen are generally deleted in the thymus </li></ul><ul><li>May be a small # of autoreactive cells still present </li></ul><ul><li>In autoimmune illness, the regulatory mechanisms that keep these T cells in check are not working properly </li></ul><ul><li>Without regulation, autoreactive T cells can proliferate </li></ul>
  74. 75. Immune Dysregulation <ul><li>Molecular mimicry </li></ul><ul><ul><li>Self-protein is structurally similar to non – self-antigen </li></ul></ul><ul><ul><li>T cells can recognize self-antigens if they bear enough similarity to the non – self-antigen </li></ul></ul>
  75. 76. Immune System in MS <ul><li>Th1 cells are stimulated in the periphery by presentation with antigen </li></ul><ul><ul><li>Eg, a virus particle </li></ul></ul><ul><li>Once activated </li></ul><ul><ul><li>They proliferate </li></ul></ul><ul><ul><li>They release cytokines and metalloproteinases that break down the extracellular matrix of the BBB </li></ul></ul>
  76. 77. MS <ul><li>Once in the CNS, Th1 cells </li></ul><ul><ul><li>Are presented with a myelin protein </li></ul></ul><ul><ul><ul><li>The myelin protein is similar to the antigen presented in the periphery </li></ul></ul></ul><ul><ul><li>Become reactivated </li></ul></ul><ul><ul><li>Release damaging cytokines </li></ul></ul><ul><ul><ul><li>IFN-  , TNF-  , IL-2 </li></ul></ul></ul><ul><ul><li>Stimulate B-cell activity, antibody production, and complement activation </li></ul></ul>
  77. 78. MS Immune Response Th0 Activated Th1 Activated Th1 Activated Th1 APC Activated Th1 Th1 APC Periphery CNS TNF- α IFN- γ IL-2 MHC-II Myelin protein TCR Antigen Costimulatory molecules MMP MMP LFA-1 ICAM Microglial cell BBB B cell
  78. 79. MS Immune Response Activated Th1 APC Activated Th1 Activated Th1 Activated Th1 Th1 TNF- α IFN- γ IL-2 MMP MMP MMP Th0 BBB B cell APC
  79. 80. Results of Autoimmune Activity Within the CNS <ul><li>Neurological symptoms followed by some degree of recovery </li></ul><ul><ul><li>Relapses and remissions </li></ul></ul><ul><ul><li>Little axonal injury or damage </li></ul></ul><ul><li>Permanent damage within the CNS </li></ul><ul><ul><li>Progression </li></ul></ul><ul><ul><li>Axonal damage and loss </li></ul></ul>
  80. 81. IFN  <ul><li>Inhibits synthesis of inflammatory cytokines </li></ul><ul><ul><li>IFN-  , TNF-  </li></ul></ul><ul><li>Downregulates expression of MHC II molecules induced by IFN-  </li></ul><ul><li>Reduces antigen presentation to T cells </li></ul><ul><li>Inhibits T-cell proliferation </li></ul><ul><li>Downregulates adhesion molecules and promotes BBB integrity </li></ul>
  81. 82. IFN β Effect on MS Immune Response Th0 Activated Th1 Activated Th1 Activated Th1 APC Activated Th1 Th1 APC BBB Periphery CNS TNF- α IFN- γ IL-2 MHC-II Antigen Myelin protein TCR IFN β IFN β IFN β
  82. 83. Glatiramer Acetate <ul><li>Induces suppressor T cells </li></ul><ul><li>Structurally similar to myelin basic protein and when glatiramer acetate – induced T cells are presented with myelin basic protein in the CNS, they are stimulated to proliferate and release cytokines </li></ul><ul><ul><li>TGF-  , IL-4, IL-10 </li></ul></ul><ul><li>These T cells are thought to suppress pro-inflammatory T cells in a process called bystander suppression </li></ul>
  83. 84. Glatiramer Acetate–Induced Immune Response Th0 Activated Th2 Activated Th2 Activated Th2 APC Activated Th2 Th2 APC BBB Periphery CNS IL-4 IL-6 IL-10 MHC-II Glatiramer acetate antigen Myelin protein TCR Bystander suppression on other T cells Glatiramer acetate – induced T cell Th2
  84. 85. Research in MS APC Activated Th1 Activated Th1 Activated Th1 Activated Th1 Th1 APC TNF- α IFN- γ IL-2 MMP MMP MMP BBB Th0 Antegren Anti-IL-12 BMS-block costimulatory Campath
  85. 86. Summary <ul><li>Nurses’ role </li></ul><ul><ul><li>Education </li></ul></ul><ul><ul><li>Advocacy </li></ul></ul><ul><ul><li>Support </li></ul></ul><ul><li>Understanding of the disease </li></ul><ul><ul><li>Immune basis </li></ul></ul><ul><ul><li>Clinical features/diagnosis </li></ul></ul><ul><ul><li>MRI </li></ul></ul><ul><li>Understanding MS treatments, symptomatic management, our role, current issues, and current research </li></ul>

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