M

Lumbar puncture

Oligoclonal bands

Serum CSF

IEF in MS IEF in normals

Serum CSF

Lesions

Lesions

IEF in MS IEF in normals

Special tests in MS (IEF = isoelectric focusing)

MRI (T2-weighted image of cerebellum)

Activation. Circulating autoreactive CD4+ T lymphocytes bear antigen-specific surface receptors and can cross the blood-brain barrier (BBB) when activated, e.g., by neurotropic viruses, bacterial superantigens, or cytokines. In MS, activated T lymphocytes react with MBP, PLP, MOG, and MAG. Circulating antibodies to various components of myelin can also be detected (for abbreviations, see below1). Passage through the BBB. Activated lymphocytes and myelinotoxic antibodies penetrate the BBB at the venules (perivenous distribution of E inflammation).

Antigen presentation and stimulation. In the ^ CNS, antigen-presenting cells (microglia), recto ognition molecules (MHC class II antigens), and (5 co-stimulatory signals (CD28, B-7.1) trigger the ^ renewed activation and clonal proliferation of à; incoming CD4+ T lymphocytes into TH1 and TH2 "3 cells. Proinflammatory cytokines elaborated by •fa the Th1 cells (1L-2, IFN-y, TNF-a, LT)2 induce (<u phagocytosis by macrophages and microglia as C well as the synthesis of mediators of inflammation (TNF-a, OH-, NO)2 and complement factors. The Th2 cells secrete cytokines (1L-4,1L-5,1L-6)2 that activate B cells (^ myelinotoxic autoantibo-dies, complement activation), ultimately causing damage to myelin. The TH2 cells also produce 1L-4 and 1L-10, which suppress the TH1 cells. Demyelination. Lesions develop in myelin sheaths (which are extensions of oligoden-droglial cell membranes) and in axons when the inflammatory process outstrips the capacity of repair mechanisms.

Scar formation. The inflammatory response subsides and remyelination of damaged axons begins once the autoreactive T cells die (apopto-sis), the BBB is repaired, and local anti-inflammatory mediators and cells are synthesized. Astroglia form scar tissue that takes the place of the dead cells. Axonal damage seems to be the main cause of permanent neurological deficits, as dystrophic axons apparently cannot be remy-elinated.

Treatment

Relapse is treated with high-dose corti-costeroids, e.g., methylprednisolone, 1 g/day for 3-5 days, which produce (unselective) immuno-suppression, reduce BBB penetration by T cells, and lessen TH1 cytokine formation. Plasm-apheresis may be indicated in refractory cases. Drugs that reduce the frequency and intensity of relapses. Azathioprine p.o. (immunosuppression via reduction of T cell count), interferon beta-1b and beta-1a s.c. or i.m. (cytokine modulation, alteration of T-cell activity), glatiramer acetate s.c. (copolymer-1; blocks/competes at binding sites for encephalitogenic peptides on MHC-11 molecules), IgG i. v. (multiple modes of action), and natalizumab (selective adhesion inhibitor). Drugs that delay secondary progression. 1nter-feron beta-1b and beta-1a. Mitoxantrone suppresses B cells and decreases the CD4/CD8 ratio. Methotrexate and cyclophosphamide (different dosage schedules) delay MS progression mainly by unselective immunosuppression and reduction of the T-cell count. Slowing of primary progression. No specific therapy is known at present. Symptomatic therapy/rehabilitation. Medications, physical, occupational, and speech therapy, social, psychological, and dietary counseling, and mechanical aids (e. g., walking aids, wheelchair) are provided as needed. The possible benefits of oligodendrocyte precursor cell transplantation for remyelination, and of growth factors and immunoglobulins for the promotion of endogenous remyelination, are currently under investigation in both experimental and clinical studies.

TMBP, myelin basic protein; MOG, myelin-oligodendro-cyte glycoprotein; MAG, myelin-associated glycoprotein; PLP, proteolipid protein; S100 protein, CNPase, aß-crys-tallin, transaldolase

21L, interleukin; IFN-y, interferon-gamma; TNF-a, tumor necrosis factor-alpha; LT, lymphotoxin; OH-: hydroxyl radical; NO, nitric oxide

3p.o., orally; s.c., subcutaneously; i.m., intramuscularly; i.v., intravenously.

Major histocompatibility complex (MHC) protein

MHC/antigen protein complex Macrophage

Trimolecular interaction (MHC protein, antigen protein, T-cell receptor) Antigen peptides

MHC protein-bound peptide (antigen presentation)

Major histocompatibility complex (MHC) protein

MHC/antigen protein complex Macrophage

Trimolecular interaction (MHC protein, antigen protein, T-cell receptor) Antigen peptides

MHC protein-bound peptide (antigen presentation)

Multiple Sclerosis Demyelination

Complement Demyelination Oligodendrocyte

Activated T cell (adhering to cell wall)

Crossing the blood- -brain barrier (BBB)

Endothelium (BBB) -

T-cell (Th1/Th2) -proliferation and activation

Myelinated axon

Antigen-presenting cell in CNS (macrophage) Cerebral cortex

Lesion of myelin sheath/axon

Complement Demyelination Oligodendrocyte

Activated T cell (adhering to cell wall)

Crossing the blood- -brain barrier (BBB)

Endothelium (BBB) -

T-cell (Th1/Th2) -proliferation and activation

Myelinated axon

Antigen-presenting cell in CNS (macrophage) Cerebral cortex

Lesion of myelin sheath/axon

Cerebral lesion (plaque)

Pathogenesis of MS (schematic)

Cerebral lesion (plaque)

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