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(08-02)

Multiple Sclerosis: A Personal View

(#08-02)

p74

Although Allergic Illness have been recognized and described since ancient times, they are still imperfectly understood.

It is known, however, that allergies to specific substances are acquired by exposure to those substances and that a general tendency to react in a hypersensitive or allergic manner is hereditary.

It has been estimated that a family tendency to allergic reactions affects as much as 80% of the population in developed countries.

p75

Allergy as a medical subject grew up within the framework of Immunology: the study of immunity or resistaance to infection by the MicroOrganisms of Smallpox, Diphtheria, Tetanus, Typhoid and other Contaigious Diseases.

Besides the desirable Immune Response following the injection of dead germs (called Antigens becaause they generate AntiBodies), there is also the HyperSensitivity reactions. This led to the development of skin tests for Immunity.

These and subsequent injections form the basis of the public health immunization programs established to protect children from the numerous infections of the Nineteenth century, which were responsible for so many deaths.

However, some people became HyperSensitive or Allergic as well to the Antigens with which they were injected.

Immunity and Allergy, the two antithetical responses to inoculation with identical material, were explained as changed reactivity folowing exposure: on the one hand, Acquired or Induced Immunity; on the other, HyperSensitivity.

Both are based on the chemically understood Antigen-AntiBody reaction and are demonstrable by the skin tests which have since become the "sine qua non" of orthodox allergy practice.

In addition to their powers of general adaptation, human beings are also capable of variable degrees of adaptation in the sense of specific and individualised responses to environmental exposures occuring in the presence of equally variable degrees of individual susceptibility.

However, it is the total load of environmental exposures, both specific and nonspecific agents, that are important in determining whether an individual adapts (remaining relatively symptom free) or maladapts (manifesting chronic symptoms) at any given time.


p88

The Brain is well protected from being injured by allergic processes, untill the Blood-Brain Barrier (BBB), a physiologic system necessary for the normal function of the Brain, is breached.

Attempts to localize the site of this barrier to some specific anatomic structure led finally to the conclusion that every membrane existing between blood and Brain may contribute to the BBB.

The Brain requires an exceptionally vigorous circulation of blood during both day and night. Brain cells deprived of sufficient Oxygen, begin to die within minutes.

The Oxygen, Glucose, etc., continually conveyed to the Brain by the bloodstream pass to the Brain cells from the blood Capillaries. Under normal circumstances any blood cells, such as Lymphocytes, are prevented from leaving these.

The BBB seems to be most vulnerable, at the point where the tiny Capillaries join together to form minute Veins (Venules), and this is the beginning of the return journey of the blood from the Brain to the Heart.

It is around these Venules of the White Matter of the Brain and Spinal Cord that the Multiple Sclerotic plaques form and this happens in those regions where the circulation is most sparse.

Their development around small blood vessels is the central "hard" fact relating to Multiple Sclerotic lesions.


The first sign of a new plaque seen by the microscope is the escape of some Lymphocyte from Venule to Brain tissue. Lymphocytes are the cells that make up our Immune System. Like the Nervous System, this penetrates most tissues of the body.

Oddly, the two systems seem to avoid each other: the BBB prevents Lymphocytes from coming into contact with Nerve Cells. Thus, the movement of a Lymphocyte to Brain tissue is a visible sign of a fault in the BBB.

New plaques as seen in autopsies of acute cases are not sclerotic; they are infiltrations by fluid of the nerve tissue surrounding blood vessels. That is, the patch is not sclerotic initially but fluid, edematous; it only becomes so later.

Conversely, the old patches are sclerosed. The agent or factor that makes the coats of these vessels permeable to Serum is the crux of the matter.

p89

Evidence does indicate the frequent presence of a small Venule in the center of the younger and smaller lesions. While Venules appear to have "some influence on determining the sites of origin of the plaques, they do not determine the subsequent evolution or form of the plaque.

The view that the plaque develops as the direct result of occlusion, probably due to Thrombosis, has its champions as well as detractors.

It has been suggested that temporary Occlusion of small blood vessels in the CNS resulting from Agglutination and aggregation of blood platelets may be responsible.

And, indeed, platelet stickiness is increased during exacerbations and returns to normal in the quiescent phases. This rise in degree of Adhesiveness may be associated with Histamine, a chemical released by the platelets in response to entry into the CNS of some Allergen.

The resultant clumping of the platelets causes blockage of small Venules, although perhaps only of transient duration.

Since platelet stickiness presumably is widespread thru the bloodstream as a whole, why are the effects of the platelet MicroThrombi restricted to the CNS? Why are only the Brain and Spinal Cord affected?

One possible reason is that, in general, the peripheral tissues have relatively large ExtraCellular Spaces and a system of Lymphatic drainage.

Whereas, the ExtraCellular Spaces in the CNS is almost certainly small (Expanded ExtraCellular Space in plaque tissue is an indication of BBB insult) and the Brain and Spinal Cord have no Lymphatic System.


p90

The effects of even temporary blockage of small blood vessels are therefore likely to be greater in the CNS than in other tissues.

Also, in addition to the Hypoxia following Occlusion, the small ExtraCellular space and the absence of Lymphatic drainage, will tend to minimise the dilution of the area of Histamine; and other possible cytotoxic compounds, released from the Platelet Thrombi.

The blood supply to the Brain and Spinal Cord normally increases quickly during the first ten years of life, but then there is a surprising change, for although the blood supply of the Nerve Cells (Gray Matter) continues to increase during the second decade of life, the blood supply of the White Matter is slowly reduced during this period

Apparently due to the fact that by the age of about twelve years the Myelin sheaths have acquired their full thickness and the process of mere maintenance as opposed to growth makes less demands on circulation.

MS rarely appears before the age of fifteen, and it may be significant that at this age the vulnerable areas of the White Matter are experiencing some reduction in their supply of blood for physiologic reasons.

p95

Classical views on the BBB usually include the notion that it is not present in early life, but develops gradually as the individual develops, to become fully functional only in maturity.


The Capillaries entering the Brain are foreign structures and the Brain maintains its Basement Membrane around every Capillary.

The cause of MS is not known, therefore there is no accepted drug therapy. In cases where there's SpinoThalamic Tract involvement, Intractable Pain is often experienced.

Once the stage of exhaustion in the battle of adaptation to a particular substance has been reached, avoidance is the only remedy known.


p105

Medically speaking, we live in an age of Clinical Immunology. The thrust of all contemporary research and medical thought is Immunologic.

When we consider that our Immune System evolved in defense of life itself, it is startling to realise that its sole concern is quite simply, surfaces.

It responds to these alone, whether they surround live cells or dead; whether Bacteria, Viruses, Fungi or chemicals, countering anything it identifies as not self, the champion of our identity.

Thus is the battle for life fought, surface against surface as every attempt to graft a piece of skin or transplant an organ vividly illustrates. Unravelling the mysteries of our Immune System has been a slow and painstaking affair.


In 1925 Zinsser showed that defense against Bacterial or Viral invasion was too important for the body to leave to any one system. It therefore made use of several:

  1. The Cellular System consisting of the Granulocytes (which increased in number under Bacterial assault)
  2. Lymphocytes (which did likewise on Viral invasion)
  3. The Humoral System; made up of a combination of different but very special Serum factors.

In each and every bodily reaction to infection these three parts work together. Which one dominates depends on the kind of infection or type of material injected.


p106

In 1937, scientists finally established exactly what the Serum factors participating in the Immune Response were. There are three groups of proteins in human blood, each migrating at its own rate.

They are known as the Gamma Globulins: alpha, beta, and gamma. Collectively, we know them as AntiBodies because they are the blood proteins produced in response to bodily attacks by foreign substances, or Antigens.

AntiBodies are special proteins circulating in our bloodstreams, made up of linked Amino Acids. They are the building blocks of the body, able to couple with the surfaces of certain foreign materials.

AntiBody protein comprise two identical light and two identical heavy chains of Amino Acids.

The Gamma Globulins differ in size, Amino Acid sequence, as well as in respect of the site in the body where they do their attacking.

ImmunoGlobulin A (IgA) is secreted in our tears and saliva and is present in all our mucous membranes.

The other two AntiBodies are ImmunoGlobulin G (IgG) and ImmunoGlobulin M (IgM), the latter being larger and less mobile than the former.

There's a critical weakness in our AntiBody system. Before manufacture of the appropriate IgG and IgM AntiBodies can begin, the microbes or poisons must be present within the body.


p107

AntiBodies are manufactured by cells in our body in response to foreign markers, or Epitope, on the surface of any attacking microbes or poisons. About ten Amino Acids may contribute to the pattern of an Epitope.

The replacement of just one Amino Acid by another in a chain of protein frequently leads to the display of a different Epitope.

These Epitopes, or molecular configurations, differ from those in the membranes of our body's cells and in the materials we make for ourselves.

The large molecules that display Epitopes, that are under Genetic control, are called Antigens; it is against the Antigens on a foreign cell's surface, or an injected toxin, that Anti- Bodies are made.

AntiBodies fit snugly onto the Antigen. If the foreign substance is a poison, the AntiBody is able to neutralise the Antigen, so that the toxin circulates harmlessly.

The situation with microbes or Viruses is different; the AntiBodies do no actual harm to the Bacteria or Viruses, but once attached to the microbes surface, unlock a series of physical events leading to its death.


Besides AntiBodies and White Cells, our Immune System has a group of nine seperate proteins made in the Liver and deLivered to our circulating system in vast numbers.

Taken together the nine constitute the Complement System; the individual proteins are called, in order; C1, C2, C3, all the way to the final Complement, C9. The AntiBodies complement the action of the nine Serum proteins.

P108

Evidently, to bridge the gap between microbial invasion and the production and circulation of the correct AntiBody, the body developed a NonImmunologic protein.

It is produced in the Liver, it can combine with the surface of microorganisms and activate the Complement System. Our entire Immune System, except for the Granulocytes, is produced by the cells or Lymphocytes making up the Lymph Nodes.

These are scattered throughout the body, and are connected by a very thin-walled channels running alongside our Arteries and Veins; these comprise the second great, if poorly understood, Circulatory System.


p109

Everthing Immunologic that happens in our body stems from the White Cells with no Granules, filling every Lymph Node and travelling so persistenly back and forth.

Even twenty years ago Lymphocytes were not thought to have anything to do with the Immune System, something that seems incredible now that they are known to constitute it!

All the Lymphocytes that circulate in the tissues have arisen from Precursor Cells in the Bone Marrow.

About half of these - the T-Cells - have passed through the Thymus Gland on their way to the tissues; the other half, - the B-Cells - have not.

These cells look identical under the microscope, but behave quite differently when coming to our defence. The outer parts of each Lymph Node is filled with B-Cell Lymphocytes, the inner parts of T-Cells. Every so often a few are released into the bloodstream to circulate throughout the body.

These messanger Lymphocytes are able, somehow, to detect an Antigen (a foreigner) pick it off, carry it back to the nearest node, touch the approprite Lymphocytes (either T or B), thereby transferring the information.

This Antigen information activates either the Humoral (B-Cell) or the Cellular (T-Cell) part of our Immune Response.

Our AntiBodies, Complement, Properdin, Granulocytes and Macrophanges protect us from Bacteria and Fungi. In reacting to an unknown bacterium, one to which AntiBodies do not yet exist, the messenger Lymphocyte goes to the B-Cell area of the Lymph Node.

A B-Cell immediately begins to change into a Plasma Cell, virtually a protein factory making AntiBodies to fit exactly the Antigen brought back by the circulating Lymphocyte.

In its passage thru the Lymph Nodes, one messenger Lymphocyte can touch thousand of seperate B-Cells, stimulatiig each to form a Plasma Cell.

Acting together these produce billions of specific AntiBodies which, released into the bloodstream, will flood the infected area and deal with the attacking microbes.

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    Continued_In_(08-03)
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