MS In Detail

Brief Overview:

Multiple Sclerosis (MS) is a disease that affects a individuals Central Nervous System within the brain, spinal cord or both. It’s not known what causes this condition, which can take many an unpredictable and varying course among patients afflicted with the disease.

The body’s immune system T5 cells cross the blood brain barrier and mistakenly see the central nervous system nerves as a foreign substance and attack them.  In these attacks the T5 cells which normally attack viruses or other foreign invaders in the body mistakenly attacks nerve fiber’s myelin.  Myelin is a substance that surrounds the nerves similar to insulation over electrical wire.  Demyelination occurs as a result, the myelin is damaged leaving the nerve exposed or partially exposed.  This results in the electrical signals passing through the nerves to be weak to varied levels.

This weakening of the signals can cause other nerves receiving the signals anything from ignoring them to misinterpreting them and resulting symptoms appear.  Our Central Nervous Systems are what convey information signals to and from areas of our body from muscular movement signals to those of feelings of touch, taste or vision information, even cognitive thoughts (thinking), memory recall all utilize the Central Nervous System.

The attacks cause inflammation and scarring of the impacted tissues.  Just as if one were attacked by a swarm of bee’s the attack would leave scars and also result in inflammation of the area and surrounding areas.

An attack can strike at any area of the brain central nervous system or spinal cord area of the central nervous system or both. Thus, multiple areas hence the name Multiple Sclerosis.  Multiple areas and sclerosis meaning scars.

The human body has the ability re-myelinate.  In fact,  just as with any cells within our bodies myelin cells naturally are replaced in people on a regular basis.  With MS however the scarred areas may or may not be able to be replaced,  just as a bad bodily wound might repair itself to a certain extent but never be the same as it was prior to the injury.  Often flare-ups or further attacks called exacerbation’s again attack the same regions attacked previously thus resulting in further malfunctions of those nerves before they had time to try fully remyelinate or if they never could fully remyelinate due to scars causing further damage and / or scarring.

But lets start at the beginning with the immune system itself.

The Immune System:

The immune system is a system of many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism’s own healthy tissue.  In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity.

The Innate Immune System

The innate immune system, also known as the nonspecific immune system is an important subsystem of the overall immune system that comprises the cells and mechanisms that defend the host from infection by other organisms.  The cells of the innate system recognize and respond to pathogens in a generic way, but, unlike the adaptive immune system (which is found only in vertebrates), it does not confer long-lasting or protective immunity to the host. Innate immune systems provide immediate defense against infection, and are found in all classes of plant and animal life. They include both humoral immunity components and cell-mediated immunity components.

The innate immune system is an evolutionarily older defense strategy, and is the dominant immune system found in plants, fungi, insects, and primitive multicellular organisms.

The major functions of the vertebrate innate immune system include:

• Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators.
• Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells.
• The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells.
• Activation of the adaptive immune system through a process known as antigen presentation
• Acting as a physical and chemical barrier to infectious agents.

Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer  Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto’s thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.

The Adaptive Immune System

The adaptive immune system, also known as the acquired immune system, is a subsystem of the overall immune system that is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogen growth.  The adaptive immune system is one of the two main immunity strategies found in vertebrates. Adaptive immunity creates immunological memory after an initial response to a specific pathogen, and this leads to an enhanced response to subsequent encounters with that pathogen.  This process of acquired immunity is the basis of vaccination. Like the innate system, the adaptive system includes both humoral immunity components and cell-mediated immunity components.

Unlike the innate immune system, the adaptive immune system is highly specific to a specific pathogen. Adaptive immunity can also provide long-lasting protection: for example; someone who recovers from measles is now protected against measles for their lifetime but in other cases it does not provide lifetime protection: for example; chickenpox.  The adaptive system response destroys invading pathogens and any toxic molecules they produce.  Sometimes the adaptive system is unable to distinguish foreign molecules, the effects of this may be hayfever, asthma or any other allergies.  Antigens are any substances that invoke the adaptive immune response.  The cells that carry out the adaptive immune response are white blood cells known as lymphocytes.

There are two main broad classes: antibody responses and cell mediated immune response which are also carried by two different lymphocytes (B cells and T cells). In antibody responses, B cells are activated to secrete antibodies, which are proteins also known as immunoglobulins.  Antibodies travel through the bloodstream and bind to the foreign antigen causing it to inactivate, which does not allow the antigen to bind to the host.

In acquired immunity, pathogen-specific receptors are “acquired” during the lifetime of the organism (whereas in innate immunity pathogen-specific receptors are already encoded in the germline). The acquired response is said to be “adaptive” because it prepares the body’s immune system for future challenges (though it can actually also be maladaptive when it results in autoimmunity deficiencies).

This mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each individual lymphocyte. Because the gene rearrangement leads to an irreversible change in the DNA of each cell, all of the progeny (offspring) of that cell will then inherit genes encoding the same receptor specificity, including the memory B cells and memory T cells that are the keys to long-lived specific immunity.

A theoretical framework explaining the workings of the acquired immune system is provided by immune network theory. This theory, which builds on established concepts of clonal selection, is being applied in the search for an HIV vaccine.

This is complex!??

Yes it is, the human body is quite complex.  Micro-Biology and Physiology are amazing however.

Is it complex, oh yes.  But can we understand most of the basics?  Sure can.

The first line of defense for example is actually a person’s skin and mucous membranes where there are openings to the outside world, the stomach acid etc.

The immune system line of defense  consists of mechanisms and agents that target specific antigens (Ags). An antigen is any molecule, usually a protein or polysaccharide ( a carbohydrate), that can be identified as foreign (nonself) or self (such as MHC antigens described below). It may be a toxin (injected into the blood by the sting of an insect, for example), a part of the protein coat of a virus, or a molecule unique to the plasma membranes of bacteria, protozoa, pollen, or other foreign cells. Once the foreign antigen is recognized, an agent is released that targets that specific antigen. In the process of mounting a successful defense, the immune system accomplishes five tasks:

• Recognition. The antigen or cell is recognized as nonself. To differentiate self from nonself, unique molecules on the plasma membrane of cells called the major histocompatibility complex (MHC) are used as a means of identification.
• Lymphocyte selection. The primary defending cells of the immune system are certain white blood cells called lymphocytes. The immune system potentially possesses billions of lymphocytes, each equipped to target a different antigen. When an antigen, or nonself cell, binds to a lymphocyte, the lymphocyte proliferates, producing numerous daughter cells, all identical copies of the parent cell. This process is called clonal selection because the lymphocyte to which the antigen effectively binds is “selected” and subsequently reproduces to make clones, or identical copies, of itself.
• Lymphocyte activation. The binding of an antigen or foreign cell to a lymphocyte may activate the lymphocyte and initiate proliferation. In most cases, however, a costimulator is required before proliferation begins. Costimulators may be chemicals or other cells.
• Destruction of the foreign substance. Lymphocytes and antibodies destroy or immobilize the foreign substance. Nonspecific defense mechanisms (phagocytes, NK cells) help eliminate the invader.

• Memorization. Long‐lived “memory” lymphocytes are produced and can quickly recognize and respond to future exposures to the antigen or foreign cell.

The primary agents of the immune response are lymphocytes, white blood cells (leukocytes) that originate in the bone marrow (like all blood cells) but concentrate in lymphoid tissues such as the lymph nodes, the thymus gland, and the spleen. When lymphocytes mature, they become immunocompetent, or capable of binding with a specific antigen. An immunocompetent lymphocyte displays unique proteins on its plasma membrane that act as antigen receptors. Because all of the antigen receptors of an individual lymphocyte are identical, only a specific antigen can bind to an individual lymphocyte. The kind of antigen receptors displayed by a particular lymphocyte is determined by somatic recombination, a shuffling of gene segments during lymphocyte maturation. By mixing gene segments, more than one billion different antigen receptors can be generated.

Here are the various kinds of lymphocytes:

• B cells (B lymphocytes) are lymphocytes that originate and mature in the bone marrow. The antigen receptors of B cells bind to freely circulating antigens. When B cells encounter antigens that bind to their antigen binding sites, the B cells proliferate, producing two kinds of daughter cells, plasma cells and memory cells:
  • Plasma cells are daughter cells of B cells. Each plasma cell releases antibodies, proteins that have the same antigen binding capability as the antigen receptors of its parent B cell. Antibodies circulate through the body, binding to the specific antigens that stimulated the proliferation of plasma cells.
  • Memory B cells are long‐lived daughter cells of B cells that, like plasma cells, produce antibodies.However, memory cells do not release their antibodies in response to the immediate antigen invasion. Instead, the memory cells circulate in the body and respond quickly to eliminate any subsequent invasion by the same antigen. This mechanism provides immunity to many diseases after the first occurrence of the disease.
• T cells (T lymphocytes) are lymphocytes that originate in the bone marrow, but mature in the thymus gland. The antigen receptors of T cells bind to self cells that display foreign antigens (with MHC proteins) on their plasma membrane. When T cells bind to these aberrant self cells, they divide and produce the following kinds of daughter cells:
  • Cytotoxic T cells (killer T cells) are activated when they recognize antigens that are mixed with the MHC‐I proteins of self cells. Following activation, cytotoxic cells proliferate and destroy the recognized cells by producing toxins that puncture them, thus causing them to lyse.
  • Helper T cells are activated when they recognize antigens that are mixed with the MHC‐II proteins of self cells. Proliferation produces helper T cells that intensify antibody production of B cells. Helper T cells also secrete hormones called cytokines that stimulate the proliferation of B cells and T cells.
  • Suppressor T cells are believed to be involved in winding down a successful immune response and in preventing the attachment of uninfected self cells.
  • Memory T cells are long‐lived cells possessing the same antigen receptors as their parent T cell. Like memory B cells, they provide a rapid defense to any subsequent invasion by the same antigen.

The immune system distinguishes two groups of foreign substances. One group consists of antigens that are freely circulating in the body. These include molecules, viruses, and foreign cells. A second group consists of self cells that display aberrant MHC proteins. Aberrant MHC proteins can originate from antigens that have been engulfed and broken down (exogenous antigens) or from virus‐infected and tumor cells that are actively synthesizing foreign proteins (endogenous antigens). Depending on the kind of foreign invasion, two different immune responses occur:

• The humoral response (or antibody‐mediated response) involves B cells that recognize antigens or pathogens that are circulating in the lymph or blood (“humor” is a medieval term for body fluid). The response follows this chain of events:

1. Antigens bind to B cells.
2. Interleukins or helper T cells costimulate B cells. In most cases, both an antigen and a costimulator are required to activate a B cell and initiate B cell proliferation.
3. B cells proliferate and produce plasma cells. The plasma cells bear antibodies with the identical antigen specificity as the antigen receptors of the activated B cells. The antibodies are released and circulate through the body, binding to antigens.
4. B cells produce memory cells. Memory cells provide future immunity.

• The cell‐mediated response involves mostly T cells and responds to any cell that displays aberrant MHC markers, including cells invaded by pathogens, tumor cells, or transplanted cells. The following chain of events describes this immune response:

1. Self cells or APCs displaying foreign antigens bind to T cells.
2. Interleukins (secreted by APCs or helper T cells) costimulate activation of T cells.
3. If MHC‐I and endogenous antigens are displayed on the plasma membrane, T cells proliferate, producing cytotoxic T cells. Cytotoxic T cells destroy cells displaying the antigens.
4. If MHC‐II and exogenous antigens are displayed on the plasma membrane, T cells proliferate, producing helper T cells. Helper T cells release interleukins (and other cytokines), which stimulate B cells to produce antibodies that bind to the antigens and stimulate nonspecific agents (NK and macrophages) to destroy the antigens.

To fully understand Micro-Biology and Physiology is obviously beyond the context of this detailed description of MS.

There is a GREAT DEAL more to how our immune systems operate but you should be able to get a picture of it from the above.

It also should give you a new level of respect for those health care providers whom understand all of this and a whole lot more to be physicians.

What is the Blood Brain barrier?

The BBB is semi-permeable; that is, it allows some materials to cross, but prevents others from crossing. In most parts of the body, the smallest blood vessels, called capillaries, are lined with what are called endothelial cells.   Endothelial tissue has small spaces between each individual cell so substances can move readily between the inside and the outside of the vessel. However, in the brain, the endothelial cells fit tightly together and substances cannot pass out of the bloodstream.

Functions of the Blood Brain Barrier

The BBB has several important functions:

1. Protects the brain from “foreign substances” in the blood that may injure the brain.
2. Protects the brain from hormones and neurotransmitters in the rest of the body.
3. Maintains a constant environment for the brain.

General Properties:

1. Large molecules do not pass through easily.
2. Low lipid (fat) soluble molecules do not penetrate into the brain. However, lipid soluble molecules, such as barbituate drugs, rapidly cross through into the brain.
3. Molecules that have a high electrical charge are slowed.

Through extensive study, scientists have found that compounds that are very small and/or fat-soluble, including antidepressants, anti-anxiety medications, alcohol, cocaine, and many hormones are able to slip through the endothelial cells that make up the blood-brain barrier without much effort. In contrast, larger molecules, such as glucose or insulin, must be ferried across by proteins. These transporter proteins, located in the brain’s blood vessel walls, selectively snag and pull the desired molecules from the blood into the brain.

Cells within and on either side of the blood-brain barrier are in constant communication about which molecules to let through and when. For instance, if the nerve cells in a region of the brain are working particularly hard, they will signal to the blood vessels to dilate, allowing cell-powering nutrients to quickly travel from the blood to the nerve cells in need.

The Blood Brain Barrier And MS

The presence of the blood–brain barrier (BBB) restricts the movement of soluble mediators and leukocytes from the periphery to the central nervous system (CNS).  Leukocyte entry into the CNS is nonetheless an early event in multiple sclerosis (MS), an inflammatory disorder of the Central Nervous System. Whether BBB dysfunction precedes immune cell infiltration or is the

consequence of leukocyte accumulation remains enigmatic, but leukocyte migration modifies BBB permeability. Immune cells of MS subjects express inflammatory cytokines (proteins), reactive oxygen species (ROS) and enzymes that can facilitate their migration to the Central Nervous System by influencing BBB function, either directly or indirectly.

Normally the blood brain barrier prevents large molecules, immune cells, and disease-causing organisms (eg viruses) from passing from the blood stream into the central nervous system (brain and spinal cord).

In multiple sclerosis, immune cells are able to enter the central nervous system, implying that the blood-brain barrier is damaged, compromised or in some fashion instructed or tricked into allowing immune cells past the blood brain barrier. These immune cells attack the myelin in the brain and spinal cord, causing the lesions which lead to MS symptoms.

There is considerable research that is ongoing about how immune cells pass through the blood brain barrier and why the cells then begin to attack the Central Nervous System.

Many of the therapies and treatments now available to MS patients essentially work to stop those cells from passing through the barrier hence they are not cures for the disease but instead are deemed Disease Modifying Therapies (DMT’s).  A cure would entail solving the perplexing problem of why the Immune System and cells thereof think they need attack the Central Nervous System and what are the catalysts that are involved for the immune system’s response.

The Multiple Sclerosis Attack

When the disease manifests immune cells cross the blood brain barrier and begin attacking the Central Nervous System.  Specifically the Myelin which acts as an insulator of the nerve fibers the myelin encases.  The nerves carry electrical impulses that control bodily functions and our various senses.  An attack can result in any number of symptoms and is not limited to one area of the brain or spinal cord nor is an attack or “exacerbation” as its called limited to only one instance.  In other words, several areas of the brain or spinal cord may be attacked in an exacerbation.

As immune cells attack the myelin sheath insulator it is damaged and this damage results in weakened signals across the Axon of the nerve cell which carries the electrical impulses.  Sometimes nerve axon as well are damaged.

Symptoms when an attack occurs can vary quite widely such as:

• Blurred or double vision, color distortions.
• Thinking or cognition problems.
• Clumsiness or a lack of coordination.
• Loss of balance.
• Numbness.
• Tingling.
• Weakness in an arm or leg
• Unusual sensations such as a “pins and needles”, itching, burning, stabbing, or tearing pains.
• Bladder problems.
• Trouble walking.
• Numbness in hands, feet, face or other bodily regions.
• Dizziness or lightheaded feelings., vertigo.
• Fatigue or sleepiness.
• Slowed thinking.
• Tremors.
• Speech problems.
• Spastic feelings.
• Muscle Spasms.
• Memory recall issues.
• Sensory problems such as taste, sight, hearing impacts.
• Sexual dysfunctions.
• And the list goes on….

Since no particular area of the brain or spinal cord seem to be a focal point of MS the range of symptoms varies from person to person making diagnosis of Multiple Sclerosis more of a challenge for Health care professionals.   Since impacts of the attacks can mimic impacts that other disorders may have as symptoms.  Further, it can be complicated if a person does have other disorders.