Hypersensitivity: Autoimmune Diseases




Autoimmune Diseases Due to Antibodies

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?

Answer.



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.

Autoimmune Disorders Involving T cells

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.

You may have noticed that an autoimmune disorder may have more than one factor causing the damage. They might be several reasons. One is that, 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?

Answer.



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 stiffening and freezing of the joint, which is called 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?

Answer.


One risk factor for rheumatoid arthritis is elevated C-reactive protein. Can you trace the sequence of events that would explain this?

Answer.



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 1 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:


QUICK QUIZ:


QUESTION: You notice someone who has a drooping eyelid. It begins closing soon after it is opened. Which one of the above autoimmune disorders do you think seems most likely?
ANSWER

QUESTION: What type of diabetes is autoimmune?
ANSWER

QUESTION: What type of autoimmune disorder is rheumatoid arthritis?
ANSWER

QUESTION: You notice a doctor treating a sore throat quite aggressively. What might be the reason?
ANSWER

QUESTION: Name three autoimmune disorders that we covered in which only antibodies attack cells of the body.
ANSWER




Fill in Answer Correct False Correct Answer
What term refers to the stiffening of a destroyed joint?
What organ is affected by Grave's disease?
What disorder above attacks proteins associated with DNA? (Give abbreviation)
What specific membrane is attacked in rheumatoid arthritis?

(Spelling must be correct)
OK, Go ahead and give me:

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