Multiple sclerosis

Courtesy of Intermountain Medical Imaging, Boise, Idaho.

Multiple sclerosis (MS) - an autoimmune disease that effects every patient differently based on the neurologic lesions inflicted throughout the body. While some can go through their lives with relatively mild symptoms and short periods of relapse, others can become incapacitated within years or even months. Defined by Nylander and Hafler, MS is a "multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual." Inflammation is the primary cause of damage in MS, and though the effects of the disease are well known, and various treatments exist for the disease, the exact identity of an antigen or infectious agent that causes the initiation of a myriad of symptoms is unknown.

There are three ways in which MS is categorized: relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS). In RRMS, the patient experiences periods of time in which the symptoms increase considerably, although the neurological function of the patient usually returns to normal after the episode. Those with SPMS have symptoms like RRMS, but do not return to normal neurological function after the episode, rather they sustain the neurological damage (such as permanently losing the use of an arm). In PPMS, the patient has an initial episode that never ends. That is, once the symptoms begin, there is no remission in the neurological degradation. A constant autoimmune attack on the patient's body causes increasingly severe symptoms, which can sometimes lead to death.

Taking a biochemical look at the immunopathology and some of the various treatments that exist for MS helps in the understanding that MS is no longer a diagnosis which is hopeless, but is in fact full of hopeful and helpful treatments.

spinqualitylabelsall models Click on the green links to the left to observe the various proteins involved in MS immunopathology (PDB entry: 1tcr) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Immunopathology Classical MS pathology has been characterized by white matter plaques which are typically located in the subcortical or periventricular white matter, optic nerve sheaths, brain stem, and spinal cord. The lesions that occur in these regions are generally identified by perivascular infiltrates that contain clonally expanded CD8+ T cells (two ectodomains shown, 3qzw), as well as a smaller amount of CD4+ T cells (3t0e), monocytes (2ra4), and rare B cells (4e96) and plasma cells (2wq9). Pathologists disagree on whether there are different mechanisms for the inflammatory and degenerative components of MS, especially given that older patients have generally progressed further along with their degeneration. There are many proposed degeneration mechanisms including Wallerian degeneration secondary to demyelination, and axonal transection, damage from reactive oxygen species and nitric oxide, or energy failure from mitochondrial dysfunction. Many antigens have been investigated to determine whether they are the cause of T cell autoreactivity (extracellular domain shown, 1tcr) in the hopes to determine a single culprit including: myelin basic protein (MBP, 1bx2) with a peptide shown; proteolipid protein (PLP, 2xpg) with peptide shown; oligodendrocyte glycoprotein (MOG, 3csp); oligodendroglia-specific enzyme transaldolase, and heat shock protein alphaB crystallin (2y1z). Interesting discoveries have been made on possible inhibitors of myelin repair functions within the body, with an obvious application to MS treatment. The structure of the lingo-1 ectodomain is a module implicated in central nervous system repair inhibition. The interactions of lingo-1 with receptors lead to neurite and axonal collapse. Lingo- 1 also regulates oligodendrocyte differentiation and myelination, thus leading to the suggestion that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Interferon-β Interferon-β is a protein growth factor that stimulates an antiviral defense. Its encoding gene is one of only two known vertebrate structural genes that lacks introns. Interferon-β is a relatively simple biological response modifier, with several identifiable regions. It consists of five alpha helices, as well as multiple interconnecting loop regions. Helices A, B and D run parallel to one another, and helices C and E run anti-parallel to the other three helices, but parallel to one another. Helix A consists of residues 6-23; Helix B consists of residues 49-65; Helix C consists of residues 77-91; Helix D consists of residues 112-131; and Helix E consists of residues 135-155. Interferon Alpha, Interferon Beta, and Interferon Receptors 1 & 2 Since a PDB reference does not exist for interferon beta interacting with interferon receptors 1 or 2, and a multitude of files exist on Interferon-α interacting with the receptor, a comparison to interferon-α will be made prior to demonstrating the types of bonding that occur between the interferon and its receptor. To see more information regarding interferons, please visit the Interferons site. Interferon alpha has a 31% sequence homology to interferon beta. It, too, has many identifiable regions with two disulfide bonds: one between the N-terminus and Helix E, and the other between Loop AB and Helix G. It has seven alpha helices, as compared to the five of interferon-β, and therefore has several more loop regions. The helices A, C, and F run parallel to one another, and anti-parallel to B, E, and G which run parallel to each other. Helix D does not run parallel or anti-parallel to either set, but rather runs at a 45-90 degree angle to them. Helix A consists of residues 10-12; Helix B of 40-43; Helix C of 53-68; Helix D of 70-75; Helix E of 78-100; Helix F of 109-132; and Helix G of 137-158. Interferons -α and -β interact with a receptor at the cell surface. This receptor has three domains: an N-domain, with two disulfide bonds, a C-domain, with one disulfide bond, and a linker region. The termini regions of the receptor have no secondary structure, allowing for some serious flexibility, leading to eight clashes amongst the domains. Interferon-α binds to an interferon receptor mainly with helices C and G. There are many residues within 4 angstroms of one another. These residues could form many different types of bonds, illustrated in white dotted lines. Given that interferon-α does not undergo many structural changes upon binding to interferon receptor II, Quadt-Akabayov et al. have concluded that the binding mechanism is similar to that of a lock and key.

Relevant 3D Structures

Interferon Beta

3qzw - Homo sapiens

3t0e, 2ra4 - Mus musculus

Interferon Receptors

4e96, 2wq9, 1tcr, 1bx2, 2xpg, 3csp, 2y1z, Interferons, 3s8w, 3s9d - Homo sapiens

Proteopedia Page Contributors and Editors (what is this?)

Kirsten Eldredge