Beyond the Basics: Immune Response

CEU Review Form Beyond the Basics: Immune Response (PDF) Valid until August 4, 2008

     The human immune response is arguably among the most difficult processes for an EMS provider to understand. The immune system provides front-line defense to any potentially inflammatory process, with the goal of destroying or inactivating pathogens, abnormal cells and foreign substances. The system includes the thymus, spleen, lymph nodes, lymphoid tissues (as in the GI tract and bone marrow), macrophages, lymphocytes, including B and T cells, and antibodies, among others. On the surface, the skin and stomach acid serve as physical barriers to invasion. This article will primarily concentrate on the immune response to allergies, but will discuss some other immune disorders to illustrate the role of the immune system in common disease processes.

PHYSIOLOGY OF THE IMMUNE SYSTEM
     The immune system is critically important to human survival because of continuous exposure to pathogens, toxins and other foreign substances. As time progresses, the immune system continually matures to meet environmental changes. Without immune-mediated responses, the body would not be capable of developing memory for normal cell identification, abnormal cell and foreign body recognition, or defense mechanisms, and the patient would die. The inclusion of these criteria defines the immune system as "immunocompetent." Without the development of cell memory, re-exposure to an antigen will cause serious illness and, in some cases, death.

     Immune response is categorized into either cellular or humoral immunity. Cellular immunity is mediated by cells; humoral immunity is mediated by noncellular bodily fluids. In cellular immunity, the immune system cells envelop and deactivate or destroy the offending antigen. The majority of antigens are proteins. In humoral immunity, the biochemical substances in the body fluid deactivate or destroy the offending antigen through chemical processes. The mediators of the chemical attack are antibodies, or immunoglobulins.

     Immunoglobulins are created by particular cells of the immune system called B lymphocytes or B cells. There are five different classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM. The humoral immune response begins with the body's exposure to an antigen. Following exposure, antibodies are released from immune system cells and attach themselves to the invading substance to facilitate its removal from the body by other cells of the immune system.

     The circulatory system is key to the process, as it moves cells and antibodies throughout the body in conjunction with maintaining fluid volumes within the circulatory system. Failure to maintain the fluid volume balance will result in altered circulation, followed by shock. Just as the kidneys act to regulate volume within blood vessels, the lymphatic system acts to remove excess fluid from the tissues to maintain fluid volume balance. As the volume is pushed through the lymph system, it passes along the lymph nodes to provide the immune cells with an opportunity to identify antigens and subsequently adhere to the antigen for mitigation.

     If the immune system does not develop appropriate memory or does not function effectively, the patient will become immunocompromised. Conversely, an exaggerated immune response will lead to an untoward event including allergic reaction, autoimmune disease, sepsis or even cancer. Failure of the lymphatic system will create an environment where an infectious disease will flourish or normal fluid balance will be disrupted.

     The remainder of this article will highlight a few common disease processes influenced by the immune system.

ALLERGIC REACTION
     Allergic reaction is a fairly well- known process to EMS providers; however, its relationship to immune response may not be as well understood. Also known as hypersensitivity reactions, allergic reactions result from an exaggerated response to a typically non-pathogenic substance. The immune response can vary in its composition, just as normal immune response does. Different compositions of cells, protein, complement, antibody and other vasoactive substances may all contribute to an allergic reaction. Its severity may range from a mild reaction with local involvement (hives in the area of contact) to a fatal anaphylactic shock event (cardiovascular collapse and/or respiratory failure).

     The most common allergic reaction is a Type I response, which results from exposure to environmental antigens or allergens. The Type I response occurs in the following sequence: Initially, the body is exposed to an antigen, such as venom from a bee sting. During the first exposure, the protein antigens are exposed to antigen-presenting cells, which then interact with B and T cells to create an IgE antibody. During this first exposure, there may be mild nonspecific irritation and inflammation, but there is very little systemic effect.

     IgE immunoglobulins are the most common mediators of allergic reactions, but their effects are not typically seen unless there is exposure to high levels of allergens and a subsequent hypersensitivity reaction. Not all IgE responses are negative. The IgE response is helpful in the destruction of parasites when an allergic response ensues.

     As an IgE response develops, however, there are several key chemical mediators that influence the transition from an allergic reaction to an anaphylactic reaction. The first of these chemicals is histamine, a potent chemical that causes constriction of bronchial smooth muscle (bronchoconstriction), increased vascular permeability (fluid shifting into the tissues, or swelling) and vasodilation. Although histamine is not the only chemical mediator involved in an IgE-mediated reaction, it is the first to enter the picture.

     Once a recurrent exposure occurs with the same invading antigen, IgE will bind to the antigen and activate MAST cells, which contain memory and release and carry high quantities of vasoactive substances, including histamine, bradykinin, serotonin and cytokines, to the site of invasion. During the early phase of the reaction, vasodilation occurs locally and possibly systemically for the purpose of carrying nutrients and immunoglobulins to the tissues and to carry waste products away. In minor cases like seasonal allergies, itchiness, edema, sneezing and eye irritation can occur. If the reaction progresses, anaphylaxis will develop.

     While symptoms typically resolve spontaneously or with treatment, there may be a second insult, or late phase response, which happens 6–8 hours postexposure as the eosinophils and MAST cells have released inflammatory cells to the area.

     Some examples of Type I allergic reactions and the areas they affect are:

• Hay fever/rhinitis: upper respiratory tract
• Allergic bronchospasm: lower respiratory tract
• Insect venoms: local wheal and flare or systemic anaphylaxis
• Food allergy: GI and systemic
• Drugs: systemic allergy or anaphylaxis.

     Treatments for allergic and anaphylactic reactions vary, depending on symptoms and severity. In an allergic reaction, treatment generally includes histamine 1 blockers (Benadryl) or leukotriene inhibitors. As the patient progresses to anaphylaxis, these treatments are indicated, but also include steroids, beta agonist inhalers and epinephrine therapy. Benadryl, while a great treatment for allergic reactions, is not the optimal pharmacologic agent in the management of the anaphylactic patient. The non-histamine chemical mediators may not respond to Benadryl because they also include kinins, prostaglandins and leukotrienes; however, the manifesting symptoms of anaphylaxis may be reversed by epinephrine, making it the drug of choice.

     A Type II or cytotoxic reaction is IgG- and IgM-mediated. Typically, these antibodies result in activation of complement as well as inflammatory cells and their direction against the body's own tissues. Some interesting examples of tissue reactions include autoimmune anemia or thrombocytopenia, transfusion reactions, hyperacute transplant organ rejection and rheumatic fever (the body mistakes heart muscle for its similarity to streptococcal antigen). Other reactions directed not at tissues but at activating or blocking cellular receptors include myasthenia gravis (muscle weakness) and Graves' disease (hyperthyroidism).

     A Type III immune complex-mediated reaction results when antibodies bind to an antigen and become large complexes that get trapped in capillaries. The antibodies are still able to recruit inflammatory cells and chemicals, resulting in vasculitis and tissue death. Some examples of Type III reactions include systemic lupus erythematosus (lupus), rheumatoid arthritis, subacute bacterial endocarditis and serum sickness from repeat antivenin exposure.

     Type IV delayed hypersensitivity allergic reactions are cellular processes. Type IV reactions are classified as delayed because the T cell-mediated reaction occurs 24–48 hours after exposure to the invading allergen. The response happens after antigen-presenting cells stimulate CD4 T cells to activate other inflammatory cells. An example of a Type IV reaction includes contact dermatitis (poison ivy rash). Other nonconfirmed Type IV reactions include autoimmune processes like juvenile diabetes (T cells attack pancreas beta cells), multiple sclerosis (T cells attack nerve sheath protein) and rheumatoid arthritis (T cells attack joint cartilage).

RHEUMATOID ARTHRITIS
     Rheumatoid arthritis is a chronic autoimmune disease, mainly characterized by inflammation of the lining of the joints, that can lead to long-term joint damage and result in chronic pain, loss of function and disability.

     Rheumatoid arthritis (RA) progresses in three stages. The first stage is swelling of the synovial lining, causing pain, warmth, stiffness, redness and swelling around the joint. Second is rapid division and growth of cells, which causes the joint lining to thicken. In the third stage, the inflamed cells release enzymes that may digest bone and cartilage, often causing the involved joint to lose its shape and alignment, with more pain and loss of movement.

     Because it is a chronic disease, RA continues indefinitely and frequent flares in disease activity can occur. RA is a systemic disease, which means it can affect other body organs. Early diagnosis and treatment is critical for patients to continue living a productive lifestyle. Studies have shown that early aggressive treatment of RA can limit joint damage, which in turn limits loss of movement, decreased ability to work, higher medical costs and potential surgery.

     The symptoms of RA include general fatigue and weakness, and joint stiffness, particularly in the morning and after sitting for long periods of time. Typically, the longer the morning stiffness lasts, the more severe the disease will be. There may also be flu-like symptoms, often with fever, and muscle pain.

     Loss of appetite, depression, weight loss, anemia, and cold and/or sweaty hands and feet are also common findings in RA.

     In the patient with RA, the primary antibodies are IgG and IgM, but occasionally involve IgA. As these antibodies are released, they bind to cells of the synovial lining and convert antibodies into autoantibodies (rheumatoid factors). Once converted to autoantibodies, the effects of the immunoglobulin become detrimental and begin to deconstruct the tissues they are exposed to.

LUPUS
     Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease that results from an antibody response against the body's own DNA. Since every cell in the body contains DNA, the potential for multisystemic effects is high.

     SLE can be caused by drugs like hydralazine (antihypertensive), isoniazid (INH used for TB) and procainamide (antiarrhythmic). Furthermore, because many patients with lupus take immunosuppressive therapy, they may also manifest symptoms resulting from steroid therapy, such as Cushing's syndrome, or opportunistic infections (commonly fungal) unrelated to the underlying SLE.

     Typically, antibodies bind to DNA and elicit a B-cell response. While severity varies, symptoms include local and systemic inflammation of soft tissues and blood vessels. Common symptoms include fever, joint pain/arthritis and a light-sensitive, butterfly-shaped rash on the cheeks. Other symptoms include kidney disease; pulmonary disease; gastrointestinal ulcers and pancreatitis; blood disorders, such as hemolytic anemia, thrombocytopenia and hypercoagulability; neurologic disease, such as seizures, stroke, migraine or psychosis; and even cardiac disease, such as endo-, myo- or pericarditis. Most of these symptoms are not present simultaneously; however, a group of them may occur together. The major immunoglobulin involved in lupus reactions is IgM.

Glossary of Terms
Antibody: An immunoglobulin molecule produced by B cells that is activated by exposure to an antigen (invading agent). These molecules are characterized by reacting specifically with the antigen in some demonstrable way.

Antigen: Any substance that, as a result of coming in contact with appropriate cells, induces a state of sensitivity and/or immune responsiveness that reacts in a demonstrable way.

B cell: A type of white blood cell—specifically, a type of lymphocyte. Many B cells mature into plasma cells that produce antibodies (proteins) necessary to fight off infections, while others mature into memory cells. It is not thymus-dependent, has a short lifespan, and is responsible for producing immunoglobulins, which are expressed on its surface. B cells mature in bone marrow.

Cytotoxic: Toxic to cells.

Immune response: Any reaction of the immune system.

Immunoglobulins: Key elements of the immune system. Proteins produced by plasma cells and lymphocytes that attach to foreign substances for the purpose of controlling and destroying them. Classes of immunoglobulins include: immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin D (IgD) and immunoglobulin E (IgE).

Pathogen: Disease-producing agent.

T cell: Type of white blood cell that is at the core of adaptive immunity—the system that tailors the body's immune response to specific pathogens—and is responsible for destroying invading agents. T cells are also known as T lymphocytes. The "T" stands for thymus—the organ in which these cells mature.

Vasculitis: Inflammation of the blood vessels.

Vasoactive: Related to dilation or constriction of a blood vessel.

CEU Review Form Beyond the Basics: Immune Response (PDF) Valid until August 4, 2008

CONCLUSION
     Although many immune system defects cannot be treated in the field, having a thorough understanding of the immune response will help EMS providers to comprehend disease progression. Without understanding the immune response, a patient can be effectively managed by employing protocol-mediated therapy. In the CE articles in the April and May issues of EMS Magazine, we discussed critical-thinking skills as a vital function of clinical management—the differentiating characteristic between a technician and a clinician. Through understanding the basics of immune response, the clinician is capable of using his or her knowledge to form a differential diagnosis of immune-mediated processes.

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William S. Krost, MBA, NREMT-P, is director of Emergency Services & Health System Access for Blanchard Valley Health System in Findlay, OH, and a nationally recognized lecturer.

Joseph J. Mistovich, MEd, NREMT-P, is a professor and chair of the Department of Health Professions at Youngstown (OH) State University, author of several EMS textbooks, and a nationally recognized lecturer.

Daniel D. Limmer, AS, EMT-P, is a paramedic with Kennebunk Fire-Rescue in Kennebunk, ME. He is the author of several EMS textbooks and a nationally recognized lecturer.