Let's make a summary of the sequence in an atopic response. (This is can also be called "type I hypersensitivity" or "immediate hypersensitivity". Also, the less technical term, "allergies", is sometimes used. However, the term is somewhat vague and often includes the responses in the category of contact dermatitis, which involves T cells and macrophages.)
First, we have the introduction of a type of antigen, here called an allergen, that inappropriately causes the formation of type 2 helper T cells (TH2 cells) rather than type 1 helper T cells (TH1 cells) . While logical in the case of a helminth infection, it is inappropriate for antigens of the allergen type. That is why the term atopic is used.
The inappropriate response occurs when a genetic predisposition is combined with antigens that present a particular signature to dendritic cells. The antigens tends to be fairly small, in low concentrations, cause little inflammation initially, and often are present in the context of a mucosa. Under circumstances like this, cytokines released by the dendritic cells, cause helper T cell development to move in the inappropriate direction to TH2.
In turn, the cytokines released by the TH2 cells steer antibody synthesis away from IgM or IgG and towards IgE. The IgE enters the circulation, but soon is mainly bound to Fc receptors on mast cells. When the specific allergen is again introduced into the body, it causes cross-linking of Fc receptors on the mast cells. The result is the sequence of events in an atopic response.
The response to an antigen in atopy involves two phases. The first is rapid, occurring within about an hour. It involves the secretion of mast cell vesicles, which contain histamine, and release of eicosanoids, such as leukotriene C4. Anti-histamines and sometimes anti-leukotriene drugs tend to be pretty effective here.
The second phase begins in about 2 to 4 hours. It first involves cytokine secretion from mast cells, notable TNF-alpha. As you know, this is a powerful inflammatory paracrine. And it also recruits more white blood cells such as TH2 cells and eosinophils. These secrete further cytokines. Also the eosinophils release their toxic proteins and oxygen radicals. All this adds to the mast cell response and is the basis for longer-term chronic inflammation.
What general category of drugs is most commonly used to treat the symptoms in this second, more chronic part of the response?
See your notes for the details about the individual types of disorders: atopic rhinoconjunctivitis, atopic food allergies, and chronic atopic dermatitis (eczema). (Asthma is covered in Spring Quarter.)
A final disorder in this category is anaphylaxis, which occurs with a systemic response to an allergen. The response occurs within minutes to hours. (And, as above, this is classified as "immediate"and "type I".) The response is severe and can affect all those areas we have discussed above. But particularly important, the dilation of blood vessels through the body can lead to a drastic lowering of arterial presssure and thus shock, which is inadequate perfusion of tissues with blood. In addition, airways may become constricted and inflammed, making breathing difficult. All this is life-threatening and can easily prove fatal. But in addition, the systemic response can lead such responses as urticaria in the skin, mucosal irritation leading to vomitting and diarrhea, and various other consequences of systemic release of histamine, TNF-alpha and other factors released by mast cells.
Anaphylaxis can occur with any allergen in this category. Bee venom is perhaps the most familiar. Also in this category is the allergic response to penicillin and to the related cephalosporins. These are haptens and thus the response occurs after binding to a protein in the body. Sometimes food allergies, such as a response to eating peanuts or other food allergens, may lead to anaphylaxis. More rarely, miscellaneous other drugs and medications can lead to anaphylaxis.
Because this is life-threatening, immediate action is required. Epinephrine (also called "adrenalin") is injected to raise the blood pressure and relax the airways. An antihistamine is also usually used for obvious reasons, although its importance in this context is debated.
A second type of hypersensitivity to a foreign antigen does not involve IgE and mast cells, but rather T cells and activated macrophages. (This is classified as "delayed" or "type IV") Trace the sequence of events from the first introduction of the antigen to a dendritic cell. Then the second introduction of the antigen produces a much larger response. This takes a day or so to develop, with macrophages producing much of the damage through mechanism by now familiar.
Contact dermatitis results from a variety of chemicals and environmental agents applied to the skin. Typically, the allergen is hapten, which binds to a skin protein to produce the complete antigen. Allergic reactions to solvents usually are of this type as well as the responses to certain substances in cosmetics. Langerhans cells in the epidermis (recall they are a type of dendritic cell) carry the antigen to a lymph node where the immune response occurs. Latex allergies may occur through this mechanism or through the atopic response discussed above.
(Gluten intolerance (celiac disease) also can be placed in this category. But we will examine gluten intolerance in Winter Quarter.)
Some autoimmune disorders are based on B cells making antibodies.
In myasthenia gravis, for example, antibodies are produced that bind to and inactivate the acetylcholine receptors on skeletal muscle. The complexes are taken in by endocytosis and degraded, thereby reducing the total number of receptors on the muscle. Muscles become weak and easy to fatigue. Those served by cranial nerves are especially affected, although the limbs and respiratory muscles may show pronounced weakness too.
Does it sound here like the antibodies produced are IgG (or IgM) or IgE?
Another example is autoimmune thrombocytopenia, which fits in with our topics this quarter. Antibodies here bind to platelets, leading to their destruction.
Graves disease is an autoimmune disease in which B-cells secrete antibody that binds to a protein. But here the antibody stimulates rather than inactivates the protein. The protein stimulated is the TSH receptor, which is found in the thyroid gland. This receptor is the normal way in which the thyroid gland is stimulated to release thyroid hormone, and thus Graves disease causes an excess secretion of thyroid hormone. The thyroid is also stimulated to grow abnormally large, which is called goiter. Other symptoms include the characteristic stare of exophthalmos, weight loss and various other problems associated with high utilization of energy. (More on this latter in the quarter.)
Rheumatic fever is an example of a disease in which antibodies produced to act on a pathogen, in this case streptococci, cross-react with molecules in the body. Damage to the heart muscle and valves is especially noteworthy and is due to antibodies that are formed in response to molecules in the bacterial cell wall.
Another possibility is for complexes of the antibody and antigen to cause the problems. The most important example here is systemic lupus erythematosus (SLE), which is an autoimmune disorder that occurs primarily in young women. The immune system makes antibodies against a number of molecules in the nucleus, especially proteins associated with double stranded DNA. Complexes of the antibody and antigen form and cause damage as they are deposited in tissues. The glomerulus of the kidney is particularly susceptible. But due to the widespread distribution of the antigens, SLE attacks multiple organs. Indeed, almost any organ in the body can be affected (unlike some autoimmune disorders which attack specific organs, such as type I diabetes mellitus, multiple sclerosis or myasthenia gravis). The joints also are usually involved, as are other connective tissue structures such as the skin. Exposure of the skin to sun readily damages the affected cells, leading to inflammation that causes an erythematous rash in the exposed areas. The widespread distribution of the antigen also implies that the antigen is never completely removed, so the attacks tend to be ongoing. Systemic lupus erythematosus is one of the most serious of the autoimmune disorders, afflicting about 250,000 people in the United States.
As with allergies, autoimmune disorders can be due not only to antibodies, but also to T cells. T cells can be the main factor, but more commonly interaction between both T cells and B cells are involved. This does not imply, however, that both are causing the symptoms or are equally responsible for the disorder. In multiple sclerosis, for example, antibodies against myelin are present, but they do not correlate well with the occurrence of symptoms.
This is a good point to insert the concept of antigen spreading. Often, as an autoimmune disorder progresses, additional self-antigens become involved in the response. Apparently, as tissue continues to be attacked by the immune system, the damage exposes more self-antigens to which the immune system might respond. The result is a set of self-antigens being attacked via several mechanisms, which obscures the factor that initiated the whole sequence.
As with the allergies due to T cells, here too the T cells release cytokines that can cause inflammation directly or activate macrophages, which promotes inflammation or tissue damage. Inflammation is a central feature of these disorders and fits the chronic type pattern. It is revealing that blocking the action of TNF-alpha is an effective treatment for a number of autoimmune disorders.
In addition to cytokines, such as TNF-alpha, what are some of the factors that activated macrophages release?
In rheumatoid arthritis, the immune system attacks the synovial membrane, which encloses the joint cavity. This leads to synovial inflammation and destruction of the structure of joints. Unlike osteoarthritis, the problems often tend to be symmetrical on the two sides of the body. Both B cells and T cells and their interaction appear to be involved. The first symptoms often appear in the patients' 20's or 30's. But it can occur at any age, and its incidence increases with age. It affects between 1% and 2% of adults, and is three times more common in women than men. While affecting primarily joints, it has general systemic effects as well.
In joints, early morning stiffness that last more than an hour is common. Also, small rheumatoid nodules may be present under the skin over certain bony areas where there is frequent movement.
As the synovial membrane of a joint becomes inflamed, it undergoes hyperplasia and creates finger like extensions. There is extensive angiogenesis. This growing, abnormal, structure is called a pannus and is created by components that might be involved in normal repair of wounds. The pannus leads to destruction of the adjacent bone and cartilage, beginning at the sides of the joint where the bone and cartilage are near the synovial membrane. Eventually the entire joint structure is destroyed . The pannus may eventually extend entirely across the destroyed joint, leading to ankylosis. As with many autoimmune disorders, the symptoms may wax and wane. Individual cases vary from mild to severe. See your class notes for some drugs used for this disorder.
One treatment for rheumatoid arthritis is to inject antibodies that bind to a cytokine, thereby removing its action. Based on what you know, what might be a logical cytokine to attack in this way?
One risk factor for rheumatoid arthritis is elevated C-reactive protein. Can you trace the sequence of events that would explain this?
In multiple sclerosis damage occurs when the immune system responds to proteins in the myelin sheath of nerve cells. Scattered islands (plaques) of demyelination occur in the central nervous system, especially in the visual pathways. The patient experiences episodes of double vision, weakness, paralysis and various other neurological symptoms, interspersed with periods of remission. The disorder usually begins in young adults and may progress to complete disability over a period of several years. For unknown reasons, multiple sclerosis is much more common in cold regions, especially among genetically predisposed persons. A viral infection might help start this autoimmune disorder. (more on this in Winter Quarter)
In type I diabetes mellitus, the cells which secrete insulin in the pancreas are attacked by the immune system, resulting in lack of insulin secretion. Both TH1 helper T cells and cytotoxic T cells are largely responsible, although autoantibodies can be detected in the blood and possibly play some role in causing the damage. (more on this later in the quarter too.)
The inflammatory bowel disease, Crohn's disease, probably fits in this category, although antigens from microbes in the gut lumen as well as self-antigens may be involved.
Based on your class notes and the "Disorders and Terminology" section of your handout , see how you can do on the questions below:
QUESTION: Name three possible treatments for atopic rhinoconjunctivitis.
QUESTION: What disorder involves antibodies against proteins associated with DNA and antibody/antigen complexes that cause damage to many organs?
QUESTION: What type of autoimmune disorder is rheumatoid arthritis?
QUESTION: A person with atopic hypersensitivity develops symptoms about 12 hours after a short exposure to the allergen. What type of regulatory molecules are likely causing the response after this interval?
QUESTION: Name three autoimmune disorders that we covered in which only antibodies attack cells of the body.