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A behind-the-scenes look at the nebulous sect of autoimmune diseases, with a spotlight on MS

Autoimmune diseases are highly complex and not completely understood. For many autoimmune diseases there is little in the way of treatments. Often the complete etiology of the disease is unknown, thus treatments, when available, are often incomplete, leaving the individual with symptoms related to the disease. As autoimmune diseases are exceedingly complex, our inquiry must begin with a basic understanding of the normally functioning immune system. The immune system exists to defend against pathogens. These pathogens include viruses, bacteria, parasites, allergens, malignant cells and harmful chemical agents. The immune system has three important characteristics:

1. Diversity and specificity. This is the ability to recognize a wide variety of pathogens with both a general and specific response.
2. Memory. This is the ability to rapidly recognize a previously encountered pathogen.
3. The ability to distinguish self from non-self. This prevents autoimmue responses.

The immune system defends on several levels. The first is through system barriers, like the walls of a castle. The skin, the mucous membranes and the cornea of the eye provide a barrier to invading pathogens. Yet these barriers are inadequate for all pathogens; the immune system also has complex mechanisms of defense at the cellular level.

CELLULAR BACKGROUND

Cells of the immune system are generated in the bone marrow and mature either in the bone marrow (B-cells) or thymus (T-cells). The immune system has two major branches: innate and acquired immunity. Innate immunity is inborn, nonspecific and does not require any previous exposure to become activated. It provides a very rapid response to a pathogen. Inflammation is one innate immune response. Phagocytic cells comprising circulating neutrophils and monocytes circulate and respond to pathogens. In addition, NK (natural killer) cells have the ability to kill viral infected cells. Finally certain antibodies are activated with innate immunity and respond along with a series of proteins, known as complement, to a pathogen. Innate immunity does not have any memory of exposure.

Acquired or adaptive immunity becomes activated with exposure to a pathogen. Adaptive immunity provides a more specific response to a pathogen and also has memory of the exposure so that a subsequent exposure has a more immediate response. Acquired immunity can be divided into two parts: cell-mediated and humoral immunity. Both involve lymphocytes that originate in the bone marrow. Cell-mediated immunity involves T-cells that mature in the thymus and humoral immunity involves B–cells (that mature in the bone marrow), T-cells, antibodies and complement.

Both B- and T-cells have receptors on their cell surface that recognize pathogens. T-cells are not able to recognize the entire pathogen and must be presented with a piece of the pathogen or antigen in order to become activated. This presentation is accomplished by specific cells such as macrophages and dendritic cells that engulf and process a pathogen. A small fragment of the pathogen, now known as an antigen, is displayed on the cell surface by a surface molecule known as a major histocompatibility complex. T-cells are only able to recognize and respond to antigens presented in this way. Different types of T-cells respond to specific MHC types. Once the T-cell recognizes the properly displayed antigen, under the influence of multiple chemicals such as interferons and cytokines, the T-cell will become activated and proliferate. T-cells are also known as helper cells. There are two major varieties: Th-1 and Th-2 cells.

Through the release of additional substances, activated T-cells are able to amplify and direct the immune response to the antigen. Activated T-cells enhance the activity of macrophages and NK cells. In addition, they help activate B-cells. Activated T-cells in circulation are able to migrate into tissues by adherence to the blood vessel endothelium and migration through to the tissue. T-cells orchestrate an immune response through recruitment and activation of other immune system cells. B-cells are involved with the immune response, but in a different way than T-cells. The receptor on the B-cell that recognizes a pathogen is an antibody molecule. It does not require any specialized presentation and recognizes the pathogen in its entirety. B-cells express specific antibodies, but each B-cell does not express all antibodies. Thus, there is specificity with the B-cell response. Activated B-cells give rise to plasma cells that can make large quantities of antibodies. Antibodies destroy pathogens by various mechanisms, including making them more susceptible to phagocytosis, and by the activation of complement.

MISFIRING, MISCOMMUNICATION

Through this complex system of physical barriers, innate immunity, and adaptive immunity, the human organism is protected from most pathogens.

Unfortunately, sometimes the immune system fails to work as intended. One example of this is autoimmune disease. As stated earlier, an important characteristic of the immune system is the ability to distinguish self from non-self. It is normal to have some autoreactivity of the immune system. However, a normally functioning immune system will automatically delete autoreactive cells. Sometimes, and for reasons that are not clear, the normal regulatory mechanisms of the immune system become faulty. When the immune system cannot distinguish self from non-self, the stage is set for an auto or “selfreactive” immune disease.

Autoimmune diseases are numerous and heterogeneous. Although far from an exhaustive list, diseases such as psoriasis, Crohns disease, lupus erythematosis, myasthenia gravis and multiple sclerosis are considered autoimmune. Multiple sclerosis is often referred to as an immune-mediated disease, as a specific antigen that provokes the disease is not known.

The etiology of MS is not known, although it is thought to be a combination of a genetic susceptibility and an environmental exposure. This suggests some type of exposure, possibly to a virus in the environment that triggers the autoimmune behavior in a genetically susceptible individual.

Yet a specific virus and specific genes have not been completely identified. In MS, the target of the immune system becomes specific proteins located in the central nervous system. The targets are the myelin coating around axons, the axons themselves, and possibly the oligodendrocytes that make myelin. The immune system may confuse these self tissues with a similar-looking viral particle. Without the regulatory mechanisims to stop autoimmune activity, the immune system can become activated and target the central nervous system.

Activated immune system cells can become attracted to the target (the CNS) and through adhesion and disruption of the blood-brain barrier with various enzymes and cytokines, gain entry to the CNS. Activated T-cells, specifically Th-1 cells are then thought to orchestrate the immune response by recruiting and activating other immune system cells to the CNS. Inflammation is caused within the CNS, and this inflammatory response is damaging to myelin. Through direct damage and loss of the trophic support that myelin provides, underlying axons can also become damaged or destroyed.

HOW TREATMENT WORKS

The goals of current MS treatment are to modulate or suppress the immune system and thus reduce the autoreactive activity and inflammation that results from such activity. To date there are six FDA approved treatments for MS. Four of these are self-injected medications that are currently considered first-line: three interferon beta products, and one glatiramer acetate. Second-line treatments are a monoclonal antibody: natalizumab and an immunosuppressant agent, mitoxantrone. Each treatment has an effect on the immune system and reduces the inflammation associated with multiple sclerosis. This effect translates into fewer relapses, less progression of disability and fewer inflammatory changes that are seen on MRI.

Interferon beta 1a and 1b are self-injected immunomodulating medications that work by reducing the ability of antigen-presenting cells to present antigen. Interferons occur naturally and have an important role in our response to viral infections. They reduce T-cell activation and proliferation. In addition, they reduce the enzyme production that disrupts the blood-brain barrier. They also reduce expression of the adhesion molecules necessary for adhesion of lymphocytes to the blood vessel endothelium. The result of this immunomodulation is fewer relapses, a delayed progression of disease, and the reduction of new areas of inflammation in the CNS. The potential adverse effects of interferon betas are elevation in hepatic enzymes, anemia, flulike symptoms, mood disorder, and injectionsite reactions.

Glatiramer acetate is also a self-injected immunomodulator but works by a different mechanism than the interferons. Glatiramer acetate is thought to work by inducing the immune system to be less inflammatory. This appears to be accomplished by inducing naïve T-cells to become activated as anti-inflammatory T-cells. These glatiramerinduced T-cells gain entry to the CNS and reduce the inflammation associated with MS by bystander suppression. In addition, there is some evidence that neuroprotective mechanisms are activated by the anti-inflammatory cells. The end result of this activity is the reduction in relapses, delay in progression, and reduction in inflammation within the CNS. The potential adverse effects associated with glatiramer acetate are injection-site reactions, which include lipoatrophy, and a rare brief post-injection reaction that can include symptoms such as flushing, tachycardia, dyspnea, weakness, chest tightness and nausea. Natalizumab is a monoclonal antibody that blocks the ability of lymphocytes to adhere to the endothelium of the blood brain-barrier and thus restricts their entry into the central nervous system. This “blockade” has the end result of reduction in relapses, delay in progression and the reduction in new CNS inflammation. Natalizumab has been associated with the development of progressive multifocal leukoencephalopathy, a rare infection of the CNS that is often fatal. In addition, other less serious infections are associated with natalizumab as well as infusion and allergic reactions.

Mitoxantrone is a powerful chemotherapeutic agent that reduces the number of inflammatory cells available to produce inflammation. This agent was studied in secondary-progressive MS patients and was found to delay progression of disease. It also reduces CNS inflammation and relapses. Adverse effects of mitoxantrone include lymphopenia, infections, cardiac damage, and increased risk for secondary leukemia.

Many additional immunomodulatory agents are in the MS treatment pipeline and each of them impacts the immune system in some way. It is important for nurses to understand the normal as well as abnormal immune system so that we can better understand the treatments for this complex disease. Effective treatments are available, and soon additional treatments will be part of our armamentarium. We will need to know how these drugs impact the immune system and the expected MS effect. We will also need to know the expected adverse effects, how to identify them, and how to help our patients manage these effects.